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.

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Week 44, 2026 · 26 Oct 2026–1 Nov 2026

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Cell cycle

Stepwise pairing and fast transition regulated by recombination drive meiotic chromosome interactions.

This paper uses live-cell 3D time-lapse imaging and recombination mutants to reveal a stepwise, recombination-regulated mechanism of meiotic homologous chromosome pairing and synaptonemal complex formation in mouse seminiferous tubules.

Authors: Luciana P de Almeida, V Meg Butler, Leandra Marin, Katarzyna P Nowak, Marcin Ostoja-Helczynski, Cole Ragsdale, Monika K Kawecka, Ky'ara D Carr, Paula E Cohen, Michael E Dresser, Sean M Burgess, Elizabeth H Finn, Roberto J Pezza
Source: PubMed
Publication date: 24 September 2026
Primary category: Cell cycle
Priority: high
Abstract: Maternal and paternal homologous chromosomes recognize each other and pair during meiosis to ensure accurate chromosome segregation. However, the mechanisms that drive chromosome pairing and their regulation remain poorly understood. To investigate this, we develop a fluorescence reporter-operator system based on the lac operator-lac repressor system, enabling real-time observation of specific genomic loci in live mouse seminiferous tubule tissues. Using 3D time-lapse imaging, we visualize and quantify telomere-led rapid chromosome movements and homologous chromosome pairing. Our results reveal that homologous chromosomes achieve pairing in discrete, well-defined steps. Initially, at the onset of meiosis, chromosomes come together from widely separated positions at an average distance of 4.8 µm, followed by an intermediate stage of pairing at an average distance of 1.7 µm. Finally, close pairing is achieved at an average distance of 0.7 µm, which correlates with the establishment of the synaptonemal complex along the homologs. Further analysis of inter-spot distance dynamics reveals a relatively rapid transition from an initial, widely separated distance to an intermediate stage of chromosome pairing. Complementary studies of recombination mutants using 3D DNA fluorescence in situ hybridization (FISH) on whole-mounted tubules and immunofluorescence on chromosome spreads reveal that double-strand breaks and early recombination events trigger the transition from a widely separated to an intermediate inter-homolog distance. Subsequently, close pairing requires crossover maturation intermediates and SYCP1/synaptonemal complex. Together, our findings reveal a recurring mechanism of meiotic chromosome pairing and how it is regulated by critical meiotic processes in higher eukaryotes.

Cep57 organizes pericentriolar material through dual architectural modules and prevents human mosaic variegated aneuploidy.

Mechanistic study of Cep57 as a centrosomal architectural organizer linking centriolar microtubules to PCM for centriole biogenesis, explaining mosaic variegated aneuploidy through chromosome segregation defects.

Authors: Jong Il Ahn, Jung-Eun Park, Hye-Yeoung Yun, Yan Zeng, Klara Kirsch, Vipin Kumar, Bonsu Ku, Arlene Bartolome, Harsha Ravishankar, Ruchi Bhardwaj, Rodolfo Ghirlando, Mahaiwon Shadang, Mohamadreza Fazel, David A Ball, Jessica Matthias, Seung Jun Kim, Neerja Gupta, Jayanth Kumar Palanichamy, Tatiana S Karpova, Kyung S Lee
Source: PubMed
Publication date: 30 September 2026
Primary category: Cell cycle
Priority: high
Abstract: Mosaic variegated aneuploidy (MVA) is a developmental disorder associated with chromosome segregation defects. Mutations in the centrosomal protein Cep57 cause MVA2 syndrome, yet the molecular basis of Cep57 function has remained unclear. Here, using MINFLUX nanoscopy, structural biology, biochemical approaches, and analyses of patient-derived cells, we show how Cep57 organizes the inner pericentriolar material (PCM) to support centriole biogenesis. We show that Cep57 acts as a molecular bridge between centriolar microtubules and the PCM through two architecturally distinct interactions. Its oligomeric C-terminus anchors to centriolar microtubules, whereas its dimeric N-terminus engages Cep63 through a conserved bundle-like interaction, thereby linking the Cep63-Cep152 platform to the centriole and recruiting Plk4 and other components required for procentriole formation. Analysis of primary T lymphocytes from MVA2 patients carrying the Cep63-binding-defective CEP57∆exon 3 mutation reveals a predominant centriole-duplication defect accompanied by minor centriole amplification, likely resulting from disorganized PCM-induced premature centriole disengagement. Our findings show Cep57 as a central architectural organizer that couples centriolar microtubules to the molecular machinery driving centriole biogenesis, providing a mechanistic framework for understanding centrosome dysfunction and aneuploidy-associated diseases.

CCAN forms the spherical shell-like structure in interphase kinetochores.

Structural and mechanistic study of CCAN organization in interphase kinetochores, directly relevant to core chromosome segregation and kinetochore biology.

Authors: Yuji Sakai, Mariko Ariyoshi, Yasuhiro Hirano, Yutaka Mahana, Aussie Suzuki, Toru Hirota, Masashi Tachikawa, Tatsuo Fukagawa
Source: PubMed
Publication date: 21 October 2026
Primary category: Cell cycle
Priority: high
Abstract: The kinetochore is an essential structure for the faithful chromosome segregation during mitosis. The 16-protein complex known as the constitutive centromere-associated network (CCAN) localizes the centromere throughout the cell cycle and forms the basis of the kinetochore. Although cryo-electron microscopy has provided a structural model of an individual CCAN unit, how multiple CCAN units are organized within cells remains unclear. Here, using in silico and in vivo analyses, we demonstrate that multiple CCAN units form a spherical shell-like structure in interphase DT40 kinetochores. CENP-T and CENP-N localize to the CCAN shell, whereas the CENP-C cupin domain clusters at the center. Molecular dynamics simulations of CCAN assembly suggest that CENP-C-DNA interactions constrain the orientation of CCAN units, supporting a spherical shell-like organization via CENP-C oligomerization. Super-resolution imaging reveals the spherical shell-like structure at DT40 kinetochores, and CENP-C knockout or expression of a CENP-C DNA binding deficient mutant abolishes the structure, consistent with the simulation-derived model. These findings provide important insights into the spatial organization of functional kinetochores within cells.

MASTL Kinase Mediates the DNA Replication Stress Response Through PP2A/B55 Phosphatase Modulation.

The paper reveals that the MASTL-ENSA-PP2A/B55 pathway, classically known for mitotic control, is also activated during S-phase to promote replication fork progression, restart, and new origin firing under replication stress, substantially revising the mechanistic understanding of this core cell-cycle module.

Authors: Odjo G Gouttia, Fengqi Zhang, Jing Zhao, Feifei Wang, Ling Wang, Gregory G Oakley, Li Lan, Aimin Peng
Source: PubMed
Publication date: 21 October 2026
Primary category: Cell cycle
Priority: high
Abstract: MASTL kinase promotes mitosis by inhibiting PP2A-B55 through ENSA/ARPP19 phosphorylation. Our analyses of cancer datasets support the involvement and diagnostic/prognostic potential of the MASTL-ENSA-PP2A/B55 module. In head and neck and other cancers, increased MASTL/ENSA or reduced B55 is associated with resistance to multiple chemotherapeutic agents, including anti-replication drugs. Experimentally, MASTL enhances cellular tolerance by promoting replication fork progression under stress, supporting fork restart, and promoting new origin firing. These effects require PP2A/B55 suppression, whereas B55 upregulation reduces stalled fork recovery and new origin firing in fiber assays, consistent with increased sensitivity to replication stress. Phosphoproteomics identifies replication factors, including RPA, MCM, and DNA polymerases, as potential downstream targets. RPA32 functions as a key effector, with its phospho-deficient mutant showing impaired replication dynamics. Furthermore, replication stress reduces RPA-associated phosphatase activity, and induces a MASTL-dependent ENSA-PP2A interaction during S-phase. Collectively, our findings indicate that the mitotic MASTL-ENSA-PP2A/B55 pathway is partially activated in response to replication stress, promoting the replication stress response, and conferring therapeutic resistance.

WEE1 opposes APC/CCDH1 activity to promote S phase entry.

WEE1 opposes APC/C-CDH1 to promote G0-to-S phase re-entry by phosphorylating CDH1, revealing a novel cell-cycle control mechanism with direct implications for WEE1 inhibitor therapy.

Authors: Luc-Alban Vuillemenot, Lucas G Morales, Calin-Mihai Dragoi, Betheney R Pennycook, Edward Harris, Liuyang C Lin, William A Weston, Jade-Ellen Brown, Emma Graham, Leelou Moulin, Ivan Andrew, Georgia Roumelioti, Alex Montoya, Laurence Game, George R Young, Keshava K Datta, Pavel Shliaha, Béla Novák, Hiroyuki Yamano, Alexis R Barr
Source: PubMed
Publication date: 21 October 2026
Primary category: Cell cycle
Priority: high
Abstract: WEE1 phosphorylates and inhibits the activity of cyclin-dependent kinases to prevent mitotic entry and establish a G2 DNA damage checkpoint1-3. Consequently, WEE1 inhibitors have been developed to be synthetically lethal in TP53-mutated tumours that become reliant on this WEE1-mediated checkpoint, and such inhibitors are undergoing clinical trials. However, WEE1 inhibitors also have efficacy in TP53-wild-type tumours, and many trials have been terminated owing to high levels of toxic side effects, suggesting that WEE1 has unknown functions. Here we show that WEE1 promotes cell cycle re-entry from quiescence (G0) by opposing the activity of the E3 ubiquitin ligase, anaphase-promoting complex-cyclosome bound to CDH1 (APC/CCDH1). WEE1 phosphorylates CDH1 (FZR1) at key residues that mediate the interaction between CDH1 and APC/C. Cells with loss of function of WEE1 during G0/G1 have delayed S phase entry, impaired G1/S transition, abnormal S phase accumulation of cyclin-dependent kinase inhibitor p21Cip1/Kip1 and a p21-dependent G2 arrest. Reduced expression of APC/CCDH1 or p21 renders cells more sensitive to acute WEE1 inhibition, and both pathways are downregulated in cells with acquired WEE1 inhibitor resistance. These results reveal a mechanism of cell cycle control that has implications for how WEE1 inhibitors should be used in the clinic.

Activator mimicry by PP6 regulatory subunits directs Aurora A dephosphorylation in mitosis.

Mechanistic study of PP6 regulatory subunits directing Aurora A dephosphorylation during mitotic spindle assembly, revealing activator mimicry and PLK1 competition.

Authors: Tomoaki Sobajima, Gege Yang, Josip Ahel, Elena Poser, Ulrike Gruneberg, Francis A Barr
Source: PubMed
Publication date: 21 October 2026
Primary category: Cell cycle
Priority: high
Abstract: Aurora A kinase is a conserved regulator of mitotic spindle assembly whose activity must be precisely balanced to ensure genome stability. Its activation at centrosomes and spindle microtubules is promoted by CEP192, TACC3 and TPX2, and counteracted by protein phosphatase 6 (PP6), which dephosphorylates the Aurora A T-loop. PP6 forms three holoenzymes defined by regulatory subunits PPP6R1-R3, yet how these confer substrate recognition and regulation is poorly understood. Here, we identify a phenylalanine-rich motif (A-box), present in PPP6R2 and PPP6R3 but absent from PPP6R1, that binds a surface on Aurora A overlapping those used by CEP192, TPX2 and TACC3. Mutation of A-box phenylalanine residues disrupts Aurora A binding and T-loop dephosphorylation, elevating spindle-associated Aurora A activity, and enlarging mitotic spindles. PPP6R2 additionally contains a unique PLK1-docking site downstream of its A-box, explaining how PLK1 competes with Aurora A for PPP6R2 and thereby suppresses PP6 activity towards Aurora A. Together, these findings show that PP6 regulatory subunits mimic Aurora A activators to direct dephosphorylation, and reveal how competing interactions regulate PP6 in mitosis.

Metazoan lagging-strand DNA synthesis is distributive.

Single-molecule imaging reveals that metazoan lagging-strand DNA synthesis is distributive, with Pol α and Pol δ rapidly recruited per Okazaki fragment rather than stably tethered to the replisome, fundamentally revising the mechanism of eukaryotic DNA replication fork coordination.

Authors: Luke D Lynch, Jinho Park, Gheorghe Chistol
Source: PubMed
Publication date: 22 October 2026
Primary category: Cell cycle
Priority: high
Abstract: DNA's anti-parallel structure presents a topological challenge to the replisome, as leading and lagging strands must be synthesized in opposite directions. How lagging-strand synthesis is coordinated with leading-strand synthesis remains unresolved in eukaryotes. To address this question, we directly visualized the dynamics of lagging-strand polymerases Pol α and Pol δ at active replication forks using single-molecule imaging in Xenopus nuclear extracts. Surprisingly, we find that neither Pol α nor Pol δ is stably tethered to the replisome. Instead, lagging-strand synthesis occurs distributively and entails the rapid recruitment of new molecules of Pol α and Pol δ for each Okazaki fragment. Consequently, leading- and lagging-strand synthesis are not intrinsically coupled. We propose that metazoans solve the problem of anti-parallel replication not by actively coordinating leading- and lagging-strand synthesis, but instead simply by recruiting new polymerases to synthesize each Okazaki fragment.

Region-specific generation and retention of acetylated cohesin shape the genome-wide pattern of sister chromatid cohesion.

This paper mechanistically dissects how ESCO2-mediated SMC3 acetylation is established and selectively retained post-replication to shape genome-wide sister chromatid cohesion, directly advancing core chromosome segregation and cohesin biology.

Authors: Mai I Shimizu, Masashige Bando, Atsunori Yoshimura, Toyonori Sakata, Tomoko Nishiyama, Katsuhiko Shirahige, Takashi Sutani
Source: PubMed
Publication date: 24 October 2026
Primary category: Cell cycle
Priority: high
Abstract: Sister chromatid cohesion depends on ESCO2-mediated acetylation of the cohesin subunit SMC3, yet how this modification is established and maintained across the genome remains poorly understood. Here, we examined the chromatin-binding dynamics of ESCO2 and its enzymatic activity using quantitative ChIP-seq of human cells synchronously progressing through S phase. ESCO2 bound broadly along chromosomes without forming discrete peaks and preferentially localized to transcriptionally inactive regions, but was not confined to H3K9me3- or H3K27me3-enriched heterochromatin. Consistent with this binding pattern, ESCO2-dependent SMC3 acetylation showed a similarly broad distribution in these regions. In contrast, ESCO1, a paralog of ESCO2, primarily mediated SMC3 acetylation at cohesin peak sites. Notably, most of the broadly distributed, ESCO2-dependent SMC3 acetylation generated during S phase was progressively lost from chromatin after replication, whereas the fraction that persisted into late G2 accumulated in domains enriched for the repressive H3K27me3 modification. Our work identifies selective post-replicative retention of acetylated cohesin as a previously unappreciated step in shaping the genome-wide architecture of sister chromatid cohesion.

Slender lobes is a spindle matrix protein regulated by spindle envelope kinase Greatwall in oocytes.

The paper identifies Slender lobes as a spindle matrix protein regulated by Greatwall kinase in Drosophila oocytes, directly involving MASTL/Greatwall and core chromosome segregation/spindle biology.

Authors: Rayane Kaade, Emma Peat, Charlotte Repton, Julia Niziol, Carmela Silva Mason, Li Ern Yap, Gera Pavlova, Hiroyuki Ohkura
Source: PubMed
Publication date: 26 October 2026
Primary category: Cell cycle
Priority: high
Abstract: Chromosome segregation is mediated by microtubule-based machinery, the spindle. Microtubule-independent structures, often called the spindle matrix or the spindle envelope, have been reported to embed or surround the spindle, respectively. The concepts have been around for several decades, but they still remain enigmatic. Here, we show the spindle matrix and the spindle envelope form one functional unit crucial for spindle structure and function in oocytes. We found that in Drosophila oocytes, Slender lobes (Sle) protein is an integral component of the spindle matrix, which has a composition different from that in mitotic cells. We further found that Greatwall (Gwl) kinase localizes to the spindle envelope tightly surrounding the Sle spindle matrix in oocytes. Gwl promotes assembly of the Sle spindle matrix, which in turn determines the location of the Gwl spindle envelope. sle silencing in oocytes resulted in spindle abnormalities. Cosilencing experiments revealed that Sle buffers the impacts of compromised kinetochore-microtubule interaction on centromere bi-orientation in meiotic metaphase I.

Cell cycle-coupled CK1δ turnover, autoinhibition, and activity.

This paper reveals cell-cycle-coupled regulation of CK1δ activity and turnover, including APC/C-CDH1-mediated degradation in G1, stabilization in S phase for DNA damage signaling, and mitotic autoinhibition via phosphatase downregulation, directly advancing understanding of cell-cycle control mechanisms.

Authors: Fidel Emmanuel Serrano, Bianca Ruppert, Axel C R Diernfellner, Michael Brunner
Source: PubMed
Publication date: 28 October 2026
Primary category: Cell cycle
Priority: high
Abstract: Casein kinase 1δ (CK1δ) is a ubiquitously expressed kinase involved in diverse cellular processes, including cell-cycle regulation. CK1δ activity is attenuated by (auto)phosphorylation. However, inhibitory phosphorylation is efficiently opposed by cellular phosphatases as CK1δ accumulates in its hypophosphorylated, active state. CK1δ is a target of the nuclear ubiquitin ligase APC/C-CDH1, yet the kinase is apparently stable. Thus, the physiological relevance of CK1δ (auto)phosphorylation, autoinhibition, and regulated turnover has remained unclear. Previously, we showed that CK1δ is dynamically regulated in a manner that is dependent on kinase activity, subcellular localization, and interaction with its binding partners, such as PER2 (Serrano et al., 2026). Here, we show that CK1δ activity and abundance are additionally coordinated in a cell cycle-dependent manner. During G1, assembled CK1δ kinase is stable while free active kinase is degraded. In S phase, unassembled CK1δ seems to be no longer degraded, likely to support functions in DNA damage signaling. Upon mitotic entry, the downregulation of phosphatases promotes CK1δ (auto)phosphorylation and consequent autoinhibition, thereby preserving a pool of kinase to rapidly re-establish the post-mitotic steady state.

An unexpected function of a cell-cycle enzyme might explain the toxic effects of its inhibitors.

The title references a cell-cycle enzyme and its inhibitors, suggesting relevance to cell-cycle control, but the absence of an abstract prevents confirmation of the specific mechanism or protein involved.

Authors: Authors not listed
Source: PubMed
Publication date: 28 October 2026
Primary category: Cell cycle
Priority: high
Abstract: No abstract available.

Genome stability

Characterization of post-mitotic DNA synthesis and its regulation in human cells.

This paper characterizes post-mitotic DNA synthesis (post-MiDAS) in G1, revealing that APC/C-CDH1 restrains excessive post-MiDAS at centromeres and telomeres in ALT-positive cancer cells, linking cell-cycle regulation to genome stability and identifying an ALT-specific vulnerability.

Authors: Julia Vornberger, Ralph Imhof, Virginia Pasti, Beatrice Bianchi, Mingxuan Wei, Jeannette Alisha Straw, Sandhya Manohar, Matthias Altmeyer
Source: PubMed
Publication date: 28 September 2026
Primary category: Genome stability
Priority: high
Abstract: DNA replication stress promotes cancer development and is associated with DNA synthesis beyond S-phase. Replication stress-induced DNA lesions and under-replicated DNA can persist into G2 and mitosis, where they undergo mitotic DNA synthesis (MiDAS). After cell division, inherited DNA lesions are protected by genome caretaker proteins and show signs of post-mitotic DNA synthesis (post-MiDAS) in G1. The genomic regions that undergo post-MiDAS, the cellular factors involved, and the implications for genome integrity remain poorly understood. Here, we provide evidence for post-MiDAS activity at centromeres and telomeres in cancer cells employing alternative lengthening of telomeres (ALT) and present data suggesting that a subset of these fragile genomic regions can cluster during post-MiDAS in G1. We further show that post-MiDAS is promoted by local SUMOylation and BLM recruitment into ALT-associated PML bodies (APBs) and involves DNA damage tolerance factors and proteins associated with ALT and MiDAS. Consistent with G1-specific regulation, complementary quantitative proteomics and targeted siRNA screening reveal that APC/C, together with its G1 co-activator CDH1 but independent of its mitotic co-activator CDC20, restrains excessive post-MiDAS in G1. Finally, we show that CDH1 depletion selectively impairs the survival of ALT-positive cancer cell lines, indicating that post-MiDAS might represent a potential ALT-specific vulnerability.

PrimPol toggled by ATR modulates fork slowing and repriming under oncogenic KRAS-induced replication stress.

The paper identifies PrimPol as an ATR-regulated toggle that switches between fork slowing (with SMARCAL1) and repriming under KRAS-induced replication stress, directly advancing mechanistic understanding of replication stress tolerance and genome stability.

Authors: Taichi Igarashi, Takaaki Yasuhara, Bunsyo Shiotani
Source: PubMed
Publication date: 1 October 2026
Primary category: Genome stability
Priority: high
Abstract: During the early phases of oncogenic clonal expansion, precancerous cells experience replication stress that threatens both genomic integrity and viability. How replication stress tolerance (RST) mechanisms are dynamically reprogrammed across the different stages of cancer progression remains elusive. Here, we identify PrimPol as a central regulator that executes two fundamentally distinct RST modes in response to oncogenic KRAS-induced heterochromatin-associated replication stress (K-HaRS). Unexpectedly, during acute K-HaRS, an unphosphorylated form of PrimPol cooperates with the fork remodeler SMARCAL1 to actively slow fork progression, stabilizing challenged forks and limiting engagement of error-prone DNA synthesis. As K-HaRS persists, PrimPol undergoes an ATR-dependent functional switch, whereby its phosphorylated form promotes repriming while fork slowing is attenuated, enabling replication to proceed across heterochromatin barriers despite persistent stress. Strikingly, loss of PrimPol enforces chronic reliance on the error-prone Rev1-Polζ-dependent synthesis and compromises cellular fitness under KRAS-driven stress. Thus, these findings establish PrimPol as a context-dependent regulator of RST that, through ATR-dependent toggling of its functional modes, coordinates fork slowing and repriming to safeguard replication fork stability while permitting an optimal compromise of genome stability that would fuel oncogenic clonal evolution.

Uracil overload triggers global genome instability and dUTPdysgenesis.

This paper maps how uracil overload in DNA drives global genome instability including point mutations, recombination, aneuploidy, and a novel post-zygotic isolation mechanism (dUTPdysgenesis) in S. cerevisiae, directly addressing DNA damage, repair kinetics, and chromosomal instability.

Authors: Qiao-Ling Yin, Min He, Ke Zhang, Kejing Li, Yeke Wang, Wan-Jing Ding, Yibin Zhu, Cunqi Ye, Dao-Qiong Zheng
Source: PubMed
Publication date: 24 October 2026
Primary category: Genome stability
Priority: high
Abstract: Uracil accumulation in DNA is a pervasive threat to genomic integrity, yet the global dynamics of how uracil overload drives genome instability remain elusive. Using Saccharomyces cerevisiae strains with attenuated dUTPase (DUT1) expression, we mapped the landscapes of genomic alterations including point mutations, recombination, and aneuploidy. Deletion of the UNG1 suppressed most induced mutations and loss-of-heterozygosity (LOH), identifying base excision repair as the primary driver of genomic alterations, whereas aneuploidy directly depends on the persistence of intact genomic uracil. Mechanistically, beyond localized bypass of static AP sites by translesion synthesis polymerases, the massive influx of uracil lesions induces a repair bottleneck by depleting Ung1 and Apn1. This resource titration, coupled with downstream processing intermediates, primarily drives mutagenesis at heterologous nonthymine positions. Furthermore, persistent static AP sites preferentially stimulate homologous recombination sub-pathway that yield interstitial LOH, whereas Apn1-mediated processing channels recombination toward terminal LOH. Crucially, we define a novel post-zygotic isolation mechanism, dUTPdysgenesis, where parental wild-type Ung1 unleashes an immediate enzymatic shock against a uracil-preloaded genome upon mating, triggering G1-phase chromosomal shattering and mutations. Collectively, this study transitions the paradigm of uracil mutagenesis from localized errors to a global engine of genome instability, bridging nucleotide metabolism, DNA repair kinetics, and speciation barriers.

E2 displacement of CIP2A from TOPBP1 activates the DNA damage response during papillomavirus life cycles.

The paper describes how papillomavirus E2 displaces CIP2A from TOPBP1 to activate ATM and inhibit ATR, creating an ATM-high/ATR-low DNA damage response phenotype that promotes viral replication and cell proliferation in HPV-associated contexts.

Authors: Apurva T Prabhakar, Claire D James, Allison Q Nguyen, Phoebe V Bridy, Xu Wang, Ryan J Zoldork, Jenny D Roe, Austin J Witt, Srimanya S Panidepu, Sarita Giri, Molly L Bristol, Krista Dalton, Andreas Wieland, Ahmed Diab, Anthony C Faber, Elliot J Androphy, Devraj Basu, Paul F Lambert, Megan E Spurgeon, Iain M Morgan
Source: PubMed
Publication date: 26 October 2026
Primary category: Genome stability
Priority: high
Abstract: The papillomavirus life cycle is linked to epithelial differentiation, and the virus manipulates differentiation to facilitate viral production. One such manipulation is the activation of the DNA damage response (DDR), which promotes viral replication via homologous recombination. Here, we show that the papillomavirus transcription/replication/segregation factor E2 activates the DDR. During differentiation, E2 attenuates sirtuin 1 (SIRT1) activity, enhances the acetylation of DDR factors, and displaces cancerous inhibitor of protein phosphatase 2A (CIP2A) from DNA topoisomerase II-binding protein 1 (TOPBP1), resulting in CIP2A-mediated inhibition of protein phosphatase 2A (PP2A) and ataxia-telangiectasia mutated (ATM) activation. E2 associates with TOPBP1 and ATM while reducing TOPBP1-ATR complexes and ataxia-telangiectasia and Rad3-related (ATR) activation. This ATM-high, ATR-low DDR phenotype promotes viral replication and cell proliferation. We observe this DDR activation in E2-expressing keratinocytes, human papillomavirus 16 (HPV16)-positive cells, Mus musculus papillomavirus 1 (MmuPV1)-induced lesions, HPV-positive head and neck cancer cell lines, and HPV16-positive patient-derived xenografts. ATM inhibition preferentially kills E2-expressing cells, supporting ATM signaling as a potential therapeutic target in HPV-associated disease retaining E2 expression and episomal genomes.

The 9-1-1 complex protects ssDNA gaps in BRCA2-deficient cancer.

The paper identifies the 9-1-1 complex as a critical protector of ssDNA gaps in BRCA2-deficient cells, revealing a novel ATR-independent mechanism for maintaining genome stability during replication stress and preventing pathological gap expansion.

Authors: Helen E Grimsley, Katherine Courtemanche, Shane Cox, Anthony Calder, Niamh McDermott, Xin Pei, Aman Sharma, Jackson Bright, Nadeem Riaz, Jeremy Setton, Mehmet Orman, Simon N Powell
Source: PubMed
Publication date: 26 October 2026
Primary category: Genome stability
Priority: high
Abstract: Single-stranded DNA (ssDNA) gaps are a hallmark of BRCA-deficient cells, yet the mechanisms that safeguard these lesions remain unclear. Using a genome-wide CRISPR screen in isogenic BRCA2-proficient and -deficient cancer cells, we identified the RAD9A-HUS1-RAD1 (9-1-1) complex as essential for BRCA2-deficient cell survival through an ATR-independent mechanism. In this context, loss of 9-1-1 leads to accumulation of PRIMPOL-dependent gaps that fail to undergo post-replicative repair, resulting in pathological expansion and increased DNA damage. Excessive EXO1-mediated degradation drives this genomic instability, as EXO1 depletion rescues the phenotype. We further demonstrate that the 9-1-1 complex contributes to POLζ-dependent gap filling. We propose a model in which ssDNA gaps, when extended beyond a critical length, become inaccessible to translesion synthesis (TLS)-mediated repair and rely entirely on homologous recombination. These findings establish the 9-1-1 complex as a key regulator of ssDNA gap stability and as a promising therapeutic target in BRCA2-deficient cancers.

DNA-PK enforces the S/G2 checkpoint in ATM-deficient cells to limit ATR inhibitor efficacy

This paper delineates the distinct roles of DNA-PK and ATM in enforcing S/G2 and G2/M checkpoints during ATR inhibitor exposure, revealing how DNA-PK compensates for ATM deficiency to limit ATR inhibitor efficacy in replication-stressed tumors.

Authors: Branigan, T. B., Alharthi, R., Kochupurakkal, B. S., Hao, J., Revia, S., Albers, J., Cai, M.-Y., Jiao, Y., McQueen, K., Mukkavalli, S., Roundtree, I. A., Cote, G. M., Gokhale, P. C., Parmar, K., D'Andrea, A. D., Zimmermann, A., Shapiro, G. I.
Source: bioRxiv
Publication date: 28 October 2026
Primary category: Genome stability
Priority: high
Abstract: ATR inhibition has been proposed as a strategy for tumors under replication stress or those harboring ATM deficiency. However, anti-tumor activity is limited by DNA-PK and ATM compensation. Here, we have delineated distinct roles for DNA-PK and ATM during ATR inhibitor exposure. Both kinases are activated in a cell cycle-dependent manner at the S/G2 boundary following ATR inhibition. DNA-PK imposes the S/G2 checkpoint and promotes completion of DNA replication, whereas ATM detects persistent aberrant DNA replication structures with associated DNA damage in late S and G2/M to establish a G2/M checkpoint promoting DNA repair. In ATM-deficient cells and patient tumors, DNA-PK is activated following ATR inhibition and assumes greater versatility by not only enforcing the S/G2 checkpoint but also by detecting aberrant replication structures in S phase in place of ATM, allowing cells to tolerate ATR inhibition. Consequently, DNA-PK inhibition synergizes with ATR inhibition in ATM-deficient cells and enhances ATR inhibitor efficacy in ATM-deficient PDX models. These data support clinical evaluation of combined ATR and DNA-PK inhibition in ATM-deficient cancers.

SMARCA5 facilitates cohesin localization at R-loops to prevent transcription-replication collisions.

This paper reveals a novel mechanism by which SMARCA5 recruits cohesin core subunits (RAD21, STAG1/2) to R-loops to promote transcription-coupled homologous recombination and prevent transcription-replication collisions, directly advancing our understanding of genome stability and replication stress.

Authors: Boya Gao, Elizabeth M Irvin, Fengqi Zhang, Parminder Kaur, Ruoxi W Wang, Xiaofeng A Su, Zhubing Shi, Hong Wang, Li Lan
Source: PubMed
Publication date: 28 October 2026
Primary category: Genome stability
Priority: high
Abstract: The cohesin complex is well recognized for maintaining sister chromatid cohesion during mitosis and meiosis, as well as for its role in genome organization through chromatin loop formation. Recent studies indicate that cohesin can be co-opted in cancer by aiding DNA repair processes to promote cancer cell proliferation. However, the mechanisms, protein partners, and functions by which cohesin is involved in DNA repair remain unclear. Here, we uncover a novel function of cohesin core subunits (RAD21, STAG1/2) in promoting transcription-coupled homologous recombination (TC-HR) at sites of R-loops. We demonstrate that cohesin (SMC1/3, RAD21, STAG1) preferentially localizes to R-loops in vitro and localize to DNA damage-induced R-loops in cells. Through a screen of chromatin remodelers, we identify that chromatin remodeler SMARCA5 recruits RAD21 and STAG at R-loop sites. SMARCA5 forms a complex with RAD21 via its SLIDE domain and is recruited to R-loops, providing a dual mechanism to promote the R-loop localization of the cohesin core subunits. The ATPase activity of SMARCA5 facilitates the localization of RAD21 and RAD51 at sites of R-loops to promote TC-HR and timely resolution of R-loops. Depletion of either core subunits of cohesin or SMARCA5, both of which are overexpressed in a subset of cancers, leads to aberrant R-loop accumulation, stalled replication fork progression, and elevated transcription-replication collision (TRC) events induced cell death. These findings shed new light on a previously unknown function of SMARCA5 through regulating cohesin core subunits RAD21/STAG at R-loops and established their potential as therapeutic targets in treating cancer.

Tubulin acetylation regulates nuclear shape fluctuations and DNA repair.

This paper identifies tubulin acetylation as a regulator of nuclear mechanics that promotes DNA double-strand break repair via homologous recombination, revealing a novel mechanical mechanism for genome stability.

Authors: Sam Wallis, Wai Yiu Tse, Lisa Donker, Anna Baxter, Nikita Dave, Andreas Weber, Eoin Gillespie, Baizhi Chen, Jonathan M Burden, Anoek Friskes, René H Medema, Guillaume Charras, Dinis P Calado, Susana A Godinho
Source: PubMed
Publication date: 28 October 2026
Primary category: Genome stability
Priority: high
Abstract: Genome stability depends on the accurate repair of DNA double-strand breaks (DSBs). While chromatin-based mechanisms have been well studied, emerging evidence reveals that nuclear mechanics actively shape repair outcomes, although the mechanisms remain unclear. Here we identify microtubule acetylation as a regulator of nuclear mechanics that promotes DSB repair via homologous recombination (HR). DNA damage induces progressive tubulin acetylation, leading to displacement of the perinuclear vimentin cage. Loss of the vimentin cage softens the nucleus and renders the nuclear envelope responsive to microtubule forces, which drives transient nuclear shape fluctuations, localized DSB mobility and repair. Inhibiting tubulin acetylation abolishes these fluctuations, restricts DSB mobility and negatively impacts the homology search during HR, leaving non-homologous end joining intact. Consequently, persistent DSBs coalesce and cluster at the nuclear periphery, triggering cell-cycle arrest and senescence and increasing sensitivity to DNA-damaging agents. Removal of the vimentin cage is sufficient to rescue these effects, with restored nuclear fluctuations and repair efficiency. Thus, we propose that nuclear fluctuations act as a mechanical strategy to accelerate error-free repair. These findings reveal how cytoskeletal forces shape nuclear function and establish nuclear fluctuations as a fundamental principle for maintaining genome stability.

CRISPR / gene editing

Cas9 nickase-mediated contraction of CAG/CTG repeats is associated with phenotypic improvements in a Huntington's disease mouse model.

CRISPR-Cas9 nickase-mediated contraction of CAG/CTG repeats in a Huntington's disease mouse model demonstrates a genome-editing therapeutic approach with phenotypic improvement.

Authors: Alvaro Murillo, Melanie Alpaugh, Ruban Rex Peter Durairaj, Emma L Randall, Meghan Larin, Laura Heraty, Alys N Aston, Alysha S Taylor, Alex Mas Monteys, Nina Stöberl, Aeverie E R Heuchan, Pascale Aeschlimann, Kyle Fears, Christian Landles, Georgina F Osborne, Antoine Mangin, Soumyasree Bhattacharyya, Emmanouil Metzakopian, Nicholas D Allen, Jack Puymirat, Gillian P Bates, Beverly L Davidson, Francesca Cicchetti, Mariah J Lelos, Vincent Dion
Source: PubMed
Publication date: 21 October 2026
Primary category: CRISPR / gene editing
Priority: high
Abstract: Expanded CAG/CTG repeats cause more than 15 different diseases that all remain without a disease-modifying treatment. Because repeat length accounts for most of the variation in disease severity, contracting CAG/CTG repeats presents an attractive therapeutic avenue. Here, we show that the CRISPR-Cas9 nickase targeted to CAG/CTG repeats leads to efficient repeat contractions in Huntington's disease (HD) patient-derived neurons and astrocytes and in myotonic dystrophy type 1 patient-derived neurons. The approach was allele selective and free of detectable off-target mutations. Injection of the Cas9 nickase into the striatum of the R6/1 mouse model of HD using adeno-associated viral vectors led to repeat contractions in more than half of striatal neurons. Upon injection, we observed a reduction in the number of inclusion bodies, an improved gene expression profile, and amelioration of locomotion deficits in the open field test. The effects were greater than expected from the contractions induced, suggesting that non-cell autonomous mechanisms may be involved. Our results provide the proof of concept that correction of CAG/CTG repeats can improve HD phenotypes in a mouse disease model.

A first for CRISPR: powerful prime editing alters DNA directly in the human body.

The title describes a first-in-human prime editing application, which is a major breakthrough in genome editing, but the absence of an abstract prevents confirmation of mechanistic details.

Authors: Heidi Ledford
Source: PubMed
Publication date: 22 October 2026
Primary category: CRISPR / gene editing
Priority: high
Abstract: No abstract available.