Weekly reading
Weekly Papers
A rolling archive of highlighted papers from PubMed and bioRxiv, grouped by topic but kept in each week’s original reading order.
Selected week
Week 12, 2026 · 16 Mar–22 Mar 2026
Papers
66
Status
Latest available week
Cell cycle
14Condensin accelerates long-range intra-chromosomal interactions.
Shows that condensin accelerates long-range intra-chromosomal encounters in G1 yeast, revealing a chromatin-organization function for a core chromosome biology complex.
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Condensin accelerates long-range intra-chromosomal interactions.
Shows that condensin accelerates long-range intra-chromosomal encounters in G1 yeast, revealing a chromatin-organization function for a core chromosome biology complex.
- Authors
- Fan Zou, Yi Li, Timothy Földes, Henrik Dahl Pinholt, Courtney Smith, Leonid Mirny, Lu Bai
- Source
- PubMed
- Publication date
- 16 March 2026
- Primary category
- Cell cycle
- Priority
- medium
- Abstract
- The 3D genome organization plays a key role in regulating interactions among chromosomal loci. While Chromosome Conformation Capture (3C)-based methods have provided static snapshots of chromatin architecture, the kinetics of chromosomal encounters in live cells remain poorly characterized. In this study, we employ Chemically Induced Chromosomal Interaction (CICI) to measure encounter times between multiple loci pairs in G1-arrested budding yeast. Our results show that chromosome motion closely follows the Rouse polymer model, with similar diffusion parameters at all tested loci. Surprisingly, we find that long-range intra-chromosomal encounters occur significantly faster than inter-chromosomal encounters at similar 3D distances. Using targeted depletion experiments, we identify condensin, but not cohesin, as the complex mostly responsible for these rapid intra-chromosomal interactions. This is further supported by Hi-C analysis, which reveals that condensin promotes long-distance intra-chromosomal interactions in G1 yeast. Through polymer simulations, we estimate that condensin extrudes chromatin at ~2 kb/s with a density of one complex per 1-2 Mb and a processivity of 120-220 kb. These findings uncover a novel role for condensin in shaping the interphase genome organization and provide new insights into chromosomal search dynamics in vivo.
Inhibitor-2 directs formation of PP1 holoenzymes through a docking motif-dependent transfer of catalytic subunits to adapters
The paper shows that Inhibitor-2 uses docking motifs to transfer PP1 catalytic subunits onto regulatory adapters, directly addressing PP1 holoenzyme assembly and specificity.
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Inhibitor-2 directs formation of PP1 holoenzymes through a docking motif-dependent transfer of catalytic subunits to adapters
The paper shows that Inhibitor-2 uses docking motifs to transfer PP1 catalytic subunits onto regulatory adapters, directly addressing PP1 holoenzyme assembly and specificity.
- Authors
- Varshney, N., Schlientz, A. J., Meaders, J. L., Oegema, K., Desai, A.
- Source
- bioRxiv
- Publication date
- 17 March 2026
- Primary category
- Cell cycle
- Priority
- high
- Abstract
- The catalytic subunits of protein phosphatase 1 (PP1) achieve spatiotemporal substrate specificity by assembling with diverse regulatory adapters to form holoenzymes. Three conserved proteins--Sds22, Inhibitor-2 and Inhibitor-3--facilitate loading of PP1 catalytic subunits (PP1cs) onto adapters. We show here that Inhibitor-2 is central to a dynamic cycle that directs formation of adapter-bound PP1 holoenzymes. Inhibitor-2 engages PP1cs via two adapter-like docking motifs (RVxF and SILK) and an active site-binding inhibitory region. While Inhibitor-2 depletion produced moderate phenotypes, mutation of its RVxF docking motif caused severe defects resembling global PP1c inhibition. The RVxF mutant did not prevent PP1c binding or reduce PP1c stability but inhibited formation of adapter-bound holoenzymes. The severe effects of the RVxF mutation were suppressed by linked mutation of the inhibitory active site-binding motif. These results suggest that Inhibitor-2 is integral to a dynamic cycle that delivers PP1cs to adapters, with its RVxF motif being critical for coupling relief of active site inhibition to adapter handoff.
Fidelity-Ensuring Consistency of Mitosis is Safeguarded by the 53BP1-USP28-p53 Pathway
Directly relevant mitosis paper shows the 53BP1-USP28-p53 external mitotic surveillance pathway invalidates fidelity-compromised mitoses when SAC-linked kinetochore control fails.
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Fidelity-Ensuring Consistency of Mitosis is Safeguarded by the 53BP1-USP28-p53 Pathway
Directly relevant mitosis paper shows the 53BP1-USP28-p53 external mitotic surveillance pathway invalidates fidelity-compromised mitoses when SAC-linked kinetochore control fails.
- Authors
- Shulman, A., Ozaki, K., Chang, L. R., Hoong, E., Tsou, M.-F. B.
- Source
- bioRxiv
- Publication date
- 17 March 2026
- Primary category
- Cell cycle
- Priority
- high
- Abstract
- Mitosis is monitored by and mechanically coupled to the spindle assembly checkpoint (SAC), which halts mitotic progression until fidelity is met, disregarding time efficiency. Conversely, there exists SAC-independent, efficiency-promoting surveillance mechanically uncoupled from mitosis. This external mitotic surveillance (EMS), comprising 53BP1, USP28, and p53, induces post-mitotic arrest following prolonged, inefficient mitosis. To explore additional EMS inputs, we performed comparative CRISPR-Cas9 screens for genes functionally safeguarded by EMS, identifying, among others, two components of the RZZ kinetochore complex, KNTC1 and ZWILCH. Depleting KNTC1, which impairs fidelity-ensuring activities of mitosis, including SAC, triggered population-level post-mitotic arrests without widespread, characteristic mitotic delay or catastrophe. Instead, KNTC1 depletion produced mostly viable mitosis and yet activated EMS via ectopic accumulation of 53BP1-USP28-p53 complexes over normal mitotic duration. These results suggest that when the fidelity-ensuring control within mitosis is itself compromised, mitosis is rendered invalid from without by EMS, echoing the incompleteness theorems by Godel.
Dual-site phosphorylation of SLX4 stabilizes the SLX4-MUS81 interface to promote mitotic SMX assembly and genome protection.
Shows that dual CDK1-dependent phosphorylation of SLX4 promotes mitotic SMX assembly and MUS81 activation to protect genome integrity in mitosis.
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Dual-site phosphorylation of SLX4 stabilizes the SLX4-MUS81 interface to promote mitotic SMX assembly and genome protection.
Shows that dual CDK1-dependent phosphorylation of SLX4 promotes mitotic SMX assembly and MUS81 activation to protect genome integrity in mitosis.
- Authors
- Brandon J Payliss, Hwa Young Yun, Sarina Doshi, Alexander Lemak, Ying Wah E Tse, Camila M Aprosoff, Scott Houliston, Cheryl H Arrowsmith, Haley D M Wyatt
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- Cell cycle
- Priority
- high
- Abstract
- Faithful genome transmission depends on the timely removal of branched DNA intermediates. This task is executed by the SMX tri-nuclease, a mitosis-specific complex containing three structure-selective endonucleases (SLX1, MUS81-EME1, and XPF-ERCC1) bound to the SLX4 scaffold. A critical step in SMX assembly is the recruitment of MUS81-EME1 to SLX4 in early mitosis, a process tightly regulated by cell-cycle kinases. Mechanistically, CDK1-dependent phosphorylation of SLX4 promotes folding of its SAP domain, which strengthens the SLX4-MUS81 interaction. Here, we define a site-specific phosphorylation code that stabilizes complementary structures in the SLX4-MUS81 interface. Phosphorylation of SLX4 T1571 is required for partial SAP domain folding, pre-organizing the MUS81 binding surface and reducing the entropic penalty of folding upon binding. Co-phosphorylation at T1561 enhances structural stability and promotes intermolecular β-sheet formation with MUS81, providing enthalpic stabilization. Dual-site phosphorylation converts a relatively weak interaction into a high-affinity complex that stimulates MUS81-EME1 nuclease activity. In human cells, both phosphorylation sites are required for robust SMX assembly and genome stability maintenance. Collectively, our findings reveal the structural basis for how CDK1-cyclin B controls SMX assembly in mitosis. More broadly, the SLX4-MUS81 complex illustrates how phosphorylation fine-tunes marginally stable protein interfaces at the boundary of order and disorder.
Polar chromosomes are rescued from missegregation by spindle elongation-driven microtubule pivoting.
This mitosis paper shows that spindle elongation-driven microtubule pivoting rescues polar chromosomes from missegregation and micronucleus formation in cancer cells.
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Polar chromosomes are rescued from missegregation by spindle elongation-driven microtubule pivoting.
This mitosis paper shows that spindle elongation-driven microtubule pivoting rescues polar chromosomes from missegregation and micronucleus formation in cancer cells.
- Authors
- Isabella Koprivec, Valentina Štimac, Mario Đura, Kruno Vukušić, Petra Mikec, Iva M Tolić
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- Cell cycle
- Priority
- high
- Abstract
- Polar chromosomes, which initially attach to the mitotic spindle behind the pole, are prone to missegregation and micronuclear entrapment, contributing to chromosomal instability in cancer. Yet, the mechanisms ensuring their faithful segregation remain unclear. Here, we show that polar chromosomes require a unique step involving spindle elongation, which repositions chromosome-bound astral microtubules by pivoting them around the centrosome toward the spindle surface. By modulating Eg5/KIF11 activity, we demonstrate that spindle elongation determines the direction and extent of pivoting, with microtubules from the opposite spindle half facilitating final movement. Kinetochores on polar chromosomes form mono-lateral attachments, recruiting corona components and partially Mad2, but lacking Astrin. In cancer cell lines, limited spindle elongation delays polar chromosome resolution, whereas enhanced elongation accelerates it. These findings highlight the role of spindle elongation in the timely rescue of chromosomes from the "danger zone" behind the pole, providing mechanistic insight into chromosome congression errors in cancer.
Multi-omic analyses reveal a differential contribution of chromatin-associated PP1 holoenzymes to mitotic exit and G1 re-establishment.
Direct mitotic-exit study showing distinct chromatin-associated PP1 holoenzymes control dephosphorylation, transcription restart, and G1 re-establishment.
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Multi-omic analyses reveal a differential contribution of chromatin-associated PP1 holoenzymes to mitotic exit and G1 re-establishment.
Direct mitotic-exit study showing distinct chromatin-associated PP1 holoenzymes control dephosphorylation, transcription restart, and G1 re-establishment.
- Authors
- Konstantinos Stamatiou, Florentin Huguet, Marta Budzinska, Jose I de Las Heras, Denise Ragusa, Ines J deCastro, Christos Spanos, Juri Rappsilberg, Paola Vagnarelli
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- Cell cycle
- Priority
- high
- Abstract
- Mitotic exit is an important part of the cell cycle, requiring the coordination of many chromatin and cytoskeleton remodeling events to successfully complete cell division and maintain cell identity. Protein dephosphorylation is a key step in directing mitotic exit, and protein phosphatase 1 (PP1) is essential to this process; however, the specific contribution of its numerous targeting subunits is still unknown. Here, we have investigated the function of three chromatin-associated PP1-targeting subunits in mitosis exit: Repo-Man, Ki-67, and protein phosphatase 1 nuclear targeting subunit (PNUTS). We generated endogenously tagged, auxin-degradable alleles for each subunit in the human cell line HCT116 and used a multi-omic approach to address their specific contributions toward transcription resumption, chromatin accessibility, and protein dephosphorylation at the transition from mitosis to G1. This approach identified their distinct role in mitotic exit, provided datasets for the cell-cycle community, and highlighted functions for Ki-67 and Repo-Man in genome stability and organization.
Kinase KEY1 controls pyrenoid condensate size throughout the cell cycle by disrupting phase separation interactions.
Identifies kinase KEY1 as a regulator of pyrenoid condensate dissolution and re-formation during cell division in Chlamydomonas.
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Kinase KEY1 controls pyrenoid condensate size throughout the cell cycle by disrupting phase separation interactions.
Identifies kinase KEY1 as a regulator of pyrenoid condensate dissolution and re-formation during cell division in Chlamydomonas.
- Authors
- Shan He, Linnea M Lemma, Alejandro Martinez-Calvo, Guanhua He, Jessica H Hennacy, Lianyong Wang, Sabrina L Ergun, Ashwani K Rai, Colton Wang, Luke Bunday, Angelo Kayser-Browne, Quan Wang, Clifford P Brangwynne, Ned S Wingreen, Martin C Jonikas
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- Cell cycle
- Priority
- medium
- Abstract
- Biomolecular condensates spatially organize cellular functions, but the regulation of their size, number, dissolution and re-condensation is poorly understood. The pyrenoid, an algal biomolecular condensate that mediates one-third of global CO2 fixation, typically exists as one large condensate per chloroplast, but during cell division it transiently dissolves and reconfigures into multiple smaller condensates. Here, we identify a kinase, KEY1, in the model alga Chlamydomonas reinhardtii that regulates pyrenoid condensate size and number dynamics throughout the cell cycle and is necessary for normal pyrenoid function and growth. Unlike the wild type, key1 mutant cells have multiple smaller condensates throughout the cell cycle that fail to dissolve during cell division. We show that KEY1 localizes to the condensates and promotes their dissolution by disrupting interactions between their core constituents, the CO2-fixing enzyme Rubisco and its linker protein EPYC1, through EPYC1 phosphorylation. We develop a biophysical model that recapitulates KEY1-mediated condensate size and number regulation and suggests a mechanism for controlling condensate position. These data provide a foundation for the mechanistic understanding of the regulation of size, number, position and dissolution in pyrenoids and other biomolecular condensates.
Greatwall Kinase regulates Acute Myeloid Leukaemia Cell Division through a Non-Canonical Mechanism
This preprint shows that Greatwall kinase is required for AML cell division and cytokinesis through a non-canonical pathway distinct from ENSA-PP2A-B55.
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Greatwall Kinase regulates Acute Myeloid Leukaemia Cell Division through a Non-Canonical Mechanism
This preprint shows that Greatwall kinase is required for AML cell division and cytokinesis through a non-canonical pathway distinct from ENSA-PP2A-B55.
- Authors
- Hochegger, H., Martin-Guerrero, S. M., Shields, T. S., Zach, R., Rajeeve, V., Afroz-Nishat, N., Badshah, I. I., Meredith, M., Foster, W. R., Cutillas, P. R., Casado-Izquierdo, P.
- Source
- bioRxiv
- Publication date
- 18 March 2026
- Primary category
- Cell cycle
- Priority
- high
- Abstract
- Greatwall kinase regulates mitotic progression by phosphorylating ENSA and ARPP19, thereby inhibiting PP2A-B55. Moreover, Greatwall has been implicated in oncogenesis, particularly in solid tumours, but the mechanisms by which Greatwall regulates the cell cycle in other malignancies remain unclear. Here, we show that Greatwall regulates cytokinesis and cell cycle progression in acute myeloid leukaemia (AML) cells through a pathway distinct from ENSA-PP2A-B55. AML cells require Greatwall expression and activity to proliferate, as revealed by pharmacological and systematic genetic perturbation experiments. Mechanistically, Greatwall inactivation or genetic depletion does not measurably affect the ENSA-PP2A-B55 pathway. Instead, loss of Greatwall function alters cytokinesis, and the phosphorylation of proteins involved in cytoskeletal organisation and cytokinesis, including MARK3, which we identify as a direct Greatwall substrate in AML cells. Together, these findings reveal that the Greatwall kinase signalling network is wired differently in leukemic cells, thus uncovering a novel of cell cycle regulation.
Castration-resistant prostate cancer cells are addicted to the high activity of cyclin-dependent kinase 2
This prostate cancer study shows that castration-resistant cells become selectively dependent on high CDK2 activity and are sensitized to combined CDK2 and androgen receptor inhibition.
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Castration-resistant prostate cancer cells are addicted to the high activity of cyclin-dependent kinase 2
This prostate cancer study shows that castration-resistant cells become selectively dependent on high CDK2 activity and are sensitized to combined CDK2 and androgen receptor inhibition.
- Authors
- Chatterjee, J., Marin, A., Yalala, S., Itkonen, H. M.
- Source
- bioRxiv
- Publication date
- 18 March 2026
- Primary category
- Cell cycle
- Priority
- high
- Abstract
- Background Cyclin-dependent kinases drive the progression through the cell cycle and thereby form classical targets for cancer therapy. In prostate cancer (PC), the first line of therapy typically targets androgen receptor (AR), but it frequently leads to development of incurable form of the disease, castration-resistant PC (CRPC). Here, we sought to understand if CRPC cells are selectively addicted to a specific cell cycle kinase. Methods We used PC and CRPC patient data to evaluate transcriptional changes and modeled the responses in vitro using multiple models of PC, CRPC and normal cells. Development of a CDK2 inhibitor-resistant CRPC cell line, and a compound screen were used to identify chronic and acute vulnerabilities to augment the efficacy of our candidate therapy in multiple PC, CRPC and also normal cells, to assure selectivity. Results We show that the emergence of CRPC is associated with significant upregulation of cyclins that positively regulate cyclin-dependent kinase 2 (CDK2) and downregulation of CDK4 cyclins. Accordingly, CDK2-specific inhibitors and its knock down efficiently reduce proliferation of PC and CRPC cells. CDK2 inhibitor-resistant CRPC model displayed transcriptional rewiring of cell cycle regulators, characterized by a shift towards CDK4/6-dependency and increased AR-signaling. Combinatorial drug screen discovered both antagonistic and additive combinations, and we show that AR inhibitors selectively augment the efficacy of CDK2 inhibitors against PC and CRPC cells, but the combination is not toxic to normal cells. Conclusion We discovered that CRPC cells are addicted to high CDK2 activity and show that combination of CDK2 inhibitors with the currently used anti-CRPC therapies selectively augment their efficacy.
DUSP12 promotes cell cycle progression and protects cells from ZNF622 mediated apoptosis.
Cell-cycle study identifying DUSP12 as a regulator of mitotic progression whose interaction with ZNF622 influences pre-metaphase defects and apoptosis.
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DUSP12 promotes cell cycle progression and protects cells from ZNF622 mediated apoptosis.
Cell-cycle study identifying DUSP12 as a regulator of mitotic progression whose interaction with ZNF622 influences pre-metaphase defects and apoptosis.
- Authors
- Mai Abdusamad, Xiao Guo, Ivan Ramirez, Erick F Velasquez, Whitaker Cohn, Ankur A Gholkar, Immy A Ashley, Yennifer Delgado, Mehdi Bouhaddou, Julian P Whitelegge, Robert Damoiseaux, Jorge Z Torres
- Source
- PubMed
- Publication date
- 18 March 2026
- Primary category
- Cell cycle
- Priority
- medium
- Abstract
- Protein phosphatases are critical for regulating cell signaling, cell cycle, and cell fate decisions, and their dysregulation leads to an array of human diseases like cancer. The dual specificity phosphatases (DUSPs) have emerged as important factors driving tumorigenesis and cancer therapy resistance. DUSP12 is a poorly characterized atypical DUSP widely conserved throughout evolution. Although no direct substrate has been firmly established, DUSP12 has been implicated in protecting cells from stress, regulating ribosomal biogenesis, and modulating cellular DNA content. In this study, we used affinity- and proximity-based biochemical purification approaches coupled to mass spectrometry to identify the zinc finger protein ZNF622 as a novel DUSP12 interactor, which was validated by in cell and in vitro IP assays. Interestingly, ZNF622 binds to the unique zinc-binding domain of DUSP12, which previous reports indicated was important for many of DUSP12's functions within the cell. Prior studies had implicated ZNF622 as a modulator of apoptosis, but it remained unclear if and how ZNF622 participated in the cell cycle and, more so, how it promoted cell death. Using mass spectrometry analyses, we found that overexpression of DUSP12 promoted de-phosphorylation of ZNF622 at Ser143. Overexpression of ZNF622, but not Ser143 phosphomimetic and phosphorylation-deficient mutants, led to an increase in pre-metaphase mitotic defects while knockdown of DUSP12 also showed mitotic defects in metaphase. Furthermore, knockdown of DUSP12 promoted, while knockdown of ZNF622 suppressed, stress-induced apoptosis. Our results support a model where DUSP12 protects cells from ZNF622 mediated stress-induced apoptosis.
A cell cycle-dependent transition of acetylation to phosphorylation regulates timely centrosome maturation.
The study shows that a late-G2 acetylation-to-phosphorylation switch on RNF40 enables a CDK1-RNF40-PLK1 cascade controlling centrosome maturation, spindle assembly, and chromosome segregation.
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A cell cycle-dependent transition of acetylation to phosphorylation regulates timely centrosome maturation.
The study shows that a late-G2 acetylation-to-phosphorylation switch on RNF40 enables a CDK1-RNF40-PLK1 cascade controlling centrosome maturation, spindle assembly, and chromosome segregation.
- Authors
- Jimin Li, Jianqiang Liang, Guifang Chen, Xuejie Wang, Yanyan Wang, Jingfei Zhan, Yunjing Guo, Jiadong Wang, Xuefeng Chen
- Source
- PubMed
- Publication date
- 20 March 2026
- Primary category
- Cell cycle
- Priority
- high
- Abstract
- Centrosomes must undergo maturation in the G2/M phases to activate the microtubule-organizing activity, ensuring proper bipolar spindle assembly and chromosome segregation. Polo-like kinase 1(PLK1) is crucial for centrosome maturation. How the cell cycle controls timely PLK1 recruitment and centrosome maturation remains elusive. Here, we find that the ubiquitin E3 ligase RNF40 localizes to centrosomes and is phosphorylated by CDK1 on T529/T557 in the G2/M phases. This phosphorylation primes its binding to PLK1 and promotes timely PLK1 recruitment and centrosome maturation, establishing the CDK1-RNF40-PLK1 cascade as a mechanism controlling centrosome maturation. We also find that RNF40 is acetylated in interphase and undergoes an acetylation-to-phosphorylation transition in late G2 and M phases, which permits timely activation of the CDK1-RNF40-PLK1 cascade. Constitutive RNF40 acetylation or deficient RNF40 phosphorylation impairs PLK1 localization, microtubule nucleation, and bipolar spindle assembly, causing mitotic catastrophe. Thus, the cell cycle-dependent transition of RNF40 modifications ensures timely centrosome maturation and chromosome segregation.
Microtubule end stabilisation by cooperative oligomers of Ska and Ndc80 complexes.
This mitosis paper shows cooperative oligomerization of Ska with Ndc80 stabilizes kinetochore–microtubule plus-end attachments required for faithful chromosome segregation.
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Microtubule end stabilisation by cooperative oligomers of Ska and Ndc80 complexes.
This mitosis paper shows cooperative oligomerization of Ska with Ndc80 stabilizes kinetochore–microtubule plus-end attachments required for faithful chromosome segregation.
- Authors
- Renjith M Radhakrishnan, Lauren Stokes, Matthew Day, Pim J Huis In 't Veld, Vladimir A Volkov
- Source
- PubMed
- Publication date
- 20 March 2026
- Primary category
- Cell cycle
- Priority
- high
- Abstract
- During mitosis, properly aligned chromosomes stabilise microtubule ends with the help of kinetochores to ensure timely segregation of chromosomes. Microtubule-binding components of the human outer kinetochore, such as Ndc80 and Ska complexes, are present in multiple copies and together bind several microtubule ends, creating a highly multivalent binding interface. Whereas Ndc80:Ndc80 and Ndc80:microtubule binding is crucial for interface stability, Ndc80 alone in absence of Ska is unable to support stable kinetochore-attachments. Using cryo-electron tomography, we demonstrate that oligomeric Ndc80:Ska assemblies stabilise microtubule ends against shortening by strengthening lateral contacts between tubulin protofilaments at microtubule plus-ends. We further identify a point mutation within the SKA1 microtubule-binding domain that does not affect microtubule-binding of individual Ska molecules, but does abolish Ska:Ska interactions. Finally, we report that oligomerisation of Ska, in a cooperative fashion together with the Ndc80, is necessary to maintain stable microtubule attachments both in vivo and in vitro.
Cell cycle-coupled CK1δ turnover, autoinhibition, and activity
This preprint shows CK1δ abundance and autoinhibition are coordinated across G1, S phase, and mitotic entry, with APC/C-CDH1 selectively degrading free active kinase.
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Cell cycle-coupled CK1δ turnover, autoinhibition, and activity
This preprint shows CK1δ abundance and autoinhibition are coordinated across G1, S phase, and mitotic entry, with APC/C-CDH1 selectively degrading free active kinase.
- Authors
- Serrano, F. E., Ruppert, B., Diernfellner, A., Brunner, M.
- Source
- bioRxiv
- Publication date
- 20 March 2026
- Primary category
- Cell cycle
- Priority
- medium
- Abstract
- Casein kinase 1{delta} (CK1{delta}) is a ubiquitously expressed kinase involved in diverse cellular processes, including cell cycle regulation. CK1{delta} activity is attenuated by (auto)phosphorylation. However, inhibitory phosphorylation is efficiently opposed by cellular phosphatases as CK1{delta} accumulates in its hypophosphorylated, active state. CK1{delta} is a target of the nuclear ubiquitin ligase APC/C-CDH1, yet the kinase is apparently stable. Thus, the physiological relevance of CK1{delta} (auto)phosphorylation, autoinhibition, and regulated turnover has remained unclear. Here we show that CK1{delta} activity and abundance are coordinated in a cell cycle-dependent manner. During G1, assembled CK1{delta} kinase is stable while free active kinase is degraded. In S phase, unassembled CK1{delta} is no longer degraded, likely to support functions in DNA damage signaling. Upon mitotic entry, the downregulation of phosphatases promotes CK1{delta} (auto)phosphorylation and consequent autoinhibition, thereby preserving a pool of kinase to rapidly reestablish the post-mitotic steady state.
Structural basis of the cyclin Y/14-3-3 protein-mediated activation of CDK16.
Provides structural and biophysical evidence for how cyclin Y and 14-3-3 proteins activate the cyclin-dependent kinase CDK16.
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Structural basis of the cyclin Y/14-3-3 protein-mediated activation of CDK16.
Provides structural and biophysical evidence for how cyclin Y and 14-3-3 proteins activate the cyclin-dependent kinase CDK16.
- Authors
- Klara Kohoutova, Dalibor Kosek, Adam Brzezina, Karolina Honzejkova, Veronika Obsilova, Tomas Obsil
- Source
- PubMed
- Publication date
- 20 March 2026
- Primary category
- Cell cycle
- Priority
- medium
- Abstract
- Cyclin-dependent protein kinase 16 (CDK16) regulates both physiological and pathological processes, including autophagy, spermatogenesis and cancer. Unlike other CDKs, CDK16 is regulated by an unclear mechanism involving phosphorylated cyclin Y (CCNY) in complex with 14-3-3 proteins rather than CCNY alone. The present study aims at elucidating this mechanism by structurally characterizing CDK16 in complex with CCNY and 14-3-3 using several biophysical techniques. As shown by cryo-EM analysis and hydrogen/deuterium exchange coupled to mass spectrometry, 14-3-3 binding modulates the conformation of a key moiety of the CDK binding surface of CCNY, thereby enabling CDK16 activation. CDK16 interacts with the cyclin box of CCNY, while 14-3-3 provides additional contacts, including with the activation segment of CDK16. CDK16 activation also requires interactions of CCNY with the N-terminal extension of CDK16. These findings not only clarify the role of CCNY and 14-3-3 in CDK16 activation but also highlight the potential of targeting CDK16 protein-protein interactions for cancer therapy.
Genome stability
9Genome-wide CRISPR screens identify the EXO1-CAF-1 pathway suppressing R-loop-associated DNA damage.
Genome-wide CRISPR screens show that EXO1 and CAF-1 suppress R-loop accumulation and associated DNA damage, making this a clear genome stability study.
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Genome-wide CRISPR screens identify the EXO1-CAF-1 pathway suppressing R-loop-associated DNA damage.
Genome-wide CRISPR screens show that EXO1 and CAF-1 suppress R-loop accumulation and associated DNA damage, making this a clear genome stability study.
- Authors
- Alexandra Nusawardhana, Anastasia Hale, Joshua Straka, Claudia M Nicolae, George-Lucian Moldovan
- Source
- PubMed
- Publication date
- 24 February 2026
- Primary category
- Genome stability
- Priority
- medium
- Abstract
- DNA repair is critical for cellular homeostasis under both normal conditions as well as in response to genotoxic agents such as chemotherapeutics. EXO1 is a 5'-3' exonuclease with multiple roles in DNA biology. To better understand these roles, we employed CRISPR loss-of-function genome-wide screening to identify genes required for proliferation and cisplatin sensitivity in EXO1-deficient cells. We uncovered differential regulators of cisplatin sensitivity between wildtype (WT) and EXO1-deficient cells. By analyzing the genetic networks that these regulators belong to, we found that DNA repair was the main biological process suppressing cisplatin sensitivity in WT cells, but this was not the case in EXO1-deficient cells, indicating that EXO1 is critical for the repair of cisplatin-induced DNA damage. Moreover, synthetic lethality screens identified a genetic interaction between EXO1 and the histone chaperone CAF-1. Mechanistically, we show that EXO1 and CAF-1 are independently recruited to R-loops and participate in separate, synergistic pathway of R-loop suppression. Even in the absence of DNA damage treatment, concomitant loss of EXO1 and CAF-1 causes R-loop accumulation and increased R-loop-associated DNA damage. Our work sheds light on the critical roles of EXO1 in genomic stability.
Importin α Characterizes a micronuclear environment associated with genomic instability in human cancer cells.
Importin α marks a distinct micronuclear state in cancer cells linked to impaired transport, chromatin association, and different patterns of genome instability.
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Importin α Characterizes a micronuclear environment associated with genomic instability in human cancer cells.
Importin α marks a distinct micronuclear state in cancer cells linked to impaired transport, chromatin association, and different patterns of genome instability.
- Authors
- Yoichi Miyamoto, Reo Kisanuki, Rieko Oshima, Shige H Yoshimura, Mutsumi Yokota, Kazumitsu Maehara, Yoshiatsu Aomine, Chiaki Hata, Taro Tachibana, Masaharu Hazawa, Hiroyuki Okada, Hiroshi Kimura, Masato Koike, Yasuyuki Ohkawa, Toyomasa Katagiri, Yoshihiro Yoneda, Masahiro Oka, Hisato Saitoh
- Source
- PubMed
- Publication date
- 16 March 2026
- Primary category
- Genome stability
- Priority
- high
- Abstract
- Micronuclei (MN) are membrane-enclosed chromatin bodies and hallmarks of genome instability. Here, we show that importin α, a key nuclear transport factor, accumulates prominently in a distinct subset of MN in cultured human cancer cells. The selective localization is associated with defective Ran-dependent nucleocytoplasmic recycling of importin α1 within MN, consistent with impaired nuclear export. This was supported by live-cell photobleaching analyses, which revealed markedly reduced mobility of importin α1 between MN and the cytoplasm. Notably, importin α1 was enriched in euchromatin regions within MN and colocalized with chromatin-associated molecules, defining a chromatin-linked micronuclear context. In contrast, DNA repair and DNA-sensing molecules such as RAD51, RPA2, and cGAS showed mutually exclusive localization with importin α1 in MN, indicating that MN comprise functionally distinct internal states. Consistent with the functional heterogeneity, single MN genome-wide analyses further linked distinct MN states to different patterns of genome instability in cancer cells. Together, these findings identify importin α as a molecular marker of a transport-restricted, chromatin-associated MN subset. This framework offers new insights into MN heterogeneity and genome instability during cancer progression.
Microhomology-mediated end joining acts directly on replication forks to repair single-ended double-strand breaks.
This paper shows that microhomology-mediated end joining directly repairs single-ended breaks at stalled replication forks and that ATR restrains this pathway under replication stress in cancer cells.
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Microhomology-mediated end joining acts directly on replication forks to repair single-ended double-strand breaks.
This paper shows that microhomology-mediated end joining directly repairs single-ended breaks at stalled replication forks and that ATR restrains this pathway under replication stress in cancer cells.
- Authors
- Shibo Li, Yuqin Zhao, Youhang Li, Sameer Bikram Shah, Yanmeng Shi, Tran Nguyen, Zi Wang, Chia-Yu Chang, Anagh Ray, Te-Hsuan Bu, Salvatore Loguercio, Takayo Sasaki, Jonathan H Sussman, Hailong Wang, David M Gilbert, Mirit I Aladjem, Xiaohua Wu
- Source
- PubMed
- Publication date
- 16 March 2026
- Primary category
- Genome stability
- Priority
- high
- Abstract
- Replication stress, intrinsic to oncogenesis, often leads to fork breakage and double-strand break (DSB) formation. Conventionally, break-induced replication (BIR) is considered the primary mechanism for repairing replication-associated single-ended DSBs (seDSBs). Here, we demonstrate that microhomology-mediated end joining (MMEJ) acts directly to repair seDSBs at broken replication forks (fork-MMEJ), preferentially on the leading strands, and functions cooperatively with BIR. While promoted by DNA polymerase theta (Polθ), fork-MMEJ operates independently of MRE11/CtIP-mediated end resection, relies on RPA, and produces asymmetric deletion patterns, distinct from canonical MMEJ (cMMEJ), which is defined at replication-independent double-ended DSBs (deDSBs). ATR, activated as end resection proceeds, serves as a pivotal switch to suppress fork-MMEJ while promoting BIR. The combined inactivation of ATR and Polθ synergistically kills cancer cells under high replication stress with minimal toxicity to normal cells. Together, our study provides fundamental insights into the MMEJ mechanism and offers new strategies for cancer treatment.
An ATM-AMPK-Wip1 feedback loop governing DNA-damage signaling and tumor stress responses.
The title indicates a DNA-damage signaling study centered on an ATM-AMPK-Wip1 feedback loop in tumor stress responses, but no abstract is available.
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An ATM-AMPK-Wip1 feedback loop governing DNA-damage signaling and tumor stress responses.
The title indicates a DNA-damage signaling study centered on an ATM-AMPK-Wip1 feedback loop in tumor stress responses, but no abstract is available.
- Authors
- Shantanu Gupta, Pritam Kumar Panda
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- Genome stability
- Priority
- high
- Abstract
- No abstract available.
Real-Time Visualization of G2L4 Reverse Transcriptase in DNA Repair via Microhomology-Mediated End Joining
Real-time high-speed AFM reveals how G2L4 reverse transcriptase executes microhomology-mediated end joining during double-strand break repair.
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Real-Time Visualization of G2L4 Reverse Transcriptase in DNA Repair via Microhomology-Mediated End Joining
Real-time high-speed AFM reveals how G2L4 reverse transcriptase executes microhomology-mediated end joining during double-strand break repair.
- Authors
- Zhang, P., Guo, M., Zhang, Y. J., Lambowitz, A. M., Lin, Y.-C.
- Source
- bioRxiv
- Publication date
- 17 March 2026
- Primary category
- Genome stability
- Priority
- medium
- Abstract
- Double-strand break repair (DSBR) is essential for genome integrity, yet mechanistic details of error-prone microhomology-mediated end joining (MMEJ) remain unclear. A bacterial group II intron-like reverse transcriptase, G2L4 RT, has been implicated in MMEJ, but how it executes DSBR is unknown. Using high-speed atomic force microscopy (HS-AFM), we directly visualize G2L4 RT-mediated DSBR via MMEJ. We observe that G2L4 RT dimers exhibit RT3a plug protrusion upon DNA engagement and catalyze MMEJ by binding and stabilizing a 4-bp annealed microhomology and filling adjacent single-strand gaps with dNTPs. We also observe Mn2+-stimulated terminal transferase activity that generates elongated and branched DNA intermediates prior to ligation. With T4 DNA ligase, we visualize binding near nick sites and real-time nick sealing, which stabilizes the repaired products and suppresses off-pathway branching. These results reveal how G2L4 RT and ligase activities shape MMEJ intermediates and outcomes.
Replicative gaps in DNA damage tolerance, genome instability, and cancer therapy.
This perspective focuses on replication-stress-induced single-stranded DNA gaps, their repair pathways, and how they create genome instability and cancer therapy vulnerabilities.
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Replicative gaps in DNA damage tolerance, genome instability, and cancer therapy.
This perspective focuses on replication-stress-induced single-stranded DNA gaps, their repair pathways, and how they create genome instability and cancer therapy vulnerabilities.
- Authors
- Lucia Falbo, Vincenzo Costanzo
- Source
- PubMed
- Publication date
- 20 March 2026
- Primary category
- Genome stability
- Priority
- medium
- Abstract
- Replicative single-stranded DNA gaps are emerging as central intermediates in the cellular response to replication stress. Replication frequently continues past lesions or difficult-to-replicate regions through leading-strand repriming or delayed Okazaki fragment (OKF) maturation, generating structured gaps requiring stabilization and repair. Here, we describe the major routes of gap formation, including polymerase-helicase uncoupling, impaired OKF processing, PrimPol-mediated lesion bypass, and endogenous abasic site accumulation from base excision repair and DNA methylation turnover. We examine the mechanisms that suppress, protect, and resolve these gaps, highlighting RAD51/BRCA2-mediated stabilization, PCNA modifications, PARP1- and CTC1-STN1-TEN1 (CST)-dependent fill-in pathways, and the balance between translesion synthesis and template switching. Finally, we discuss how persistent gaps drive fork degradation, genome instability, and innate immune activation, contributing to explaining the therapeutic vulnerabilities and resistance of cancer cells to PARP, polymerase Q (Pol θ), and ATR inhibitors. This perspective presents a unified model in which timely replicative gap recognition and resolution ensure genome stability.
ATM safeguards DNA replication at endogenous base lesions
This paper shows that ATM prevents PRIMPOL-driven repriming and post-replicative DNA gap accumulation at endogenous base lesions, explaining PARP inhibitor sensitivity and replication stress in ATM-deficient cells.
+
ATM safeguards DNA replication at endogenous base lesions
This paper shows that ATM prevents PRIMPOL-driven repriming and post-replicative DNA gap accumulation at endogenous base lesions, explaining PARP inhibitor sensitivity and replication stress in ATM-deficient cells.
- Authors
- Sommerova, L., King, A., Chapman, J. R.
- Source
- bioRxiv
- Publication date
- 21 March 2026
- Primary category
- Genome stability
- Priority
- high
- Abstract
- Poly(ADP-ribose) polymerase inhibitors (PARPi) exploit homologous recombination deficiency (HRD) in BRCA1/2-mutated cancers to induce synthetic lethality. PARPi also kill cancer cells lacking the DNA damage-responsive kinase ATM, however, inconsistent evidence of HRD and variable clinical responses have obscured the underlying mechanism. Here we define how PARPi induce cytotoxicity in ATM-deficient cells and reveal a critical role for ATM in regulating DNA replication. In the absence of ATM, unrestrained PRIMPOL-dependent repriming at spontaneous oxidative base adducts generates discontinuous daughter strands containing DNA gaps that activate PARP. This defect is sustained by aberrant suppression of replication fork slowing - presumably via fork reversal - by the BRCA1-A complex, whose recruitment to stalled forks is normally counteracted by ATM. The resulting gaps require homologous recombination (HR) for post-replicative repair and underlie the synthetic lethal interaction with PARPi. Suppressing repriming, reducing oxidative stress, or blocking base excision repair alleviates these defects. Collectively, our findings reveal how spontaneous base damage cooperates with replication dysfunction to drive PARPi sensitivity and establish a paradigm of post-replicative repair addiction in ATM-deficient cells. Together, our findings define a mechanistic link between oxidative DNA damage and ATM-dependent replication control, illuminating how oxidative stress may exacerbate genome instability in Ataxia Telangiectasia.
The BRCA1-A complex restricts replication fork reversal-dependent DNA repair in ATM deficient cells
In ATM-deficient cells, BRCA1-A is shown to suppress replication fork reversal and end resection, shaping chemotherapy sensitivity to fork-damaging agents.
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The BRCA1-A complex restricts replication fork reversal-dependent DNA repair in ATM deficient cells
In ATM-deficient cells, BRCA1-A is shown to suppress replication fork reversal and end resection, shaping chemotherapy sensitivity to fork-damaging agents.
- Authors
- Greenberg, R., Datta, A., Jackson, J., Morozov, Y., Qiu, J., Vindigni, A.
- Source
- bioRxiv
- Publication date
- 22 March 2026
- Primary category
- Genome stability
- Priority
- high
- Abstract
- Ataxia Telangiectasia Mutated (ATM) kinase deficiency results in cancer susceptibility and drug sensitivity. Deficiency in either the BRCA1 interacting A complex or XRCC4/Ligase 4 confers resistance to Topoisomerase I or PARP1 inhibitors in ATM-deficient cells. This suggests that BRCA1-A directs toxicity to fork-damaging agents in ATM mutated cells vis-a-vis illegitimate end-joining. Here, we show that ATM inhibition triggers combined SUMO and ubiquitin mediated BRCA1-A damaged fork recognition to restrict end-resection and cause Topoisomerase I inhibitor hypersensitivity. BRCA1-A deficient cells display elevated chromatin accessibility and nuclease activity at damaged forks, coupled with restored resection and drug resistance. Electron microscopy evidence demonstrates that ATM inhibition prevents replication fork reversal, which is restored by BRCA1-A loss to generate substrates for end resection. These findings reveal that BRCA1-A enforces a restrictive chromatin state to suppress the genesis of resection substrates, implicating fork reversal as a key determinant of chemotherapy response in ATM deficient cells.
An updated view on lagging strand DNA replication: implications for the replication stress response.
This review links lagging-strand DNA replication and Okazaki fragment synthesis to replication stress surveillance and genome stability during S phase.
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An updated view on lagging strand DNA replication: implications for the replication stress response.
This review links lagging-strand DNA replication and Okazaki fragment synthesis to replication stress surveillance and genome stability during S phase.
- Authors
- Rodrigo Martín-Rufo, Emilio Lecona
- Source
- PubMed
- Publication date
- 22 March 2026
- Primary category
- Genome stability
- Priority
- medium
- Abstract
- The process of DNA replication is inherently asymmetric. While the leading strand is synthesized continuously, the lagging strand is copied in small fragments, the Okazaki fragments, requiring the repeated priming by the DNA polymerase alpha/Primase complex (Pol α/Pri). Current evidence is consistent with a semi-distributive model for priming in the lagging strand, as Pol α/Pri acts associated to the replisome and also as a free complex. In addition, there is a strong link between the dynamics of replication in the lagging strand and the basal activation of the replication stress response (RSR) during an unperturbed S phase. We hypothesize that the RSR monitors the generation of Okazaki fragments to control the synthesis of DNA in what we call the DNA replication control (DRC) mode of the RSR. The DRC enforces a gradual progression of DNA replication by restricting origin firing, what is necessary to establish the replication program in the cell and to prevent the appearance of genomic instability. Thus, the RSR coordinates the replication program in the cell, modulating the progression of DNA replication to prevent the exhaustion of cellular resources that would endanger the stability of the genome.
Cancer biology
10MTAP Loss Is Frequent in Oncogene-Driven NSCLC and May Confer Sensitivity to Combined PRMT5 Inhibitors and Targeted Therapies.
The study defines MTAP loss as a common vulnerability in oncogene-driven NSCLC and tests combined PRMT5 inhibition with targeted therapies in preclinical models.
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MTAP Loss Is Frequent in Oncogene-Driven NSCLC and May Confer Sensitivity to Combined PRMT5 Inhibitors and Targeted Therapies.
The study defines MTAP loss as a common vulnerability in oncogene-driven NSCLC and tests combined PRMT5 inhibition with targeted therapies in preclinical models.
- Authors
- M Aldea, S Lenahan, M-A Locquet, L Liao, M Gasparro, P C Gokhale, M-R Ghigna, D N Ionescu, I Odintsov, K Ngo, X Wang, S Aziz, F Pecci, E Garbo, E Ivanova, S Nakazawa, J Kulesza, J A Tsai, L Zullo, J Lee, M Zielinska, S Simon, D Han, A Marinello, G Li, G Rossato de Almeida, J Huang, F Paoloni, E Gariazzo, V Santo, J Remon, J A Marks, J LoPiccolo, N Florez, M Nishino, B Ricciuti, J Luo, D A Barbie, D Planchard, J K Rotow, F Barlesi, R P Graf, W W Feng, B Besse, C Paweletz, L Sholl, A T Shaw, P A Jänne
- Source
- PubMed
- Publication date
- 13 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- BACKGROUND: Homozygous loss of MTAP (methylthioadenosine phosphorylase) occurs in approximately 15% of cancers and leads to partial PRMT5 inhibition, creating a selective vulnerability to PRMT5 inhibitors. The frequency and therapeutic relevance of MTAP loss in oncogene-driven non-small cell lung cancers (NSCLCs) remain underexplored. METHODS: MTAP status was assessed by next-generation sequencing (NGS) or immunohistochemistry (IHC) in >13,000 NSCLC samples in four cohorts. Prevalence was assessed across oncogenic drivers and temporal dynamics in pre- and post-treatment biopsies. Clinical outcomes were analyzed in EGFR- and ALK-rearranged NSCLC treated with first-line osimertinib and alectinib, respectively. The MTA-cooperative PRMT5 inhibitor BMS-986504 was tested alone and in combination with targeted therapies (TT) in MTAP-deleted models in vitro, ex vivo and in vivo. RESULTS: MTAP loss was frequent in ALK-rearranged (27% and 33% by NGS; 36% and 45% IHC), RET-rearranged (18.5% and 26% by NGS; 35% by IHC), and EGFR-mutant NSCLC (17% and 24% by NGS; 24% and 29% by IHC), with CDKN2A co-deletion in 98% of cases. MTAP loss was typically present prior to TT. MTAP loss did not significantly impact response or overall survival with first-line osimertinib or alectinib in EGFR mutant and ALK-rearranged NSCLC, respectively. In preclinical studies, BMS-986504 showed nanomolar activity in 11/18 MTAP-deleted models, including 5/8 EGFR- and 5/5 ALK-driven models, regardless of TT sensitivity. Synergistic or additive effects with TT were observed in 11/18 models. In ex vivo ALK-rearranged spheroids resistant to crizotinib, the combination of BMS-986504 and alectinib improved antitumor activity over monotherapy. In an osimertinib-resistant, EGFR mutant PDX model, BMS-986504 with or without osimertinib controlled tumor growth, without weight loss. CONCLUSIONS: MTAP loss is frequent in oncogene-driven NSCLC, particularly in ALK-, RET-, and EGFR-altered subtypes. MTA-cooperative PRMT5 inhibition demonstrates broad activity in MTAP-deleted, oncogene-driven models and, and may enhance targeted therapy efficacy in selected settings.
ATM functions as a rheostat of metabolic stress in small-cell lung cancer
Small-cell lung cancer study shows ATM supports MYC-ATF4 metabolic stress adaptation and redox homeostasis, creating a ferroptosis-linked therapeutic vulnerability.
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ATM functions as a rheostat of metabolic stress in small-cell lung cancer
Small-cell lung cancer study shows ATM supports MYC-ATF4 metabolic stress adaptation and redox homeostasis, creating a ferroptosis-linked therapeutic vulnerability.
- Authors
- Halder, D., Sen, U. D., Jethalia, V., Chakraborty, S., Elliott, A., Ventura, K., Vanderwalde, A., Halmos, B., Borghaei, H., Thin, T. H., Soto, A., Berisa, M., Brody, R., Demircioglu, D., Hasson, D., Sen, T.
- Source
- bioRxiv
- Publication date
- 17 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- ATM is best known as a guardian of genomic stability, yet its contributions to oncogenic signaling in aggressive malignancies like small-cell lung cancer (SCLC) remain poorly understood. Despite ATM being an established clinical vulnerability in SCLC, its influence on dysregulated tumorigenic circuits remains unclear. We demonstrate that inhibition of ATM disrupts the AKT-mTORC1-4EBP1 signaling axis, leading to attenuation of the master regulator of stress, ATF4. ATF4 and MYC appear to co-regulate one another in a feedback loop critical for redox homeostasis. ATM inhibition perturbs both the expression and function of MYC and ATF4, leading to increased intracellular reactive oxygen species, impaired glutathione recycling, and ferroptotic cell death, thereby exposing a crucial dependency of SCLC on stress-adaptive signaling. We uncover previously unrecognized metabolic vulnerability in SCLC, nominating ATM as a regulator of adaptive stress, expanding its role beyond canonical DNA damage repair (DDR) and highlighting therapeutically exploitable opportunities in aggressive tumors.
Eco-Evolutionary Dynamics of Proliferation Heterogeneity: A Phenotype-Structured Model for Tumor Growth and Treatment Response
Phenotype-structured tumor model analyzes how proliferation heterogeneity reshapes growth and treatment response through eco-evolutionary selection.
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Eco-Evolutionary Dynamics of Proliferation Heterogeneity: A Phenotype-Structured Model for Tumor Growth and Treatment Response
Phenotype-structured tumor model analyzes how proliferation heterogeneity reshapes growth and treatment response through eco-evolutionary selection.
- Authors
- Schmalenstroer, L., Rockne, R. C., Farahpour, F.
- Source
- bioRxiv
- Publication date
- 17 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- Intra-tumor heterogeneity in proliferation rates fundamentally influences cancer progression and treatment resistance. To investigate how continuous phenotypic variation shapes eco-evolutionary dynamics, we develop a phenotype-structured partial differential equation framework that explicitly models proliferation heterogeneity as a dynamic trait distribution. Our model integrates three key biological principles: (1) phenotypic diffusion capturing heritable variation in proliferation rates, (2) global resource competition enforcing density-dependent growth constraints, and (3) an experimentally grounded life-history trade-off linking elevated proliferation to increased mortality. Using adaptive dynamics, we derive the optimum proliferation rate in a growing tumor, showing that the optimal phenotype dynamically shifts toward slower proliferation as tumors approach carrying capacity. We perform \textit{in silico} treatment simulations for four different treatment regimes (pan-proliferation, low-, mid-, and high-proliferation targeting) to show how therapeutic selective pressures reshape fitness landscapes. While all treatments slow down tumor growth, they induce divergent evolutionary trajectories: low- and mid-proliferation targeting enrich fast-proliferating clones, whereas high-proliferation targeting selects for slower phenotypes. We connect these dynamics with changes in mean proliferation rates during and after treatment. We use adaptive dynamics to explain the shifts in mean proliferation rate during treatment, showing how each regimen alters the maximum fitness proliferation rate. Our work establishes a predictive, evolutionarily grounded framework for understanding how therapy reshapes tumor proliferation landscapes, offering a mechanistic basis for designing strategies that anticipate and counteract adaptive resistance.
Evidence that the protein phosphatase activity of PTEN contributes to embryonic development and tumour suppression in mice
Knock-in mice show that PTEN protein phosphatase activity contributes to embryonic development and tumor suppression independently of its lipid phosphatase function.
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Evidence that the protein phosphatase activity of PTEN contributes to embryonic development and tumour suppression in mice
Knock-in mice show that PTEN protein phosphatase activity contributes to embryonic development and tumor suppression independently of its lipid phosphatase function.
- Authors
- Tibarewal, P., Spinelli, L., Kriplani, N., Wise, H., Poncet, N., Marzano, G., Anderson, K. E., Grzes, K. M., Varyova, Z., Adil, M., Downes, C. P., Hawkins, P. T., Stephens, L. R., Storey, K. G., Cantrell, D. A., Vanhaesebroeck, B., Leslie, N. R.
- Source
- bioRxiv
- Publication date
- 17 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- PTEN (phosphatase and tensin homologue deleted on chromosome ten) is a tumour suppressor, the function of which is impaired in many diverse cancers. It has phosphoinositide lipid phosphatase activity by which it suppresses activation of the oncogenic PI3K signalling network but in vitro also displays activity against protein substrates and is able to auto-dephosphorylate its Thr366 residue. Here we generate germline knock-in mice expressing PTEN-Y138L, a mutant enzyme which selectively lacks protein phosphatase activity and retains lipid phosphatase activity. Homozygous PtenY138L/Y138L mice die in utero before E10.5. Primary MEFs and thymocytes with only a single PtenY138L allele display normal low levels of AKT phosphorylation indicating effective regulation of PI3K signalling by endogenous PTEN-Y138L in vivo. Heterozygous Pten+/Y138L mice have reduced overall survival compared to wild type littermates and develop tumours in multiple organs. Our data imply that in addition to its lipid phosphatase activity, the protein phosphatase activity of PTEN is also required for normal embryonic development and tumour suppression.
Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors.
Multimodal imaging of ovarian tumour explants shows lysosomal sequestration creates an intracellular reservoir that shapes PARP inhibitor distribution and response.
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Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors.
Multimodal imaging of ovarian tumour explants shows lysosomal sequestration creates an intracellular reservoir that shapes PARP inhibitor distribution and response.
- Authors
- Carmen R Moncayo, Restuadi Restuadi, Guanying Zhang, Daniel Marks, Paula Ortega-Prieto, Emily Doherty, Nathalie Lambie, Chad Whilding, Ivan Andrew, Alex Montoya, Bhavik Patel, Katie Tyson, Betheney R Pennycook, Lauren Pendergast, Vincen Wu, Zoltan Takats, Nik Matthews, George R Young, Priyanka Verma, Pavel Shliaha, Laurence Game, Boris Lenhard, Iain McNeish, Christina Fotopoulou, Alexis R Barr, Paula Cunnea, Zoe Hall, Louise Fets
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- For all drugs, effective target engagement requires sufficient intracellular concentrations of drug to be reached, but whether tumour heterogeneity impacts drug distribution and efficacy is poorly studied. Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed treatment opportunities for women with high-grade serous ovarian carcinoma, but resistance remains a clinical hurdle in this highly heterogeneous tumour type. Here, we present a patient-derived explant multi-modal imaging pipeline, which demonstrates that cell-intrinsic PARP inhibitor accumulation is highly variable, both between patients and within tumours. Spatial transcriptomics reveals enrichment of apoptotic and lysosomal signatures in high-drug regions. Rucaparib, an intrinsically fluorescent PARP inhibitor, accumulates heterogeneously at the single-cell level, with rucaparib-high cells demonstrating increased drug response relative to rucaparib-low. Mechanistically, lysosomal sequestration creates a rucaparib reservoir that determines drug levels in the nucleus. Perturbation of lysosomal content alters intracellular levels of weak base PARP inhibitors rucaparib and niraparib, but not olaparib. Together these data suggest that lysosomes act as a reservoir for a subset of PARP inhibitor drugs to improve drug response.
Phosphorylation-driven Targeted Protein Degradation of Oncogenic β-catenin
This preprint shows that induced proximity to casein kinase I family members promotes phosphorylation-dependent degradation of oncogenic β-catenin in colorectal cancer cells.
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Phosphorylation-driven Targeted Protein Degradation of Oncogenic β-catenin
This preprint shows that induced proximity to casein kinase I family members promotes phosphorylation-dependent degradation of oncogenic β-catenin in colorectal cancer cells.
- Authors
- Wolf, L. M., Poirson, J., Macleod, G., Lin, S., Kim, Y. H., Almeida, M. P., Taipale, M., Angers, S.
- Source
- bioRxiv
- Publication date
- 18 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- Therapeutic strategies to inhibit the Wnt signalling pathway for cancer treatment have, so far, failed to advance to the clinic. Induced-proximity drugs are revolutionizing our ability to tackle targets previously considered undruggable. Here, we used an unbiased genome-scale approach to identify induced-proximity protein candidates that inhibit the central Wnt signalling effector {beta}-catenin in colorectal cancer cells. While the identification of several E3 ubiquitin ligases validated our approach, we uncovered that inducing proximity to members of the Casein kinase I (CSNK1) family leads to {beta}-catenin degradation and inhibits the growth of colorectal cancer cells harbouring Wnt pathway mutations. We show that {beta}-catenin degradation induced by CSNK1 proximity is kinase activity- and proteasome-dependent. We propose that the formation of a neo-degron, through kinase recruitment, can expand induced-proximity drug targeting strategies.
Cancer Cell Line Encyclopedia Data Suggest that Ligands for ERBB Family Receptors May Drive BRAF-WT Melanomas
This melanoma study argues that ERBB-family ligands and G11/Gq signaling may sustain proliferation of BRAF-wild-type melanoma cell lines through ERBB4-ERBB2 signaling.
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Cancer Cell Line Encyclopedia Data Suggest that Ligands for ERBB Family Receptors May Drive BRAF-WT Melanomas
This melanoma study argues that ERBB-family ligands and G11/Gq signaling may sustain proliferation of BRAF-wild-type melanoma cell lines through ERBB4-ERBB2 signaling.
- Authors
- Wilson, E., Conway, A., Riese, D. J.
- Source
- bioRxiv
- Publication date
- 18 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- Cutaneous skin melanomas with wild-type BRAF alleles ("BRAF-WT melanomas") remain relatively difficult to treat, even though they typically possess driver mutations in a RAS gene or NF1. For example, these tumors respond relatively poorly to combinations of MEK and BRAF inhibitors, and their response to ICIs is muted compared to the response of BRAF-mutant melanomas. ERBB2 and ERBB4, which encode receptor tyrosine kinase genes, are necessary and sufficient for the proliferation of multiple BRAF-WT melanoma cell lines. Consequently, we have postulated that ERBB4-ERBB2 heterodimerization drives BRAF-WT melanomas. This mechanism is consistent with the observation that elevated ERBB4 transcription or ERBB4 mutations are found in a significant fraction of BRAF-WT melanoma tumor samples. Moreover, a subset of ERBB4 mutations found in BRAF-WT melanoma samples increases proliferation in a BRAF-WT melanoma cell line. Because the elevated ERBB4 transcription observed in BRAF-WT melanomas is typically insufficient to cause ligand-independent ERBB4 signaling, we have postulated that ligands for ERBB family receptors drive the elevated ERBB4-ERBB2 heterodimerization responsible for the proliferation of BRAF-WT melanoma cell lines. We have explored this hypothesis by analyzing data found in the Broad Institute's Cancer Cell Line Encyclopedia. These data suggest that some EGF family hormones are required for the proliferation of BRAF-WT melanoma cell lines. Likewise, the G11/Gq pathway, which can stimulate cleavage and maturation of EGF family hormones, is also required for the proliferation of BRAF-WT melanoma cell lines. Thus, these data suggest additional therapeutic targets in BRAF-WT melanomas. Moreover, because many uveal (ocular) melanomas possess elevated G11/Gq signaling, these data suggest that ligand stimulation of ERBB receptor signaling may contribute to uveal melanomagenesis or progression.
Proteasome-guided haem signalling axis contributes to T cell exhaustion.
Immunometabolism study shows a proteasome-haem pathway promotes CD8 T-cell exhaustion and limits anti-tumour efficacy, with translational relevance to CAR-T therapy.
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Proteasome-guided haem signalling axis contributes to T cell exhaustion.
Immunometabolism study shows a proteasome-haem pathway promotes CD8 T-cell exhaustion and limits anti-tumour efficacy, with translational relevance to CAR-T therapy.
- Authors
- Yingxi Xu, Yangtao Shangguan, Yu-Ming Chuang, Tzu-Hsuan Chang, Wenbing Liu, Jhan-Jie Peng, Josep Garnica, Leling Xie, Pei-Chun Hsueh, Mei-Chun Lin, Yi-Hao Wang, Karina Lobo Hajdu, Yibo Wu, Maryam Akrami, Chen Wang, Anna Kohl, Alfred Zippelius, Wei Qi, Min Wang, Bugi Ratno Budiarto, Shih-Yu Chen, Zhengtao Xiao, Panagiota Vardaka, Rahul Roychoudhuri, Zhiliang Bai, Rong Fan, Santiago Carmona, Yi-Ru Yu, Christoph Scheiermann, Jianxiang Wang, Ping-Chih Ho
- Source
- PubMed
- Publication date
- 18 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- The accumulation of depolarized mitochondria commits T cells to exhaustion1-3, yet the precise mechanism remains unclear. Here we find that exhausted CD8+ T cells increase proteasome activity owing to the accumulation of depolarized mitochondria, which drives the selective degradation of mitochondrial proteins and the release of regulatory haem through haemoprotein breakdown. In turn, increased regulatory haem disrupts BACH2-mediated transcriptional regulation, thereby exacerbating T cell exhaustion and compromising stemness-like properties. Inhibition of nuclear import of regulatory haem prevents BACH2 degradation and enhances the anti-tumour efficacy of antigen-specific T cells. We find that the therapeutic efficacy of human CD19+ chimeric antigen receptor (CAR)-T cells in patients with B cell acute lymphoblastic leukaemia negatively correlates with the proteasome gene signature in their CAR-T cells. Manufacturing CAR-T cells in the presence of bortezomib, an FDA-approved proteasome inhibitor, prevents T cell exhaustion and improves therapeutic efficacy. Our findings identify a proteasome-guided haem signalling axis, governed by mitochondrial integrity, as a regulator of CD8+ T cell exhaustion and propose innovative therapeutic strategies that exploit this pathway to optimize adoptive cellular immunotherapy.
Mechanotherapeutic Potential of Survivin in Glioblastoma
Glioblastoma cells on stiff matrices upregulate survivin and cyclins, linking mechanosensing to cell-cycle progression and extracellular matrix remodeling.
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Mechanotherapeutic Potential of Survivin in Glioblastoma
Glioblastoma cells on stiff matrices upregulate survivin and cyclins, linking mechanosensing to cell-cycle progression and extracellular matrix remodeling.
- Authors
- Inserra, G., Balghonaim, S., Jong, J., Drewes, R., Santo, B. A., Tumenbayar, B.-I., Pham, K., Babatunde, S., Tomaszewski, J. E., Ignatowski, T. A., Zhao, R., Lim, J., Kim, S., Siddiqui, A. H., Das, B. C., Tutino, V. M., Bae, Y.
- Source
- bioRxiv
- Publication date
- 20 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- Glioblastoma Multiforme (GBM) is a highly aggressive brain cancer characterized by rapid proliferation and extensive remodeling of the extracellular matrix (ECM), leading to progressive tissue stiffening. Although ECM stiffness is known to promote GBM progression, the molecular mechanisms linking mechanical cues to tumor growth remain insufficiently defined. In this study, transcriptomic comparison of GBM tumors and non-neoplastic brain tissue revealed coordinated upregulation of cell cycle regulators and matrisome-associated genes, with survivin (BIRC5) identified as a central node linking proliferative signaling and ECM remodeling networks. Analysis of GBM patient specimens further showed strong nuclear survivin expression in regions with elevated collagen deposition. To directly evaluate stiffness-dependent regulation of survivin, GBM cells were cultured on fibronectin-infused hydrogels with tunable stiffness. Stiff matrices increased survivin expression along with cyclin D1 and cyclin A, consistent with increased cell cycle progression. Pharmacologic inhibition or siRNA-mediated suppression of survivin reduced stiffness-induced proliferation and attenuated expression of matrisome components, including collagens and lysyl oxidase. These findings indicate that survivin functions as a mechanosensitive regulator that coordinates cell cycle progression with ECM production in stiff tumor microenvironments. Collectively, this study identifies survivin as a key mediator linking ECM stiffness to GBM growth and matrisome remodeling. Targeting survivin and its effectors may offer a mechanosensitive strategy to limit GBM growth.
Identification and characterization of BRAF⇔TP53 interactions in melanoma.
This melanoma study shows that BRAFV600E binds TP53, relocalizes it to the cytoplasm, and suppresses tumor-suppressive DNA damage responses.
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Identification and characterization of BRAF⇔TP53 interactions in melanoma.
This melanoma study shows that BRAFV600E binds TP53, relocalizes it to the cytoplasm, and suppresses tumor-suppressive DNA damage responses.
- Authors
- Kayla T O'Toole, Adamaris Martinez, Brandon Murphy, Gabriela Fort, Fatima Al-Sudani, Anastasia Prokofyeva, Sanjana Boggaram, Eric A Smith, Elliott L Paine, Deevya Baral, David Lum, Wei Zhang, Erika Egal, Gennie L Parkman, Eric L Snyder, Robert Judson-Torres, Joshua L Andersen, Martin McMahon
- Source
- PubMed
- Publication date
- 20 March 2026
- Primary category
- Cancer biology
- Priority
- medium
- Abstract
- Activating mutations in BRAF are common in cutaneous melanoma, yet mutational inactivation of the tumor suppressor TP53 is relatively rare despite widespread attenuation of TP53 function, suggesting alternate mechanisms of TP53 inhibition. Using proximity-dependent proteomic mapping, we define a BRAFV600E-specific interactome and identify a selective interaction between oncogenic BRAF and TP53. We demonstrate that BRAFV600E engages the DNA-binding domain of TP53, drives its localization from the nucleus to the cytoplasm, and suppresses TP53 activity. This functional inhibition persists following DNA damage or pharmacologic disruption of TP53 pathways, demonstrating that oncogenic BRAF constrains TP53 activity. These findings establish a protein interaction through which BRAFV600E functionally inactivates TP53 and reveal a mechanism by which melanoma bypasses TP53-mediated tumor suppression without requiring genetic alteration.
Senescence
4Both genome instability and replicative senescence stem from the shortest telomere in telomerase-negative cells.
Using telomerase-negative yeast, the study shows that a single critically short telomere can trigger replicative senescence while also driving telomere-proximal genomic instability.
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Both genome instability and replicative senescence stem from the shortest telomere in telomerase-negative cells.
Using telomerase-negative yeast, the study shows that a single critically short telomere can trigger replicative senescence while also driving telomere-proximal genomic instability.
- Authors
- Prisca Berardi, Veronica Martinez-Fernandez, Anaïs Rat, Fernando R Rosas Bringas, Pascale Jolivet, Rachel Langston, Stefano Mattarocci, Alexandre Maes, Théo Aspert, Bechara Zeinoun, Karine Casier, Hinke G Kazemier, Gilles Charvin, Marie Doumic, Michael Chang, Maria Teresa Teixeira
- Source
- PubMed
- Publication date
- 15 March 2026
- Primary category
- Senescence
- Priority
- medium
- Abstract
- In the absence of telomerase, telomere shortening triggers replicative senescence, a tumor suppressor mechanism that is also associated with oncogenic genomic instability. Yet, the precise mechanism that connects these seemingly opposing forces remains poorly understood. To directly study the complex interplay between senescence, telomere dynamics, and genomic instability, we develop a system in Saccharomyces cerevisiae to generate and track telomeres of precise length in the absence of telomerase. Using single-telomere and single-cell analyses combined with mathematical modeling, we identify a threshold length at which telomeres switch into dysfunction. A single shortest telomere below the threshold length is necessary and sufficient to trigger the onset of replicative senescence in a majority of cells. At population level, fluctuation assays establish that rare genomic instability arises predominantly in cis to the shortest telomere as Pol32-dependent non-reciprocal translocations that result in re-elongation of the shortest telomere and likely transient escape from senescence. The switch of the shortest telomere into dysfunction and subsequent processing in telomerase-negative cells thus serves as the mechanistic link between replicative senescence onset, genomic instability and the initiation of post-senescence survival.
The Cyclin C-CDK8/19 Mediator kinase module controls PRCC-TFE3 driven senescence in renal epithelium and tumorigenesis in TFE3-RCC.
This paper shows that the Cyclin C-CDK8/19 Mediator kinase module is required for PRCC-TFE3-driven oncogene-induced senescence in renal epithelium and also supports TFE3-rearranged renal tumor growth.
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The Cyclin C-CDK8/19 Mediator kinase module controls PRCC-TFE3 driven senescence in renal epithelium and tumorigenesis in TFE3-RCC.
This paper shows that the Cyclin C-CDK8/19 Mediator kinase module is required for PRCC-TFE3-driven oncogene-induced senescence in renal epithelium and also supports TFE3-rearranged renal tumor growth.
- Authors
- Shoichiro Kuroda, Shintaro Funasaki, Hidekazu Nishizawa, Laura S Schmidt, Ryoma Kurahashi, Takaaki Ito, Yuichiro Arima, Miwa Tanaka, Atsuya Kitada, Amy M James, Hisashi Hasumi, Ryosuke Jikuya, Kazuhide Makiyama, Daisuke Kurotaki, Takashi Minami, Simone Difilippantonio, W Marston Linehan, Yuichi Oike, Tomohiro Sawa, Yasuhito Tanaka, Toshio Suda, Ryuji Yokokawa, Takuro Nakamura, Masaya Baba, Tomomi Kamba
- Source
- PubMed
- Publication date
- 16 March 2026
- Primary category
- Senescence
- Priority
- medium
- Abstract
- TFE3-rearranged renal cell carcinoma (TFE3-RCC) is an aggressive kidney cancer driven by oncogenic TFE3 fusion transcription factors, yet the molecular machinery that enables these fusions to reprogram transcription and drive tumor growth remains poorly defined. Here, we identify the Cyclin C-CDK8/19 Mediator kinase module as an essential co-regulator of TFE3 fusion driven transcriptional programs and tumorigenesis. Inducible expression of PRCC-TFE3 in HK-2 cells, immortalized from normal renal epithelial cells, triggered a robust oncogene-induced senescence (OIS) phenotype. Using OIS as a functional readout, we performed a genome-wide CRISPR/Cas9 loss-of-function screen and identified CCNC, encoding Cyclin C, as an essential gene required for PRCC-TFE3 activity. Genetic disruption of CCNC or pharmacologic inhibition of CDK8/19 abrogated PRCC-TFE3 induced OIS, establishing the Mediator kinase module as a critical cofactor for PRCC-TFE3 dependent transcription. Mechanistically, PRCC-TFE3 promoted nuclear accumulation of Cyclin C and their co-occupancy at genomic regions bound and transcriptionally activated by PRCC-TFE3. RNA sequencing revealed that PRCC-TFE3 induced transcriptional programs, including lysosomal, TFEB-associated, and metabolic pathways, were broadly suppressed by CDK8/19 inhibition. Importantly, while PRCC-TFE3 and Cyclin C-CDK8/19 drive OIS in non-cancerous renal epithelial cells, this same transcriptional axis exerts a context dependent pro-tumorigenic function in TFE3-RCC. In xenografts established from patient derived TFE3-RCC cell lines, genetic deletion of CCNC suppressed tumor growth, whereas in an orthotopic syngeneic TFE3-RCC mouse model, pharmacologic CDK8/19 inhibition significantly reduced tumor progression. These findings define the Mediator kinase module as a mechanistic and therapeutic vulnerability in PRCC-TFE3 driven TFE3-RCC, providing a rationale for mechanism based targeted therapy.
RasG12V Oncogene-Induced Epithelial Senescence and Its Relay Promotes Host Metabolic Syndrome in Drosophila
Demonstrates that RasG12V-driven oncogene-induced senescence and SASP-like signaling trigger systemic metabolic syndrome in Drosophila.
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RasG12V Oncogene-Induced Epithelial Senescence and Its Relay Promotes Host Metabolic Syndrome in Drosophila
Demonstrates that RasG12V-driven oncogene-induced senescence and SASP-like signaling trigger systemic metabolic syndrome in Drosophila.
- Authors
- Parihar, S. S., Tripathi, J., Kundu, S., Banerjee, S., Anerao, I. M., SINHA, P.
- Source
- bioRxiv
- Publication date
- 17 March 2026
- Primary category
- Senescence
- Priority
- medium
- Abstract
- Precancerous oncogenic activation in a target organ often induces senescence, a tumor-suppressive response known as oncogene-induced senescence (OIS). Clinical observations indicate a strong association of metabolic syndrome (MetS) with the precancerous and early-stage cancers. Notably, cells displaying OIS are characterized by a senescence-associated secretory phenotype (SASP), in which they secrete factors, including inflammatory cytokines. Thus, SASP from cells displaying OIS may trigger host MetS, which likely underpins its association with cancers, such as colorectal cancer (CRC). Here, we tested this hypothesis and show that, in Drosophila, the activated RasG12V oncogene, which is frequently implicated in human CRC, induces OIS in imaginal disc epithelium and systemically triggers host larval MetS via the conserved cytokine Upd1/IL6. Thus, the larval host with RasG12V-induced epithelial OIS displays MetS, characterized by obesity, increased lipid and glycogen accumulation in the fat body, and altered insulin signaling, marked by transition from hyperinsulinemia to insulin resistance, all at a precancerous stage. Further, we also noted hyperphagia and increased expression of insulin-like peptides (dILP2/3/5) in the brain of larvae displaying RasG12V-induced OIS. Notably, RasG12V-induced OIS is systemically relayed, leading to activation of a senescence-like program in the distant fat body. Genetic suppression of upd1 or pharmacological intervention with the senomorphic agent, Metformin, attenuated fat body senescence and mitigated MetS-associated phenotypes. Our findings thus identify a causal relationship between OIS and host MetS, suggesting its utility as an early biomarker for detecting cancers such as CRC and its potential as a prophylactic target.
Protein quality control of thermosensitive nuclear transport factor Importin α.
Shows that thermosensitive Importin α subtypes accumulate in denatured form in senescent cells, linking nuclear transport quality control to cellular aging.
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Protein quality control of thermosensitive nuclear transport factor Importin α.
Shows that thermosensitive Importin α subtypes accumulate in denatured form in senescent cells, linking nuclear transport quality control to cellular aging.
- Authors
- Yutaka Ogawa, Naoko Imamoto
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- Senescence
- Priority
- medium
- Abstract
- Intracellular proteins have a wide range of thermal stabilities; some are very sensitive to temperature and may be denatured even in normal physiological conditions. Here, we show that members of the nuclear transport factor Importin α family have a variety of thermosensitivities, and some subtypes can be denatured at physiological temperature. The thermal stabilities of Importin α subtypes changed remarkably depending on their binding partners. Proteomic analyses of Importin α-interacting proteins in the cytoplasm revealed that continuous nuclear transport cycles help maintain Importin α quality. Additionally, in senescent cells, the proportions of denatured thermosensitive Importin α subtypes increased, indicating that a low transport rate leads to further inhibition of transport efficiency. The denaturing temperatures of Importin α family members correlate with the body temperatures of the animals in which they are present, thus their thermosensitivity may be important for heat stress response and other cellular functions related to aging and growth.
CRISPR / gene editing
3Improved vector toolkit for genome writing in mammalian cells
The study presents an improved vector toolkit for large-payload genome writing in mammalian cells using mSwAP-In and CRISPR/Cas9-enabled payload release.
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Improved vector toolkit for genome writing in mammalian cells
The study presents an improved vector toolkit for large-payload genome writing in mammalian cells using mSwAP-In and CRISPR/Cas9-enabled payload release.
- Authors
- Barriball, K., Berrios, B., Pinglay, S., Zhao, Y., Chalhoub, N., Tsou, T., Atwater, J. T., Boeke, J. D., Zhang, W., Brosh, R.
- Source
- bioRxiv
- Publication date
- 16 March 2026
- Primary category
- CRISPR / gene editing
- Priority
- medium
- Abstract
- Efficient genome writing in mammalian cells requires robust methods for integrating large DNA payloads. The previously described method mammalian Switching Antibiotic resistance markers Progressively for Integration (mSwAP-In) enables iterative, biallelic genome rewriting in mammalian stem cells with DNA payloads exceeding 100 kb. However, the lack of standardized vectors and certain technical constraints have limited its broader adoption. Here we present an improved plasmid toolkit designed to streamline the implementation of mSwAP-In. The toolkit includes two core vectors. pLP-TK (pCTC174) is a landing-pad plasmid compatible with Golden Gate assembly of genomic homology arms and supports both mSwAP-In and the recombinase-mediated cassette exchange method Big-IN. mSwAP-In MC2v2 (pKBA135) is a versatile Big DNA assembly and delivery vector that supports Gibson-based assembly and incorporates positive, negative, and fluorescent selection markers, as well as a backbone counterselection cassette to minimize unwanted plasmid integration. The vector architecture also enables propagation in yeast and bacterial hosts, inducible plasmid copy-number amplification in standard E. coli strains, and CRISPR/Cas9-mediated payload release through preinstalled guide RNA target sites. We further characterize the FCU1/5-FC counterselection system in mouse embryonic stem cells and define conditions that minimize its bystander toxicity. Finally, we provide a set of Cas9-gRNA expression plasmids optimized for common mSwAP-In applications. Together, these reagents constitute a standardized and experimentally validated toolkit that simplifies large-scale genome writing using mSwAP-In.
Improving the efficiency of high-fidelity Cas9 by enhancing PAM-distal interactions.
Mechanistic CRISPR study showing that extending sgRNA spacers restores SuperFi-Cas9 activity and couples this with deep-learning prediction of optimal guide length.
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Improving the efficiency of high-fidelity Cas9 by enhancing PAM-distal interactions.
Mechanistic CRISPR study showing that extending sgRNA spacers restores SuperFi-Cas9 activity and couples this with deep-learning prediction of optimal guide length.
- Authors
- Rong Zheng, Zhike Lu, Rongwei Wei, Young-Cheul Shin, Jiang Du, Qingfeng Zhang, Jianbo Li, Xiaoqi Wang, Yi Wei, Botao Liu, Yang Chen, Lihong Ding, Heng Zhang, Hui Chen, Jing Huang, Lijia Ma
- Source
- PubMed
- Publication date
- 18 March 2026
- Primary category
- CRISPR / gene editing
- Priority
- medium
- Abstract
- Engineering CRISPR enzymes for high fidelity often impairs cleavage activity. Meanwhile, a mechanistic understanding of why high-fidelity mutations reduce Cas9's cleavage activity remains unclear, presenting a challenge in balancing nuclease specificity and efficiency for clinical applications. In this study, we show that extending the spacer region to 21 or 22 nucleotides restores the impaired cleavage activity of SuperFi-Cas9, a high-fidelity Cas9 variant with 7 mutations in the RuvC domain at the protospacer adjacent motif (PAM)-distal region. Cryo-electron microscopy structures and mutational analyses reveal that the negatively charged mutations in a protruding loop of the RuvC domain create repulsive forces that destabilize the nuclease-single guide (sg)RNA-DNA complex. Spacer extension enhances interactions in the PAM-distal region, effectively restoring cleavage activity and balancing editing efficiency with specificity. In addition, we develop a deep learning model, AIdit-SuperFi, to predict optimal sgRNA length for high-fidelity genome editing. Our findings introduce a straightforward strategy to enhance CRISPR complex stability and provide mechanistic insights into the impaired cleavage activity of engineered high-fidelity Cas9, presenting a pathway toward precise and efficient genome editing and clinical translation of CRISPR technologies.
Extending guide RNA length restores high-fidelity CRISPR-Cas9 activity.
This CRISPR-Cas9 methodology paper appears directly relevant to guide RNA design and high-fidelity genome editing, but the missing abstract leaves the exact scope uncertain.
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Extending guide RNA length restores high-fidelity CRISPR-Cas9 activity.
This CRISPR-Cas9 methodology paper appears directly relevant to guide RNA design and high-fidelity genome editing, but the missing abstract leaves the exact scope uncertain.
- Authors
- Authors not listed
- Source
- PubMed
- Publication date
- 20 March 2026
- Primary category
- CRISPR / gene editing
- Priority
- medium
- Abstract
- No abstract available.
Imaging
2CellPheno: A High-throughput Computational Platform for Quantifying Cellular Resolution Whole Brain Microscopy Images
3D nuclei instance-segmentation platform enables high-throughput whole-brain light-sheet microscopy quantification and morphometry at cellular resolution.
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CellPheno: A High-throughput Computational Platform for Quantifying Cellular Resolution Whole Brain Microscopy Images
3D nuclei instance-segmentation platform enables high-throughput whole-brain light-sheet microscopy quantification and morphometry at cellular resolution.
- Authors
- Wei, Z., Curtin, I., Kyere, F. A., Borland, D., Yi, H., Kim, M., Dere, M., McCormick, C. M., Krupa, O., Shih, Y.-Y. I., Zylka, M. J., Stein, J. L., Wu, G.
- Source
- bioRxiv
- Publication date
- 19 March 2026
- Primary category
- Imaging
- Priority
- medium
- Abstract
- Advances in tissue clearing and light-sheet microscopy enable cellular resolution whole-brain 3D imaging. However, whole-brain quantification tools do not yet meet demands for efficiency or assess morphometry. Here we present CellPheno, a 3D nuclei instance segmentation framework for high-throughput cellular phenotyping. CellPheno quantifies an entire P4 mouse brain within 15 hours. We showcase whole-brain morphometry, enhanced stitching, and co-localization across multiple cell types in 53 brains.
Technologies to measure and modulate protein subcellular localization.
This review surveys microscopy, proximity labeling, and related technologies to map and perturb protein subcellular localization, making it directly relevant to cell-imaging methods.
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Technologies to measure and modulate protein subcellular localization.
This review surveys microscopy, proximity labeling, and related technologies to map and perturb protein subcellular localization, making it directly relevant to cell-imaging methods.
- Authors
- William Leineweber, Reika Tei, Anna Mäkiniemi, Alice Ting, Emma Lundberg
- Source
- PubMed
- Publication date
- 19 March 2026
- Primary category
- Imaging
- Priority
- medium
- Abstract
- How proteins localize to specific compartments, function in coordination with other biomolecules and, ultimately, contribute to diverse cellular activities are crucial questions in cell biology. Complicating the answers to these questions are multilocalizing and multifunctional proteins, whose impact on the cell depends on both spatial and temporal contexts. Therefore, contextualizing protein functions based on their subcellular localization is necessary to fully understand cell behaviours. Recent advances in instrumentation and protein labelling techniques are rapidly increasing the availability of tools, technologies and applications that measure and control protein localization and compartment-specific function. In this Review, we first discuss microscopy, mass spectrometry-based correlation profiling and proximity labelling methods that assign localizations to proteins, ranging from cellular compartments to protein-protein interactions. We next examine the available tools for manipulating protein localization and measuring the effects of these manipulations, including localization tags and bifunctional molecules. For each technology, we assess the strengths and weaknesses that ultimately determine their usefulness. We conclude with an outlook on future technological advances in the field of spatial subcellular proteomics and their potential implications for cell biology and clinical applications.
AI & biology
12Daily briefing: 'Virtual cell' simulates nearly every chemical reaction in the real thing.
Title describes a virtual-cell model simulating cellular chemistry, suggesting computational biology relevance but no abstract is available to disambiguate scope.
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Daily briefing: 'Virtual cell' simulates nearly every chemical reaction in the real thing.
Title describes a virtual-cell model simulating cellular chemistry, suggesting computational biology relevance but no abstract is available to disambiguate scope.
- Authors
- Flora Graham
- Source
- PubMed
- Publication date
- 11 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- No abstract available.
Gateway analysis reveals transient molecular programs at cell-fate transitions
Gateway analysis is a computational single-cell framework that detects rare boundary cells and transient gene programs during cell-fate transitions.
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Gateway analysis reveals transient molecular programs at cell-fate transitions
Gateway analysis is a computational single-cell framework that detects rare boundary cells and transient gene programs during cell-fate transitions.
- Authors
- Cang, H., Sun, S.
- Source
- bioRxiv
- Publication date
- 16 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- Single cell atlases have transformed our view of cell identity, but they still struggle to resolve the transient states that accompany cell fate change. These rare interface cells are outnumbered by the stable populations on either side. As a result, the molecular programs that accompany lineage transitions are hard to detect. We developed gateway analysis, a framework that identifies cells at fate boundaries and pinpoints bell and valley genes that peak or dip there. It defines cell neighborhoods from binary mutual information (BMI) in gene on/off patterns and preserves that structure in a regularized latent model. Across four single cell atlases spanning reprogramming, gastrulation, pancreatic endocrinogenesis, and kidney injury (3,696 126,578 cells), gateway analysis recovered rare boundary populations and the transient gene programs that distinguish them from their flanking states. These signals were missed by standard comparisons of stable endpoint states. They included epithelial remodeling at the late MET to iPSC interface, a gate versus basin partition of gastrulation regulators, a transient Cck enriched peak at endocrine hub entry together with a candidate BH4 associated signal at a shared endocrine hilltop, and a proteostasis program at the kidney injury boundary. Orthogonal support from optimal-transport fate probabilities, known markers, and published perturbation phenotypes indicate that gateway cells mark bona fide biological transition intervals. Gateway analysis therefore provides a practical framework for detecting rare transition state cells and the bell/valley genes that define them in single cell atlases.
AetherCell: A generative engine for virtual cell perturbation and in vivo drug discovery
AetherCell is a generative transcriptomic foundation model for virtual cell perturbation, drug-response prediction, and drug repurposing across organoids and clinical cohorts.
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AetherCell: A generative engine for virtual cell perturbation and in vivo drug discovery
AetherCell is a generative transcriptomic foundation model for virtual cell perturbation, drug-response prediction, and drug repurposing across organoids and clinical cohorts.
- Authors
- Xie, Z., Li, W., Chen, Y., Peng, Z., Xiang, L., Wang, D.
- Source
- bioRxiv
- Publication date
- 16 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- Virtual cell modeling is currently hindered by a "data-utility paradox": biological information is fragmented between context-rich clinical RNA-seq and perturbation-dense experimental assays, leading to poor predictive generalization in human contexts. Here, we introduce AetherCell, a generative foundation model that unifies these disparate domains into a shared, platform-aligned transcriptomic manifold. By implementing a specificity-driven learning framework, AetherCell successfully recovers low-frequency, mechanism-specific signals often obscured by systematic noise. Across extensive benchmarks, AetherCell demonstrates robust generalization, accurately predicting responses to unseen compounds and genetic perturbations. We show that the model effectively translates signals from simple cell lines to complex 3D organoids, achieving high-fidelity, whole-transcriptome prediction. Building on this foundational manifold, we demonstrate precise drug response prediction across biological scales-including patient-derived organoids and clinical cohorts. We also implement a phenotype-knowledge mixture-of-experts strategy for precision drug repurposing. This approach is validated by the in vivo discovery of teriflunomide for dry eye disease and dabigatran for ulcerative colitis. Together, AetherCell establishes a scalable, human-centric virtual cell framework for translational biology and accelerated drug discovery.
Illuminating cell states by a comprehensive and interpretable single cell foundation model.
Introduces a large interpretable single-cell foundation model and multimodal graph framework for biological discovery from massive cell atlases.
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Illuminating cell states by a comprehensive and interpretable single cell foundation model.
Introduces a large interpretable single-cell foundation model and multimodal graph framework for biological discovery from massive cell atlases.
- Authors
- Jue Wang, Cheng Tan, Zhangyang Gao, Sida Shao, Shiping Liu, Stan Z Li
- Source
- PubMed
- Publication date
- 16 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- Advances in single-cell sequencing have enabled AI-driven foundation models with powerful data representation. However, their practical use is limited by real-world data sparsity, heterogeneity, and poor interpretability. To overcome these, we introduce CellVQ. To enhance generalizability, we incorporate a large-scale single-cell dataset comprising 68 million cells, model parameters totaling 500 million, and challenging pretraining tasks. Notably, we introduce a Single-Cell Discretization (SCD) module that effectively represents cell embeddings, addressing data heterogeneity. For improved interpretability, the SCD module transforms high-dimensional and sparse single-cell data into a "cell code," facilitating recognition and analysis. Additionally, we also present CellVQ-Graph, a plug-and-play tool that integrates CellVQ's features with multimodal data (genes, cell communication, annotations) to build a knowledge graph for biological discovery. Extensively evaluated, CellVQ outperforms strong baselines in all downstream tasks, and also uncovered intriguing biological phenomena with compelling explanations. CellVQ aspires to serve as a truly applicable and generalizable AI tool for the cell biology community.
A network-based deep learning model integrating subclonal architecture for therapy response prediction in cancer
SubNetDL uses deep learning with subclonal mutation architecture and interaction networks to predict cancer therapy response and nominate biomarkers.
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A network-based deep learning model integrating subclonal architecture for therapy response prediction in cancer
SubNetDL uses deep learning with subclonal mutation architecture and interaction networks to predict cancer therapy response and nominate biomarkers.
- Authors
- Kim, S., Ha, D., Nam, A.-r., Cheong, S., Lee, J., Kim, S., Park, S.
- Source
- bioRxiv
- Publication date
- 17 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- Predicting treatment response remains challenging in oncology, particularly given the growing diversity of therapeutic options. Despite efforts using gene expression signatures, or integrative multi-omics frameworks, robust and interpretable biomarkers remain limited. We present SubNetDL, a deep learning framework that integrates subclonal mutation profiles and protein-protein interaction networks via network propagation. Unlike condition-specific approaches, SubNetDL leverages somatic mutations alone and is applicable across diverse cancer types and treatment modalities. Applied to ten TCGA cancer-drug combinations, SubNetDL achieved consistently strong performance (median AUROC = 0.74) and successfully generalized to two independent immunotherapy datasets (median AUROC = 0.77). Importantly, it identified candidate biomarker genes with treatment-specific relevance. SubNetDL prioritized genes that were not central in the network, highlighting its ability to capture context-specific patterns beyond traditional metrics. In conclusion, our approach offers a robust and interpretable framework for identifying predictive biomarkers and stratifying patients based on mutation profiles and network context.
CellVoyager: AI CompBio agent generates new insights by autonomously analyzing biological data.
Describes an LLM-based agent that autonomously analyzes scRNA-seq studies and generates biologically meaningful hypotheses and findings.
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CellVoyager: AI CompBio agent generates new insights by autonomously analyzing biological data.
Describes an LLM-based agent that autonomously analyzes scRNA-seq studies and generates biologically meaningful hypotheses and findings.
- Authors
- Samuel Alber, Bowen Chen, Eric Sun, Alina Isakova, Aaron J Wilk, James Zou
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- Modern biology increasingly relies on complex, high-dimensional datasets such as single-cell RNA sequencing (scRNA-seq), which present a vast space of potential hypotheses. Systematically exploring this space is often impractical, as scRNA-seq analyses are time-consuming and require substantial computational and domain expertise. To address this challenge, we introduce CellVoyager, an AI agent built on large language models that autonomously generates and implements scRNA-seq analyses within a Jupyter notebook environment. We evaluate CellVoyager on CellBench, a benchmark of 76 published scRNA-seq studies, where it outperforms GPT-4o and o3-mini by up to 23% in predicting which analyses authors ultimately conducted, given only the papers' background sections. Across three in-depth case studies, CellVoyager generated novel findings in COVID-19, cell-cell communication and aging that experts consistently rated as creative and scientifically sound. These results demonstrate CellVoyager's potential to accelerate computational biology and uncover missing insights by autonomously analyzing biological data at scale.
AlphaFold hits 'next level': the AI database now includes protein pairing.
This appears to be a news item about AlphaFold protein-pair prediction rather than a primary AI-for-biology research article, and no abstract is available.
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AlphaFold hits 'next level': the AI database now includes protein pairing.
This appears to be a news item about AlphaFold protein-pair prediction rather than a primary AI-for-biology research article, and no abstract is available.
- Authors
- Ewen Callaway
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- AI & biology
- Priority
- low
- Abstract
- No abstract available.
Pushing the boundaries of autonomous biological discovery.
Commentary on autonomous biological discovery in Nature Methods, clearly AI-related but lacking an abstract for detailed assessment.
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Pushing the boundaries of autonomous biological discovery.
Commentary on autonomous biological discovery in Nature Methods, clearly AI-related but lacking an abstract for detailed assessment.
- Authors
- Juexiao Zhou, Xiaonan He, Kai Kang, Xin Gao
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- AI & biology
- Priority
- low
- Abstract
- No abstract available.
A foundation model for nucleotide sequences.
Annotation-aware nucleotide foundation model trained across species improves genomics and transcriptomics prediction tasks.
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A foundation model for nucleotide sequences.
Annotation-aware nucleotide foundation model trained across species improves genomics and transcriptomics prediction tasks.
- Authors
- Xilin Shen, Jia Xin Li, Meng Yang, Lei Shi, Kexin Chen, Xiangchun Li
- Source
- PubMed
- Publication date
- 19 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- Foundation models have demonstrated exceptional performance across diverse downstream tasks. However, in genomics and transcriptomics, the integration of nucleotide sequences with their rich annotations remains underexplored, potentially limiting model generalizability across species and biological contexts. Here, we introduce OmniNA (Omni-applicable foundation model for nucleic acid), a self-supervised generative foundation model trained on 91.7 million nucleotide sequences and their associated annotations, totaling 1076.2 billion bases and 197 million words spanning diverse species. Unlike most existing approaches that focus solely on functional genomic element recognition, OmniNA jointly learns from both sequences and annotations, leveraging their complementarity to enhance semantic understanding and representation learning. We demonstrate that OmniNA captures sequence grammar and annotation semantics, facilitating robust transfer across nucleotide-level tasks. OmniNA can be fine-tuned under natural language paradigms and achieves state-of-the-art or competitive performance in 23 benchmarks, including sequence detection and species classification. Its learned representations also help reveal mutation effects on DNA and RNA processing. We release the model publicly as a community resource for genomics and transcriptomics research. OmniNA represents a step toward advancing foundational modeling by integrating annotation-aware learning, offering a powerful tool for genomics and transcriptomics research.
BioReason-Pro: Advancing Protein Function Prediction with Multimodal Biological Reasoning
Presents a multimodal reasoning model for protein function prediction that integrates sequence, structure, ontology, and interaction information.
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BioReason-Pro: Advancing Protein Function Prediction with Multimodal Biological Reasoning
Presents a multimodal reasoning model for protein function prediction that integrates sequence, structure, ontology, and interaction information.
- Authors
- Fallahpour, A., Seyed-Ahmadi, A., Idehpour, P., Ibrahim, O., Gupta, P., Naimer, J., Zhu, K., Shah, A., Ma, S., Adduri, A., Güloglu, T., Liu, N., Cui, H., Jain, A., de Castro, M., Fallahpour, A., Cembellin-Prieto, A., Stiles, J. S., Nemcko, F., Nevue, A. A., Moon, H. C., Sosnick, L., Markham, O., Duan, H., Lee, M. Y. Y., Salvador, A. F. M., Maddison, C. J., Thaiss, C. A., Ricci-Tam, C., Plosky, B. S., Burke, D. P., Hsu, P. D., Goodarzi, H., Wang, B.
- Source
- bioRxiv
- Publication date
- 20 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- Protein function annotation is fundamental to understanding biological mechanisms, designing therapeutics, and advancing biomedical research. Current computational methods either rely on shallow sequence similarity or treat function prediction as isolated classification tasks, failing to capture the integrative reasoning across sequence, structure, domains, and interactions that expert biologists perform to infer function. We introduce BioReason-Pro, the first multimodal reasoning large language model (LLM) for protein function prediction that integrates protein embeddings with biological context to generate structured reasoning traces. A key input into BioReason-Pro is the set of GO term predictions made by GO-GPT, our autoregressive transformer that captures hierarchical and cross-aspect dependencies of GO terms. BioReason-Pro is trained via supervised fine-tuning on synthetic reasoning traces generated by GPT-5 for over 130K proteins and further optimized through reinforcement learning. It achieves 73.6% Fmax on GO term prediction and an LLM judge score of 8/10 on functional summaries, substantially outperforming previous methods. Evaluations with human protein experts show that BioReason-Pro annotations are preferred over ground truth UniProt annotations in 79% of cases. Remarkably, BioReason-Pro de novo predicted experimentally confirmed binding partners with per-residue attention localizing to the exact contact residues resolved in cryo-EM structures of those complexes. Together, GO-GPT and BioReason-Pro establish a framework for protein function prediction that combines precise ontology modeling with interpretable biological reasoning.
Open and sustainable AI: challenges, opportunities and the road ahead in the life sciences.
This Perspective addresses reproducibility, reuse and sustainability of AI methods across the life sciences and provides practical guidance for open AI deployment.
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Open and sustainable AI: challenges, opportunities and the road ahead in the life sciences.
This Perspective addresses reproducibility, reuse and sustainability of AI methods across the life sciences and provides practical guidance for open AI deployment.
- Authors
- Gavin Farrell, Eleni Adamidi, Rafael Andrade Buono, Mihail Anton, Omar Abdelghani Attafi, Salvador Capella Gutierrez, Emidio Capriotti, Leyla Jael Castro, Davide Cirillo, Lisa Crossman, Christophe Dessimoz, Alexandros Dimopoulos, Raúl Fernández-Díaz, Styliani-Christina Fragkouli, Carole Goble, Wei Gu, John M Hancock, Alireza Khanteymoori, Tom Lenaerts, Fabio G Liberante, Peter Maccallum, Alexander Miguel Monzon, Magnus Palmblad, Lucy Poveda, Ovidiu Radulescu, Denis C Shields, Shoaib Sufi, Thanasis Vergoulis, Fotis Psomopoulos, Silvio C E Tosatto
- Source
- PubMed
- Publication date
- 20 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- Artificial intelligence (AI) has seen transformative breakthroughs in the life sciences, expanding possibilities to interpret biological information at an unprecedented capacity. To maximize return on growing investments and accelerate progress, it is urgent to address long-standing research challenges arising from the rapid adoption of AI methods. We review the erosion of trust in AI outputs driven by poor reusability and reproducibility, and highlight their impact on environmental sustainability. Furthermore, we discuss the fragmented components of the AI ecosystem and lack of guiding pathways to support open and sustainable AI model development. In response, this Perspective introduces practical open and sustainable AI recommendations mapped to over 300 ecosystem components and provides guiding implementation pathways. Our work connects researchers with relevant AI resources, facilitating the implementation of sustainable, reusable and reproducible AI. Built upon community consensus and aligned to existing efforts, these outputs will aid future policy development and structured pathways for guiding AI implementation.
Generative AI in structure-based drug discovery.
This review surveys generative AI methods that design protein-binding compounds from three-dimensional target structures for drug discovery.
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Generative AI in structure-based drug discovery.
This review surveys generative AI methods that design protein-binding compounds from three-dimensional target structures for drug discovery.
- Authors
- Zhuoya Zhong, Jacob D Durrant
- Source
- PubMed
- Publication date
- 21 March 2026
- Primary category
- AI & biology
- Priority
- medium
- Abstract
- Generative artificial intelligence is reshaping how researchers discover protein-binding compounds and develop them into drug candidates. Unlike traditional methods that screen existing molecules, structure-based generative AI designs novel compounds tailored to a protein's three-dimensional binding pocket. This review outlines how these approaches are applied in early drug discovery, focusing on general principles. We categorize methods according to their generative modeling paradigms and their strategies for using structural data to guide molecular design, distinguishing de novo incremental builders from models that generate full structures. We also survey lead-optimization techniques, highlighting a recent shift toward generation-driven medicinal chemistry.
Other biology
9The kinase inhibitor palbociclib binds to HIV TAR RNA with very low nanomolar affinity and exquisite specificity.
This molecular virology study finds that palbociclib binds HIV TAR RNA with very high specificity and blocks recruitment of the viral super elongation complex.
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The kinase inhibitor palbociclib binds to HIV TAR RNA with very low nanomolar affinity and exquisite specificity.
This molecular virology study finds that palbociclib binds HIV TAR RNA with very high specificity and blocks recruitment of the viral super elongation complex.
- Authors
- Ravinth Reddy Ramireddy, Matthew D Shortridge, Venkata Vidalala, Bhawna Chaubey, Changyan Tang, Gregory L Olsen, Gabriele Varani
- Source
- PubMed
- Publication date
- 24 February 2026
- Primary category
- Other biology
- Priority
- medium
- Abstract
- We report that the kinase inhibitor Palbociclib is a very low nanomolar ligand for the HIV-1 TAR, a paradigmatic 'difficult-to-drug' RNA. Binding is exquisitely specific, since simple chemical modifications of the small molecule, single nucleotide substitutions, or base pair inversions abolish high affinity binding, and is independent from kinase inhibition. Palbociclib also inhibits recruitment of the super elongation complex (SEC) at low nM concentration, the long-standing aim of Tat-TAR targeting efforts. Thus, we demonstrate that low nM affinity, specificity, and potent biochemical activity against 'undruggable' RNAs can be readily found within the chemical space of drugs. The structural basis for binding and biochemical activity is demonstrated in the accompanying manuscript.
Daily briefing: Genomes shake up the shark family tree.
Briefing title points to comparative genomics and shark evolution rather than cell biology, and no abstract is provided.
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Daily briefing: Genomes shake up the shark family tree.
Briefing title points to comparative genomics and shark evolution rather than cell biology, and no abstract is provided.
- Authors
- Flora Graham
- Source
- PubMed
- Publication date
- 13 March 2026
- Primary category
- Other biology
- Priority
- low
- Abstract
- No abstract available.
Aurora A kinase activation contributes to the fibrotic phenotype in Systemic Sclerosis through primary cilia shortening
The study shows that aberrant Aurora A activity shortens primary cilia and drives fibroblast activation and fibrosis in systemic sclerosis.
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Aurora A kinase activation contributes to the fibrotic phenotype in Systemic Sclerosis through primary cilia shortening
The study shows that aberrant Aurora A activity shortens primary cilia and drives fibroblast activation and fibrosis in systemic sclerosis.
- Authors
- Wells, R. A., Caballero-Ruiz, B., Mulipa, P., Timmis, A. J., Teves, M. E., Varga, J., Del Galdo, F., Ross, R. L., Riobo-Del Galdo, N. A.
- Source
- bioRxiv
- Publication date
- 16 March 2026
- Primary category
- Other biology
- Priority
- medium
- Abstract
- Background: Systemic sclerosis (SSc) is a severe autoimmune disease characterised by progressive fibrosis driven by fibroblast activation. Primary cilia, key hubs for profibrotic signalling, are markedly shortened in SSc fibroblasts, but the mechanisms underlying this phenotype remain unclear. This study aimed to define the signalling pathways responsible for primary cilia shortening and fibroblast activation in SSc. Methods: Primary dermal fibroblasts from SSc patients and healthy controls were analysed for cilia incidence and length by immunofluorescence, profibrotic marker expression by qPCR, and contractility using gel contraction assays. Cells were treated with TGF{beta}1 and pharmacological inhibitors targeting AURKA, HDAC6, ROCK2, and Smad3 signalling. CAV1-silenced fibroblasts were used as an in vitro model of SSc. Results: Maintenance of the constitutively short primary cilia phenotype in SSc fibroblasts did not require active TGF{beta} signalling. However, TGF{beta}1 induced reversible cilia shortening in healthy fibroblasts and further shortened cilia in SSc fibroblasts to a similar final length, mediated by Rho/ROCK2 rather than canonical Smad3-dependent signalling. Constitutive cilia shortening in SSc was driven by aberrant AURKA activity upstream of HDAC6, promoting ciliary disassembly. Pharmacological inhibition of AURKA or HDAC6 selectively elongated cilia in SSc fibroblasts, reduced profibrotic marker expression, and abrogated fibroblast contractility. CAV1-silenced fibroblasts similarly exhibited constitutive cilia shortening that was reversed by AURKA inhibition without affecting healthy cells. Conclusions: Aberrant activation of the AURKA/HDAC6 axis maintains short primary cilia and promotes fibroblast activation in SSc. These findings reveal a mechanistic link between cilia morphology and fibrosis and identify AURKA as a potential therapeutic target for SSc-associated tissue remodelling.
Ribosome-associated quality control and related mechanisms.
Review summarizing ribosome-associated quality control mechanisms that protect translation and proteostasis and connect to disease.
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Ribosome-associated quality control and related mechanisms.
Review summarizing ribosome-associated quality control mechanisms that protect translation and proteostasis and connect to disease.
- Authors
- Toshifumi Inada
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- Other biology
- Priority
- medium
- Abstract
- Ribosome-associated quality control (RQC) safeguards translation by detecting and resolving collided ribosomes and triaging their nascent chains. This Review outlines mechanisms, crosstalk and disease implications of RQC cascades and presents RQC as a 'first responder' that prevents escalation to global stress responses and provides protection against proteostasis collapse.
A single-cell CRISPR screen defines a gene regulatory network governing human pluripotency in primed and naive cells.
A pooled single-cell CRISPR screen maps the transcription factor network controlling self-renewal and lineage restriction in human pluripotent stem cells.
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A single-cell CRISPR screen defines a gene regulatory network governing human pluripotency in primed and naive cells.
A pooled single-cell CRISPR screen maps the transcription factor network controlling self-renewal and lineage restriction in human pluripotent stem cells.
- Authors
- Gal Keshet, Nissim Benvenisty
- Source
- PubMed
- Publication date
- 17 March 2026
- Primary category
- Other biology
- Priority
- medium
- Abstract
- Human pluripotent stem cells (hPSCs) can self-renew indefinitely and differentiate into all three embryonic germ layers. We previously defined the essentialome of hPSCs using a genome-wide CRISPR screen, but the functions of each gene remain obscure. Here, we used a pooled single-cell CRISPR screen to investigate pluripotent-specific essential transcription factors (TFs). We found that most TFs form a highly interconnected gene regulatory network (GRN) that governs key aspects of pluripotency, including self-renewal, differentiation, survival, and transposable element expression. Interestingly, we identify multiple TFs that act as lineage-specific gatekeepers, blocking exit from pluripotency, and others that inhibit pluripotency, potentially balancing self-renewal and differentiation responsiveness. Finally, perturbing the GRN in naive hPSCs revealed both conserved and state-specific regulatory roles relative to primed cells. Altogether, our analysis defines an extended GRN for human pluripotency, offering insights into early human development. These findings may inform strategies to improve hPSC-based disease models and regenerative therapies.
The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation.
Mechanistic molecular biology paper defines how the ZSWIM8-CUL3 E3 ligase recognizes Argonaute complexes to drive target-directed microRNA degradation.
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The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation.
Mechanistic molecular biology paper defines how the ZSWIM8-CUL3 E3 ligase recognizes Argonaute complexes to drive target-directed microRNA degradation.
- Authors
- Jakob Farnung, Elena Slobodyanyuk, Peter Y Wang, Lianne W Blodgett, Daniel H Lin, Susanne von Gronau, Brenda A Schulman, David P Bartel
- Source
- PubMed
- Publication date
- 18 March 2026
- Primary category
- Other biology
- Priority
- medium
- Abstract
- MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to form complexes that down-regulate target RNAs, including messenger RNAs from most human genes1-3. Within each complex, the miRNA pairs to target RNAs, and AGO provides effector function while also protecting the miRNA from cellular nucleases2-5. Although much is known about miRNA-directed gene regulation, less is known about how miRNAs themselves are regulated. One pathway that regulates miRNAs involves unusual targets called 'trigger' RNAs, which reverse the canonical regulatory logic and instead down-regulate miRNAs6-9. This target-directed miRNA degradation (TDMD) is thought to require a cullin-RING E3 ligase because it depends on the cullin protein CUL3 and other ubiquitylation components, including the BC-box protein ZSWIM8 (refs. 10,11). ZSWIM8 is required for murine perinatal viability and for destabilization of most short-lived miRNAs, which suggests biological importance of TDMD11-13. Here, biochemical and cellular assays establish AGO binding and polyubiquitylation by the ZSWIM8-CUL3 E3 ligase as the key regulatory steps of TDMD, and thereby define a unique cullin-RING E3 ligase class. Cryogenic electron microscopy analyses show ZSWIM8 recognizing distinct AGO and RNA conformations shaped by pairing of the miRNA to the trigger. Specificity of AGO ubiquitylation is established through generalizable RNA-RNA, RNA-protein and protein-protein interactions. The substrate features recognized by the E3 ligase do not conform to a conventional degron14,15 but instead establish a two-RNA-factor authentication mechanism for specifying a protein ubiquitylation substrate.
Distinct Cdc42 protein levels differentially regulate polarized growth and cell fusion in Schizosaccharomyces pombe.
Fission yeast cell-biology study showing mating and cell fusion require higher Cdc42 levels than mitotic polarized growth and reveal a switch-like response.
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Distinct Cdc42 protein levels differentially regulate polarized growth and cell fusion in Schizosaccharomyces pombe.
Fission yeast cell-biology study showing mating and cell fusion require higher Cdc42 levels than mitotic polarized growth and reveal a switch-like response.
- Authors
- Sajjita Saha, Aiswarya Sajeevan, Laura Merlini, Vincent Vincenzetti, Sophie G Martin
- Source
- PubMed
- Publication date
- 19 March 2026
- Primary category
- Other biology
- Priority
- medium
- Abstract
- The conserved Cdc42 GTPase is a key driver of symmetry breaking and polarized growth, forming zones of activity that locally recruit effectors to organize the cytoskeleton and polarize secretion. Here, we show that Cdc42 also functions in cell-cell fusion during Schizosaccharomyces pombe sexual reproduction, but concentrates at the fusion site through mechanisms distinct from those proposed in Saccharomyces cerevisiae. Notably, the cdc42-mCherrySW allele, which is functional for cell polarization and has been used across organisms for dynamic studies, exhibits a strong fusion defect. These cells block fusion before cell wall digestion but after actin fusion focus formation, indicating that Cdc42 is required to translate the vesicle cluster into polarized cargo delivery. We trace the defect to instability of Cdc42-mCherrySW and demonstrate that mating and cell fusion require higher Cdc42 protein levels than mitotic polarized growth. Remarkably, by constructing an allelic series driving Cdc42 expression over a 5-fold range, we discover that mitotic polarized growth responds linearly to Cdc42 protein levels, whereas mating exhibits a sharp switch-like response. We further trace this all-or-none response to pheromone-induced polarized growth. Thus, polarized growth in response to intrinsic or extrinsic cues exhibits distinct requirements to Cdc42 protein levels.
MDM2 Inhibition with Alrizomadlin (APG-115) in TP53 wild-type salivary gland cancers: a phase I clinical trial.
Phase I clinical trial of the MDM2 inhibitor alrizomadlin in TP53 wild-type salivary gland cancers, mainly a specialized oncology treatment study.
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MDM2 Inhibition with Alrizomadlin (APG-115) in TP53 wild-type salivary gland cancers: a phase I clinical trial.
Phase I clinical trial of the MDM2 inhibitor alrizomadlin in TP53 wild-type salivary gland cancers, mainly a specialized oncology treatment study.
- Authors
- Alexander T Pearson, Jameel Muzaffar, Kedar Kirtane, Emily Bellile, Krithika Suresh, Ari J Rosenberg, Francis Worden, Christine H Chung, Everett Vokes, J Chad Brenner, Apurva Bhangale, Jon McHugh, Kristy Warner, Felipe Nor, Jacques E Nor, Keri Innes, Yifan Zhai, Tommy Fu, Paul L Swiecicki
- Source
- PubMed
- Publication date
- 19 March 2026
- Primary category
- Other biology
- Priority
- low
- Abstract
- Preclinical studies have evaluated murine double minue 2 (MDM2) inhibitors as a treatment for adenoid cystic carcinoma (ACC), but clinical trials are lacking. This phase I trial (NCT03781986) assesses the safety and antitumor activity of an oral MDM2 inhibitor, alrizomadlin (APG-115), +/- carboplatin in TP53 wild type unresectable recurrent/metastatic salivary gland cancers (R/M SGC) with a planned 1:1 randomization to carboplatin chemotherapy. The co-primary endpoints are determination of dose-limiting toxicity (DLT) and response rate (RR) for alrizomadlin monotherapy +/- carboplatin. Secondary endpoints include safety, survival, and RR by tumor histology. After enrollment of 4 patients to combination therapy, the trial was modified to a single arm study of alrizomadlin monotherapy due to excess toxicity. 1 DLT was seen in the combination arm, all patients had ≥ G3 treatment related adverse events (TRAE). 37 patients were enrolled to alrizomadlin monotherapy. 3 DLTs were encountered, 67% of patients had ≥ G3 TRAE. The RR was 15% with median progression free survival 10.5 months. These findings demonstrate encouraging tolerability of alrizomadlin monotherapy with antitumor activity in patients with TP53 wild type SGC, especially ACC.
Protein overabundance is driven by growth robustness.
The study shows that many essential bacterial proteins are expressed above the minimum required level because overabundance improves robustness of cell growth.
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Protein overabundance is driven by growth robustness.
The study shows that many essential bacterial proteins are expressed above the minimum required level because overabundance improves robustness of cell growth.
- Authors
- H James Choi, Teresa W Lo, Kevin J Cutler, Dean Huang, William Ryan Will, Paul A Wiggins
- Source
- PubMed
- Publication date
- 20 March 2026
- Primary category
- Other biology
- Priority
- medium
- Abstract
- Protein expression levels optimize cell fitness: Too low an expression level of essential proteins will slow growth by compromising essential processes, whereas overexpression slows growth by increasing the metabolic load. This trade-off naïvely predicts that cells maximize their fitness by sufficiency, expressing just enough of each essential protein for function. We test this prediction in the naturally competent bacterium Acinetobacter baylyi by characterizing the proliferation dynamics of essential-gene knockouts at a single-cell scale (by imaging) as well as at a genome-wide scale. In these experiments, cells proliferate for multiple generations as target protein levels are diluted from their endogenous levels. This approach facilitates a proteome-scale analysis of the fitness landscape with respect to protein abundance. We find that most essential proteins are subject to a threshold-like fitness landscape: Growth is independent of protein abundance above a critical threshold and arrests below that threshold. We have recently analyzed the implications of this landscape for growth robustness. Confirming signature predictions of this model, we find that (i) roughly 70% of essential proteins are overabundant, (ii) overabundance increases as the expression level decreases, and (iii) the lowest abundance proteins are in vast excess (>10×) of what is required for growth in the typical cell. These results reveal that robustness plays a fundamental role in determining the expression levels of essential genes and that overabundance is a key mechanism for ensuring robust growth.
Not biology
3PhD students are turning to side hustles to make ends meet, finds Nature poll.
Nature news item about PhD students taking side jobs concerns academic workforce issues rather than biology research.
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PhD students are turning to side hustles to make ends meet, finds Nature poll.
Nature news item about PhD students taking side jobs concerns academic workforce issues rather than biology research.
- Authors
- Katie Kavanagh
- Source
- PubMed
- Publication date
- 16 March 2026
- Primary category
- Not biology
- Priority
- low
- Abstract
- No abstract available.
An easy way to improve lab meetings.
Opinion piece about lab-meeting culture and scientific careers rather than biological research.
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An easy way to improve lab meetings.
Opinion piece about lab-meeting culture and scientific careers rather than biological research.
- Authors
- Cara Glynn, Tiago Monteiro
- Source
- PubMed
- Publication date
- 18 March 2026
- Primary category
- Not biology
- Priority
- low
- Abstract
- Sharing positive and negative experiences at lab meetings can make a career in science a little less hard, a little more pleasant, and a little more human.
Agentic AI and the next intelligence explosion.
Commentary on agentic AI and intelligence growth, with no biological application described and no abstract available.
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Agentic AI and the next intelligence explosion.
Commentary on agentic AI and intelligence growth, with no biological application described and no abstract available.
- Authors
- James Evans, Benjamin Bratton, Blaise Agüera Y Arcas
- Source
- PubMed
- Publication date
- 19 March 2026
- Primary category
- Not biology
- Priority
- low
- Abstract
- No abstract available.