bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–06–29
fourteen papers selected by
Valentina Piano, Uniklinik Köln
  1. Mutational analysis of the Drosophila CMG helicase reveals relationships among chromosome integrity and the maintenance of spindle and centrosome structure.
  2. A coordinated kinase and phosphatase network regulates Stu2 recruitment to yeast kinetochores.
  3. Hedgehog signaling controls astral microtubules and mitotic spindle orientation in neural progenitors and iPSCs.
  4. Spindle Orientation Regulation Is Governed by Redundant Cortical Mechanosensing and Shape-Sensing Mechanisms.
  5. PLK-1 suppresses centrosome maturation and microtubule polymerization to ensure faithful oocyte meiosis.
  6. Ubiquitin-dependent proteolysis of KNL2 driven by APC/CCDC20 is critical for centromere integrity and mitotic fidelity.
  7. Dynamic Phosphorylation of MIS12 Ensures Accurate Kinetochore-Microtubule Attachment by Expanding the Fibrous Corona.
  8. Spatiotemporal orchestration of mitosis by cyclin-dependent kinase.
  9. Fass and C3/C4 contribute to the activities and levels of the protein phosphatase 2A catalytic subunit pool and regulate mitotic events in Arabidopsis.
  10. WIP1 mutations suppress DNA damage triggered bypass of the mitotic timer.
  11. Linker Histone H1.5 Contributes to Centromere Integrity in Human Cells.
  12. Proteasome-dependent Orc6 removal from chromatin upon S-phase entry safeguards against MCM reloading and tetraploidy.
  13. Evolutionarily recent transcription factors partake in human cell cycle regulation.
  14. Loss of G1-phase CDK-inhibition biases instability between genomic regions by unevenly reducing activity among replication origins.
  1. Genetics. 2025 Jun 27. pii: iyaf124. [Epub ahead of print]
    Mutational analysis of the Drosophila CMG helicase reveals relationships among chromosome integrity and the maintenance of spindle and centrosome structure.
    Lucia Graziadio, Livia Scatolini, Elisabetta Bucciarelli, Grazia Daniela Raffa, Silvia Bonaccorsi, Maurizio Gatti.
      The CMG (Cdc45-MCM-GINS) complex is a conserved helicase that plays an essential DNA unwinding function at replication forks. Here we analyzed the mitotic phenotypes caused in Drosophila by knockdown of Cdc45, Mcm5 and the four GINS genes (Sld5, Psf1, Psf2 and Psf3). Silencing of these genes resulted in virtually identical mitotic phenotypes. Brain cells from mutant and RNAi larvae showed severe defects in chromosome condensation, chromosome breakage and frequent polyploid mitotic figures. In addition, mutant cells showed reduced Cid (Cenp-A) incorporation at centromeres and strong alterations in spindle and centrosome structures. Our cytological and genetic analyses suggest that replication-related DNA damage and Cid-dependent centromere/kinetochore defects trigger the spindle assembly checkpoint (SAC) that arrests the cells in a prometaphase-like stage. The arrested cells undergo mitotic slippage accompanied by Cyclin B degradation, and eventually return to G1 giving rise to polyploid cells. Our analyses further suggest that during the prolonged prometaphase arrest both the centrosomes and the spindles undergo severe structural degeneration, and that the spindle defects are not the consequence of the aberrant centrosome behavior. Most studies on mitotic slippage have been carried out in cells exposed to anti-microtubule agents and could not address the behavior of the spindle. Conversely, our results illuminate the complex consequences of replication stress and reveal what happens to the mitotic apparatus during the prolonged SAC-induced mitotic arrest. Because prolonged mitosis is a common event in human cancers, our results could provide useful information for studies on cancer etiology and therapy.
    Keywords:   Drosophila ; CMG complex; Meier-Gorlin syndrome; centrosome behavior; chromosome breakage; chromosome condensation; mitotic slippage; replication stress; spindle checkpoint; spindle morphology
    DOI:  https://doi.org/10.1093/genetics/iyaf124
  2. J Cell Biol. 2025 Aug 04. pii: e202410196. [Epub ahead of print]224(8):
    A coordinated kinase and phosphatase network regulates Stu2 recruitment to yeast kinetochores.
    Michael G Stewart, Joseph S Carrier, Jacob A Zahm, Stephen C Harrison, Matthew P Miller.
      Cells coordinate diverse events at anaphase onset, including separase activation, cohesin cleavage, chromosome separation, and spindle reorganization. Regulation of the XMAP215 family member and microtubule polymerase, Stu2, at the metaphase-anaphase transition determines a redistribution from kinetochores to spindle microtubules. We show that cells modulate Stu2 kinetochore-microtubule localization by Polo-like kinase1/Cdc5-mediated phosphorylation of T866, near the Stu2 C-terminus, thereby promoting dissociation from the kinetochore Ndc80 complex. Cdk/Cdc28 likely primes Cdc5:Stu2 interaction. Cdc28 activity is also required for Stu2 nuclear import. PP2ACdc55 actively opposes Cdc5 activity on Stu2T866 during metaphase. This counter-regulation allows for switch-like redistribution of Stu2pT866 at anaphase onset when separase inhibits PP2ACdc55. Blocking Stu2T866 phosphorylation disrupts anaphase spindle progression, and we infer that PP2ACdc55 regulates the mitotic spindle by dephosphorylating multiple MAPs, including Stu2. These data support a model in which increased phosphorylation at anaphase onset results from phosphatase inhibition and point to a larger regulatory network that facilitates rapid cytoskeletal modulation required for anaphase spindle function.
    DOI:  https://doi.org/10.1083/jcb.202410196
  3. Front Cell Dev Biol. 2025 ;13 1582924
    Hedgehog signaling controls astral microtubules and mitotic spindle orientation in neural progenitors and iPSCs.
    Fengming Liu, Anna Medyukhina, Kris M Olesen, Abbas Shirinifard, Hongjian Jin, Lei Li, Marina Mapelli, Khaled Khairy, Young-Goo Han.
      Mitotic spindle orientation is crucial for cell fate determination and tissue organization. Although the intracellular machinery governing spindle orientation is well characterized, whether and how secreted factors, such as morphogens, regulate this process remains poorly understood. This study investigated the role of Hedgehog (HH) signaling in modulating mitotic spindle orientation in neural progenitor cells and in induced pluripotent stem cells (iPSCs). Time-lapse microscopy of cerebral organoids and iPSCs revealed that HH signaling increases the angle of the mitotic spindle relative to the apical surface, prolongs mitosis, and enhances spindle rotation. Mechanistically, HH signaling reduces both the number and the length of astral microtubules, key regulators of spindle orientation. This reduction correlates with increased spindle angle in iPSCs. Furthermore, we show that canonical HH signaling, involving GLI-dependent transcriptional regulation, contributes to these effects. RNA sequencing and gene set enrichment analysis (GSEA) revealed that HH signaling upregulates genes associated with microtubule depolymerization, suggesting a transcriptional mechanism by which HH signaling influences astral microtubule dynamics and, consequently, mitotic spindle orientation. These findings highlight a novel link between a morphogen, transcriptional regulation, and the control of mitotic spindle orientation, with implications for development and tissue homeostasis.
    Keywords:  astral microtubule; division angle; hedgehog; mitotic spindle; neocortex; neural progenitor; radial glia; stem cell
    DOI:  https://doi.org/10.3389/fcell.2025.1582924
  4. Int J Mol Sci. 2025 Jun 15. pii: 5730. [Epub ahead of print]26(12):
    Spindle Orientation Regulation Is Governed by Redundant Cortical Mechanosensing and Shape-Sensing Mechanisms.
    Rania Hadjisavva, Paris A Skourides.
      Spindle orientation (SO) plays a critical role in tissue morphogenesis, homeostasis, and tumorigenesis by ensuring accurate division plane positioning in response to intrinsic and extrinsic cues. While SO has been extensively linked to cell shape sensing and cortical forces, the interplay between shape- and force-sensing mechanisms remains poorly understood. Here, we reveal that SO is governed by two parallel mechanisms that ensure redundancy and adaptability in diverse cellular environments. Using live-cell imaging of cultured cells, we demonstrate that the long prometaphase axis (LPA) is a superior predictor of SO compared to the long interphase axis, reflecting adhesive geometry and force distribution efficiently at prometaphase. Importantly, we uncover a pivotal role for focal adhesion kinase (FAK) in mediating cortical mechanosensing to regulate SO in cells undergoing complete metaphase rounding. We show that in cells with complete metaphase rounding, FAK-dependent force sensing aligns the spindle with the major force vector, ensuring accurate division. Conversely, in cells retaining shape anisotropy during mitosis, a FAK-independent shape-sensing mechanism drives SO. These findings highlight a dual regulatory system for SO, where shape sensing and force sensing operate in parallel to maintain division plane fidelity, shedding light on the mechanisms that enable cells to adapt to diverse physical and mechanical environments.
    Keywords:  focal adhesion kinase; mitosis; spindle orientation
    DOI:  https://doi.org/10.3390/ijms26125730
  5. J Cell Biol. 2025 Sep 01. pii: e202503080. [Epub ahead of print]224(9):
    PLK-1 suppresses centrosome maturation and microtubule polymerization to ensure faithful oocyte meiosis.
    Juhi G Narula, Sarah M Wignall.
      Sexual reproduction relies on meiosis, a specialized cell division program that produces haploid gametes. Oocytes of most organisms lack centrosomes, and therefore chromosome segregation is mediated by acentrosomal spindles. Here, we explore the role of Polo-like kinase 1 (PLK-1) in Caenorhabditiselegans oocytes, revealing mechanisms that ensure the fidelity of this unique form of cell division. Previously, PLK-1 was shown to be required for nuclear envelope breakdown and chromosome segregation in oocytes. We now find that PLK-1 is also required for establishing and maintaining acentrosomal spindle organization and for preventing excess microtubule polymerization in these cells. Additionally, our studies revealed an unexpected new role for this essential kinase. While PLK-1 is known to be required for centrosome maturation during mitosis, we found that either removal of PLK-1 from oocytes or inhibition of its kinase activity caused premature recruitment of pericentriolar material to the sperm-provided centrioles following fertilization. Thus, PLK-1 suppresses centrosome maturation during oocyte meiosis, which is opposite to its role in mitosis. Taken together, our work identifies PLK-1 as a key player that promotes faithful acentrosomal meiosis in oocytes and demonstrates that its catalytic activity is required for carrying out these important roles.
    DOI:  https://doi.org/10.1083/jcb.202503080
  6. Plant Cell. 2025 Jun 25. pii: koaf164. [Epub ahead of print]
    Ubiquitin-dependent proteolysis of KNL2 driven by APC/CCDC20 is critical for centromere integrity and mitotic fidelity.
    Manikandan Kalidass, Venkata Ganesh Jarubula, Maryia Ratnikava, Jothipriya Ramakrishnan Chandra, Samuel Le Goff, Aline V Probst, Silvia Esposito, Klaus D Grasser, Astrid Bruckmann, Jérôme F Gagneux, Reinier F Prosée, Twan Rutten, Veit Schubert, Dmitri Demidov, Esther Lechner, Florian A Steiner, Pascal Genschik, Inna Lermontova.
      Kinetochores are large protein complexes that serve as attachment sites for spindle microtubules, ensuring proper chromosome segregation during cell division. KINETOCHORE NULL2 (αKNL2) is a key kinetochore protein required for the incorporation of the centromeric histone variant CENH3. The precise regulation of αKNL2 levels is crucial, but the molecular mechanisms controlling this process remain largely unexplored. In this study, we demonstrated that the Anaphase-Promoting Complex/Cyclosome (APC/C) mediates the ubiquitin-dependent proteolysis of αKNL2 during mitosis. Our findings revealed that αKNL2 accumulates in the presence of 26S proteasome inhibitors, and our yeast two-hybrid and proteomic screens showed that proteins from the ubiquitin-proteasome pathway interact with KNL2 in Arabidopsis (Arabidopsis thaliana) and nematode (Caenorhabditis elegans). Arabidopsis αKNL2 directly interacts with Anaphase-Promoting Complex subunit 10 (APC10) and Cell Division Cycle 20.1 (CDC20.1), two substrate recognition components of the APC/C. RNAi-mediated depletion of APC/C resulted in the accumulation and mislocalization of endogenous αKNL2. Additionally, mutation or deletion of the D-box1 region, or substitution of residues K336 and K339, impaired αKNL2 degradation. The expression of a proteasome-resistant αKNL2 variant in planta caused severe defects in growth, fertility, and mitotic division. These findings show that APC/CCDC20-mediated degradation of αKNL2 is critical for proper kinetochore function and centromere integrity.
    Keywords:  APC/C; Cell division; Centromeres; D-box; Degradation; E3 ligases; Kinetochore Null2; Mass spectrometry; Plant development; Protein-protein interactions; Ubiquitination; Yeast-two hybrid
    DOI:  https://doi.org/10.1093/plcell/koaf164
  7. Mol Biol Cell. 2025 Jun 25. mbcE25020087
    Dynamic Phosphorylation of MIS12 Ensures Accurate Kinetochore-Microtubule Attachment by Expanding the Fibrous Corona.
    Qi Li, Qingzhou Chen, Tao Zheng, Junlin Teng, Haining Zhou, Jianguo Chen.
      Genomic integrity in mammalian cells relies on faithful chromosome segregation. Kinetochores capture microtubules and establish robust kinetochore-microtubule attachment to achieve accurate segregation. The MIS12 complex, a tetramer comprising MIS12, DSN1, NSL1, and PMF1, plays a critical role in kinetochore-microtubule attachment. However, how the MIS12 complex functions at the kinetochore-microtubule interface is not fully understood. Here, we found that MIS12 is phosphorylated at Ser177 by NEK2A from prophase to prometaphase. Phosphorylation of MIS12 expands the projection of the outer kinetochore, known as the fibrous corona, thus facilitating the attachment of kinetochores to microtubules. When chromosomes align at the equatorial plate, Ser177 on MIS12 is dephosphorylated by PP1, which is required for kinetochore compaction and end-on attachment conversion. We uncovered that the dynamic phosphorylation of MIS12 regulates the expansion-compaction transition of the outermost layer of kinetochores, ensuring accurate kinetochore-microtubule attachment and faithful chromosome segregation.
    DOI:  https://doi.org/10.1091/mbc.E25-02-0087
  8. Nature. 2025 Jun 25.
    Spatiotemporal orchestration of mitosis by cyclin-dependent kinase.
    Nitin Kapadia, Paul Nurse.
      Mitotic onset is a critical transition for eukaryotic cell proliferation. The commonly held view of mitotic control is that the master regulator, cyclin-dependent kinase (CDK), is first activated in the cytoplasm, at the centrosome, initiating mitosis1-3. Bistability in CDK activation ensures that the transition is irreversible, but how this unfolds in a spatially compartmentalized cell is unknown4-8. Here, using fission yeast, we show that CDK is first activated in the nucleus, and that the bistable responses differ markedly between the nucleus and the cytoplasm, with a stronger response in the nucleus driving mitotic signal propagation from there to the cytoplasm. Abolishing cyclin-CDK localization to the centrosome led to activation occurring only in the nucleus, spatially uncoupling the nucleus and cytoplasm mitotically, suggesting that centrosomal cyclin-CDK acts as a 'signal relayer'. We propose that the key mitotic regulatory system operates in the nucleus in proximity to DNA, which enables incomplete DNA replication and DNA damage to be effectively monitored to preserve genome integrity and to integrate ploidy within the CDK control network. This spatiotemporal regulatory framework establishes core principles for control of the onset of mitosis and highlights that the CDK control system operates within distinct regulatory domains in the nucleus and cytoplasm.
    DOI:  https://doi.org/10.1038/s41586-025-09172-y
  9. Plant Physiol Biochem. 2025 Jun 21. pii: S0981-9428(25)00715-6. [Epub ahead of print]227 110187
    Fass and C3/C4 contribute to the activities and levels of the protein phosphatase 2A catalytic subunit pool and regulate mitotic events in Arabidopsis.
    Adrienn Kelemen, Zoltán Kónya, László Ujlaky-Nagy, Tamás Garda, Ferenc Erdődi, Csongor Freytag, Gabriella Petra Juhász, Taras P Pasternak, Milán Riba, Csaba Máthé.
      The serine-threonine protein phosphatase PP2A holoenzymes regulate many eukaryotic cellular processes. They consist of catalytic (C), regulatory (B) and scaffolding (A) subunits. C3-C4 and their interacting B" (Fass) subunits of PP2A were in the focus of this study. Our tools were Arabidopsis wild-type plants and phosphatase mutants-fass (B"), c3c4 and microcystin-LR (MCY-LR), a specific inhibitor of PP2A/PP1. We have studied their role in the regulation of protein phosphatase activities and expression. In relation to this, we have focused on their involvement in mitotic activity and histone H3 phosphorylation. We show here for the first time that besides C3-C4, B"/Fass subunit has a crucial role in the maintenance of normal protein phosphatase activities and levels in Arabidopsis. fass mutants show increased activities of PP2A and PP1 (a phosphatase related to PP2A) and increased expression of PP2A/C. Both overall PP2A and PP1 activities are inhibited in c3c4. Fass and C3-C4 are involved in the regulation of mitotic activity. C3-C4 have less direct influence on the onset of mitosis, but Fass is involved in the regulation of metaphase-anaphase transition. In wild-type plants, MCY-LR inhibited PP2A/C activities, related to alterations of mitotic events. Distinct effects of MCY-LR in mutants also reveal the role of Fass/C3-C4 in the biochemical functionality of PP2A. Fass and C3-C4 regulate the phosphorylation of histone H3, but this effect is not related to the regulation of mitotic onset in Arabidopsis. This study gives new insights into the regulatory roles of Fass and C3-C4 subunits during mitosis in plants.
    Keywords:  C3-C4 subunits; Fass- B″ subunit; Histone H3 phosphorylation; Microcystin-LR; Mitosis; PP2A; Protein phosphatase
    DOI:  https://doi.org/10.1016/j.plaphy.2025.110187
  10. EMBO J. 2025 Jun 23.
    WIP1 mutations suppress DNA damage triggered bypass of the mitotic timer.
    Tomoaki Sobajima, Luke J Fulcher, Caleb Batley, Susanna J Alsop, Jonah Veakins, Francis A Barr.
      Prolonged mitosis results in the destruction of MDM2, initiating a p53-dependent G1 cell-cycle arrest in the absence of DNA damage. Here, we investigate how DNA damage earlier in the cell cycle affects this mitotic-timer response. We find that G2-DNA damage triggers highly penetrant bypass of mitosis and of the mitotic timer, generating tetraploid cells arrested in G1. Collapse of G2 to G1 after DNA damage is initiated by p21-mediated CDK2 inhibition and rendered irreversible by the destruction of G2/M-cyclins A and B. This behaviour is altered in cells with cancer-associated mutations in the p53-phosphatase WIP1 (PPM1D), which increase the threshold for DNA-damage signalling, enabling DNA-damaged G2 cells to enter mitosis with elevated levels of MDM2, thereby suppressing mitotic-timer-dependent G1 cell-cycle arrest. Importantly, neither WIP1 mutations nor knockout prevent p53-dependent G1-arrest in response to prolonged mitosis in the absence of DNA damage. Prolonged mitosis and G2-DNA damage thus promote p53-dependent G1 cell-cycle exit through discrete routes with differential requirements for WIP1 and genotoxic stress.
    Keywords:  Cell Cycle; Cell Cycle Checkpoints; DNA Damage; Mitosis
    DOI:  https://doi.org/10.1038/s44318-025-00495-0
  11. bioRxiv. 2025 Jun 03. pii: 2025.06.03.657682. [Epub ahead of print]
    Linker Histone H1.5 Contributes to Centromere Integrity in Human Cells.
    Ankita Saha, Minh Bui, Daniël P Melters, Ganesan Arunkumar, Songjoon Baek, Reda S Bentahar, Yamini Dalal.
      Mammalian H1 linker histones comprise a group of 11 non-allelic variants which have key roles in modulating chromatin. H1 variant specific genomic distribution contributes to fine tuning regulation of gene expression and chromatin architecture. Contradictory reports on the presence and role of H1 histones at centromeres led us to further investigate whether H1s impact centromeric chromatin. In this study, we focused on H1.5 and by in vitro assays we showed that H1.5 directly interacts with centromeric-protein A (CENP-A) mononucleosomes. Notably, our in vitro findings revealed that H1 variants H1.0 and H1.2 can also bind CENP-A nucleosomes, although with differing affinities and signatures, asserting centromeric localization may not be unique to H1.5. In human cells, H1.5 localized to the centromere and chromatin immuno-precipitation revealed an interaction between H1.5 with CENP-A nucleosomes. Knocking down of H1.5 resulted in the loss of centromeric α-satellite transcription, reduction in loading of new CENP-A, and the accumulation of mitotic defects. These data point to an unreported role for histone H1 in the regulation of mitotic integrity in human cells.
    DOI:  https://doi.org/10.1101/2025.06.03.657682
  12. J Cell Sci. 2025 Jun 18. pii: jcs.263596. [Epub ahead of print]
    Proteasome-dependent Orc6 removal from chromatin upon S-phase entry safeguards against MCM reloading and tetraploidy.
    Yoko Hayashi-Takanaka, Ichiro Hiratani, Tokuko Haraguchi, Yasushi Hiraoka.
      DNA replication is tightly regulated to occur only once per cell cycle, as untimely re-initiation can lead to aneuploidy, which is associated with early senescence and cancer. The pre-replication complex (comprising Orc1-6, Cdc6, Cdt1, and MCM) is essential for the initiation of DNA replication, but the dynamics and function of Orc6 during the cell cycle remain elusive. Here, we demonstrate that Orc6 associates with chromatin during G1-phase and dissociates upon S-phase entry. The dissociation of Orc6 from chromatin is dependent on proteasome activity, and inhibition of the proteasome leads to the accumulation of chromatin-bound Orc6, which promotes abnormal MCM loading after S-phase entry without undergoing mitosis in human immortalized hTERT-RPE1 cells. Following release from proteasome inhibition, cells with elevated levels of chromatin-bound Orc6 and MCM proceed to the next replication phase as tetraploid cells. Our findings suggest that the proteasome-dependent dissociation of Orc6 after DNA replication is critical for preventing inappropriate MCM reloading and tetraploid formation.
    Keywords:  DNA replication; MCM; Orc6; Proteasome; Single-cell plot analysis; Tetraploid
    DOI:  https://doi.org/10.1242/jcs.263596
  13. Cell Genom. 2025 Jun 20. pii: S2666-979X(25)00179-X. [Epub ahead of print] 100923
    Evolutionarily recent transcription factors partake in human cell cycle regulation.
    Cyril Pulver, Romain Forey, Alex R Lederer, Martina Begnis, Olga Rosspopoff, Joana Carlevaro-Fita, Filipe Martins, Evarist Planet, Julien Duc, Charlène Raclot, Sandra Offner, Alexandre Coudray, Arianna Dorschel, Didier Trono.
      The cell cycle is a fundamental process in eukaryotic biology and is accordingly controlled by a highly conserved core signaling cascade. However, whether recently evolved proteins also influence this process is unclear. Here, we systematically map the influence of evolutionarily recent transcription factors (TFs) on human cell cycle progression. We find that the genomic targets of select young TFs, many of which belong to the rapidly evolving Krüppel-associated box zinc-finger protein (KZFP) family, exhibit synchronized cell cycle expression. Systematic perturbation studies reveal that silencing recent TFs disrupts normal cell cycle progression, which we experimentally confirm for ZNF519, a simian-restricted KZFP. Furthermore, we show that the therian-specific KZFP ZNF274 sets the cell cycle expression and replication timing of hundreds of clustered genes, many of which are KZFPs. These findings highlight an underappreciated level of lineage specificity in cell cycle regulation.
    Keywords:  H3K9me3; KRAB zinc-finger proteins; Perturb-seq; ZNF274; ZNF519; cell cycle; epigenetics; heterochromatin; regulation of transcription; replication timing
    DOI:  https://doi.org/10.1016/j.xgen.2025.100923
  14. iScience. 2025 Jun 20. 28(6): 112757
    Loss of G1-phase CDK-inhibition biases instability between genomic regions by unevenly reducing activity among replication origins.
    Fábia Gomes, Fernando Devesa, Pilar Ayuda-Durán, Pablo Aza, Arantxa Agote-Arán, Debora Cavero, Azman Embarc-Buh, Ana González, Rodrigo Bermejo, Arturo Calzada.
      Most cancer cells deregulate the pathway that prevents premature CDK activation in late G1. When this occurs, replication stress, under-replication, and chromosomal instability ensue, with heterogeneous genomic incidence by poorly understood mechanisms. Using budding yeast as a model, here we show that depletion of the CDK-inhibitor Sic1, which controls G1/S phase transition, unevenly impairs replication and stability of genomic regions by irregularly reducing activity across replication origins. This induces variable regional concentration of defective origins. Deficiency of neighboring active and dormant origins within a region reduces origin redundancy to increase local instability due to unrestricted mitosis entry with ongoing DNA synthesis, but without inducing an S-phase checkpoint response. In contrast, when a single active origin is defective within unaffected dormant origins, only minor regional under-replication and instability ensue. These findings suggest that CDK-inhibition loss during G1 induces differential under-replication and instability across the genome by heterogeneously diminishing replication origin redundancy.
    Keywords:  Cell biology; Genomics; Health sciences; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112757
This page is being maintained by Thomas Krichel. It was last updated on 2025‒09‒21 at 10:43.