bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–12–14
fourteen papers selected by
Valentina Piano, Uniklinik Köln
  1. Motorized chromosome models of mitotic chromosome folding.
  2. The mitotic functions of a fission yeast CK1 enzyme are regulated by Cdk1-dependent and auto-phosphorylation.
  3. Cell size reduction drives spindle scaling but not chromosome segregation in C. elegans.
  4. Actin dynamics during contractile ring assembly drives mitotic nuclear displacement in fission yeast.
  5. Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
  6. Evidence of centromeric histone 3 chaperone involved in DNA damage repair pathway in budding yeast.
  7. Phase-Separation of YAP Mediates AJUBA Super Enhancer Activation to Promote Aberrant Mitosis in Breast Cancer.
  8. The KIF18A Inhibitor ATX020 Induces Mitotic Arrest and DNA Damage in Chromosomally Instable High-Grade Serous Ovarian Cancer Cells.
  9. Cancer-associated USP28 missense mutations disrupt 53BP1 interaction and p53 stabilization.
  10. Structure-based identification of Jervine as a potent dual-targeting inhibitor of cell cycle kinases.
  11. Organization principles of dynamic three-dimensional genome architecture associated with centromere clustering states.
  12. Mutations and mitotic recombination events in nondividing cells.
  13. A low-level Cdkn1c/p57kip2 expression in spinal progenitors drives the transition from proliferative to neurogenic modes of division.
  14. Cellular Dynamics and Molecular Signaling Networks of Plant Cytokinesis.
  1. Nat Commun. 2025 Dec 12. 16(1): 11085
    Motorized chromosome models of mitotic chromosome folding.
    Zhiyu Cao, Chaoqun Du, Zhonghuai Hou, Peter G Wolynes.
      During mitosis, near-spherical chromosomes reconfigure into rod-like structures to ensure their accurate segregation to daughter cells. We explore here, the interplay between the nonequilibrium activity of molecular motors in determining the chromosomal organization in mitosis and its characteristic symmetry-breaking events. We present a hybrid motorized chromosome model that highlights the distinct roles of condensin I and II in shaping mitotic chromosomes. Guided by experimental observations, the simulations suggest that condensin II facilitates large-scale scaffold formation, while condensin I is paramount in local helical loop arrangement. Together, these two distinct grappling motors establish the hierarchical helical structure characteristic of mitotic chromosomes, which exhibit striking local and, sometimes global, chirality and contribute to the robust mechanical properties of mitotic chromosomes. Accompanying the emergence of rigidity, the model provides mechanisms of forming defects, including perversions and entanglements, and shows how these may be partially resolved through condensin activity and topoisomerase action. This framework bridges coarse-grained energy landscape models of chromosome dynamics and non-equilibrium molecular dynamics, advancing the understanding of chromosome organization during cell division and beyond.
    DOI:  https://doi.org/10.1038/s41467-025-66025-y
  2. J Biol Chem. 2025 Dec 05. pii: S0021-9258(25)02859-5. [Epub ahead of print] 111007
    The mitotic functions of a fission yeast CK1 enzyme are regulated by Cdk1-dependent and auto-phosphorylation.
    Kazutoshi Akizuki, Sierra N Cullati, Alyssa E Johnson, Jun-Song Chen, Alaina H Willet, Kathleen L Gould.
      CK1 enzymes are conserved regulators of diverse cellular processes. In Schizosaccharomyces pombe, the CK1 orthologs of CK1δ and CK1ε, Hhp1 and Hhp2, are required for a mitotic checkpoint that delays cytokinesis when the mitotic spindle is disrupted. Here, we show that Hhp2, but not Hhp1, undergoes transient hyperphosphorylation during mitosis. Hhp2 autophosphorylates at four residues and is phosphorylated by the cyclin-dependent kinase Cdk1 at three additional sites. Functionally, these phosphorylation events inhibit Hhp2 catalytic activity, as phospho-ablating mutants exhibited enhanced in vitro kinase activity. In vivo, a mutant combining all seven sites (hhp2-7A) behaved as a gain-of-function mutant in the mitotic checkpoint and also had the unexpected phenotype of accelerating mitosis and cytokinesis in unperturbed conditions. Further genetic analyses indicated that Hhp2 likely promotes mitotic progression in parallel with the Polo-like kinase, Plo1. These findings establish that mitotic phosphorylation of Hhp2 serves as a negative regulatory mechanism that silences checkpoint activity and modulates cell cycle timing. Because mitotic phosphorylation of human CK1δ has been observed, our results suggest that Cdk1-mediated inhibition of CK1 enzymes is a conserved mechanism coupling the core cell cycle control machinery to CK1-dependent signaling pathways.
    Keywords:  Casein kinase 1; Cdk1; Hhp2; Schizosaccharomyces pombe; cell cycle control; mitotic checkpoint; phosphoregulation
    DOI:  https://doi.org/10.1016/j.jbc.2025.111007
  3. Res Sq. 2025 Dec 01. pii: rs.3.rs-7923379. [Epub ahead of print]
    Cell size reduction drives spindle scaling but not chromosome segregation in C. elegans.
    Chukwuebuka William Okafornta, Reza Farhadifar, Gunar Fabig, Hai-Yin Wu, Maria Köckert, Martin Vogel, Daniel Baum, Robert Haase, Michael Shelley, Daniel Needleman, Thomas Müller-Reichert.
      How embryos adapt their internal cellular machinery to reductions in cell size during development remains a fundamental question in cell biology 1-11 . Here, we use high-resolution lattice light-sheet fluorescence microscopy and automated image analysis to quantify lineage-resolved mitotic spindle and chromosome segregation dynamics from the 2- to 64-cell stages in Caenorhabditis elegans embryos. While spindle length scales with cell size across both wild-type and size-perturbed embryos, chromosome segregation dynamics remain largely invariant, suggesting that distinct mechanisms govern these mitotic processes. Combining femtosecond laser ablation 12,13 with large-scale electron tomography 14 , we find that central spindle microtubules mediate chromosome segregation dynamics and remain uncoupled from cell size across all stages of early development. In contrast, spindle elongation is driven by cortically anchored motor proteins and astral microtubules, rendering it sensitive to cell size 12,13,15-17 . Incorporating these experimental results into an extended stoichiometric model for both the spindle and chromosomes, we find that allowing only cell size and microtubule catastrophe rates to vary reproduces elongation dynamics across development. The same model also accounts for centrosome separation and pronuclear positioning in the one-cell C. elegans embryo 18 , spindle-length scaling across nematode species spanning ~100 million years of divergence 17 , and spindle rotation in human cells 19 . Thus, a unified stoichiometric framework provides a predictive, mechanistic account of spindle and nuclear dynamics across scales and species.
    DOI:  https://doi.org/10.21203/rs.3.rs-7923379/v1
  4. Biochem Biophys Res Commun. 2025 Dec 04. pii: S0006-291X(25)01814-5. [Epub ahead of print]795 153098
    Actin dynamics during contractile ring assembly drives mitotic nuclear displacement in fission yeast.
    Woosang Hwang, Takashi Toda, Masashi Yukawa.
      Nuclear positioning during mitosis is crucial for cell survival, yet its regulation remains unclear. We previously observed that, during a prolonged mitotic arrest in fission yeast, the nucleus becomes displaced from the cell center in an actin-dependent manner. Here, we examined the role of actin cable dynamics in nuclear displacement, which is essential for contractile actomyosin ring (CAR) assembly. Time-lapse imaging revealed that nuclear movement begins before CAR formation. Further genetic analysis indicated that proper CAR assembly is a prerequisite for mitotic nuclear displacement. Forced tethering of the actin-cable-nucleator formin to the nuclear pore component altered actin cable localization and abolished nuclear displacement, underscoring the importance of non-medial actin cable transport required for CAR assembly. These findings demonstrate that nuclear displacement is driven by the spatial organization of actin cables during CAR assembly, providing new insight into the mechanical regulation of nuclear positioning.
    Keywords:  Actin cables; Contractile actomyosin ring; Fission yeast; Mitosis; Nuclear displacement
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153098
  5. J Mol Cell Biol. 2025 Dec 10. pii: mjaf054. [Epub ahead of print]
    Filippi syndrome-associated CKAP2L modulates microtubule dynamics essential for mitosis and ciliary length regulation.
    Qian Lyu, Yinghao Wang, Jun Zhou, Huijie Zhao, Tao Zhong, Qingchao Li.
      Mutations in the gene encoding cytoskeleton-associated protein 2-like (CKAP2L) have been identified as a causative factor for Filippi syndrome, a rare developmental disorder characterized by facial dysmorphism, syndactyly, and microcephaly. However, the cellular and molecular mechanisms by which CKAP2L contributes to the pathogenesis of this syndrome remain largely unknown. Here, we generate a Ckap2l knockout mouse model to investigate the in vivo and cellular roles of CKAP2L. Interestingly, Ckap2l knockout mice show no overt developmental abnormalities, with the exception of reduced male fertility, evidenced by decreased sperm count, impaired motility, and abnormally elongated flagella. At the cellular level, CKAP2L is a bona fide microtubule-associated protein that localizes to microtubule-based organelles, including the centrosome, mitotic spindle, and ciliary basal body. Depletion of CKAP2L leads to shortened mitotic spindles and cytokinesis failure, resulting in multinucleation. Furthermore, we uncover a conserved function for CKAP2L as a negative regulator of primary cilium length; its loss markedly increases ciliary length in both human and mouse cells. Collectively, these findings position CKAP2L as a multifunctional regulator of microtubule-based organelles and propose that Filippi syndrome can be classified as a 'centrosomopathy' arising from concurrent defects in cell proliferation and ciliary function.
    Keywords:  CKAP2L; centrosome; cilia; microtubule; mitosis
    DOI:  https://doi.org/10.1093/jmcb/mjaf054
  6. Elife. 2025 Dec 10. pii: e104431. [Epub ahead of print]14
    Evidence of centromeric histone 3 chaperone involved in DNA damage repair pathway in budding yeast.
    Prakhar Agarwal, Anushka Alekar, Shubhomita Mallick, Kannan Harini, Santanu K Ghosh.
      The centromeric protein-A (CENP-A) is an evolutionarily conserved histone H3 variant that marks the identity of the centromeres. Several mechanisms regulate the centromeric deposition of CENP-A as its mislocalization causes erroneous chromosome segregation, leading to aneuploidy-based diseases, including cancers. The most crucial deposition factor is a CENP-A specific chaperone, HJURP (Scm3 in budding yeast), which specifically binds to CENP-A. However, the discovery of HJURP as a DDR (DNA damage repair) protein and evidence of its binding to Holliday junctions in vitro indicate a CENP-A-deposition-independent role of these chaperones. In this study, using budding yeast, we demonstrate that Scm3 is crucial for the DDR pathway as Scm3-depleted cells are sensitive to DNA damage. We further observe that Scm3 depletion genetically interacts with the rad52 DDR mutant and is compromised in activating DDR-mediated arrest. We demonstrate that Scm3 associates with DNA damage sites and undergoes posttranslational modifications upon DNA damage. Overall, from this report and earlier studies on HJURP, we conclude that DDR functions of CENP-A chaperones are conserved across eukaryotes. The revelation that these chaperones promote genome stability in more than one pathway has clinical significance.
    Keywords:  DNA damage; HJURP; S. cerevisiae; Scm3; budding yeast; cell biology; centromere; chromosome
    DOI:  https://doi.org/10.7554/eLife.104431
  7. Adv Sci (Weinh). 2025 Dec 08. e09341
    Phase-Separation of YAP Mediates AJUBA Super Enhancer Activation to Promote Aberrant Mitosis in Breast Cancer.
    Rui Zhang, Qingwen Huang, Zhuo Chen, Weijian Meng, Hongliang Dong, Zhihong Qi, Liang Liu, Jie Shen, Daxing Xie.
      Aberrant mitosis is a hallmark of cancer, which drives chromosomal instability, gene dysregulation, tumor heterogeneity, immune evasion, and therapy resistance. In this study, it is observed that dysregulation of YAP signaling can cause supernumerary centrosome clustering, thereby triggering pseudo-bipolar/multipolar diversion during anaphase in breast cancer. Mechanistically, the YAP can accumulate and hyperactivate the super-enhancer of the spindle assembly checkpoint, AJUBA, in a phase-separation-dependent manner, thus leading to aberrant mitosis. These findings reveal a crucial biological role of YAP-mediated super enhancer activation and provide new insights into aneuploidy formation in breast cancer.
    Keywords:  AJUBA; YAP; aberrant mitosis; breast cancer; super enhancers
    DOI:  https://doi.org/10.1002/advs.202409341
  8. Cells. 2025 Nov 26. pii: 1863. [Epub ahead of print]14(23):
    The KIF18A Inhibitor ATX020 Induces Mitotic Arrest and DNA Damage in Chromosomally Instable High-Grade Serous Ovarian Cancer Cells.
    Jayakumar Nair, Tzu-Ting Huang, Maureen Lynes, Sanjoy Khan, Serena Silver, Jung-Min Lee.
      High-grade serous ovarian cancer (HGSOC) is the most common (~80%) and lethal ovarian cancer subtype in the United States, characterized by TP53 mutations and DNA repair defects causing chromosomal instability (CIN). KIF18A is an essential cytoskeletal motor protein for cell division in CIN+ cancer cells, but it is not necessary for cell division in normal cells. Therefore, KIF18A represents a promising target for therapeutic interventions in CIN+ cancers. We investigated the use of a novel KIF18A inhibitor ATX020, for selectively targeting CIN+ HGSOC cells using growth inhibition assays, invasion assays, immunoassays, cell cycle analysis, and immunofluorescence techniques. Using DepMap and flow cytometry, we classified a panel of HGSOC cell lines based on aneuploidy scores (AS) and ploidy levels and identified a correlation between these classifications and sensitivity against ATX020. ATX020 induced cytotoxicity through mitotic arrest and DNA damage, and reduced tumor growth in HGSOC with high aneuploidy scores (AS). Mechanistically, ATX020 blocks KIF18A's plus-end movement on spindle fibers, increasing spindle length, resulting in chromosomal mis-segregation, aneuploidy, and DNA damage. Our findings suggest that ATX020 inhibits CIN+ HGSOC cells mainly by inducing mitotic arrest and DNA damage, disrupting KIF18A's function crucial for mitosis.
    Keywords:  ATX020; DNA damage; HGSOC; KIF18A; metaphase; ovarian cancer
    DOI:  https://doi.org/10.3390/cells14231863
  9. Nat Commun. 2025 Dec 09. 16(1): 10310
    Cancer-associated USP28 missense mutations disrupt 53BP1 interaction and p53 stabilization.
    Hazrat Belal, Esther Feng Ying Ng, Midori Ohta, Franz Meitinger.
      Cellular stress response pathways are essential for genome stability and are frequently dysregulated in cancer. Following mitotic stress, the ubiquitin-specific protease 28 (USP28) and the p53-binding protein 1 (53BP1) form a stable, heritable complex to stabilize the tumor suppressor p53, triggering cell cycle arrest or apoptosis. Here, we demonstrate that USP28 stabilizes p53 through deubiquitination. We further show that USP28 is required not only for an efficient stress response but also for maintaining basal p53 levels in some cancer cells. Loss of functional USP28 allows cells to evade mitotic stress and DNA damage responses in a manner that is specific to cell type and cancer context. We identify a prevalent, shorter USP28 isoform critical for p53 stabilization. Its C-terminal domain mediates PLK1-dependent binding to 53BP1, a dimerization-driven interaction necessary for mitotic stress memory, p53 stabilization, and cell cycle arrest. Cancer-associated missense mutations in this domain disrupt 53BP1 binding, impair nuclear localization, and destabilize USP28, compromising p53 stabilization. Notably, mutations in the 53BP1-binding domain occur more frequently in tumors than those in the catalytic domain, suggesting a potential role in cancer progression and implications for therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-025-66341-3
  10. Front Pharmacol. 2025 ;16 1662556
    Structure-based identification of Jervine as a potent dual-targeting inhibitor of cell cycle kinases.
    Md Nayab Sulaimani, Khadija Imtiyaz, Md Imtaiyaz Hassan, Fohad Mabood Husain, Aanchal Rathi, Mir Ovais Farooq, Anam Ashraf, Ravins Dohare, Sukhwinder Singh Sohal, Saba Noor.
      Mitotic regulators play an essential role in cell cycle progression by ensuring correct chromosomal alignment, segregation, DNA replication, repair, and division, thereby maintaining genomic stability. Aberrant activity of cell cycle kinases, including aurora kinase B (AURKB) and cyclin-dependent kinase 1 (CDK1), might lead to disrupted mitotic checkpoints, causing aneuploidies and uncontrolled proliferation, which are critical hallmarks of cancers. Targeted inhibition of cell cycle kinases is an attractive strategy to combat cancers with minimal side effects. This study employed a comprehensive multi-staged computational approach to discover dual-targeting inhibitors against AURKB and CDK1, which are reported as key promoters of tumorigenesis. High-throughput screening of phytochemicals available in the Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) database was conducted to identify common lead/s from top hits. Jervine (IMPHY000366), a steroid alkaloid, emerged as a common compound depicting high binding affinity and ligand efficiency for AURKB and CDK1. In addition, this compound qualified all drug-like filters. After structure analysis, the docked complex was subjected to 300 ns MD simulation studies, confirming structural integrity in AURKB and CDK1 upon binding of Jervine. H-bonding pattern, secondary structural content, free energy landscape, and principal component analysis further supported Jervine's strong and stable affinity for AURKB and CDK1. Lastly, MMPBSA showed a higher negative free energy in the presence of Jervine than VX-680 when complexed with AURKB. Finally, our results suggest that Jervine is a potent, dual-targeting kinase inhibitor with favourable pharmacokinetic and therapeutic properties, warranting further experimental validation for anticancer drug development.
    Keywords:  MD simulation; aurora kinase B; cyclin-dependent kinase 1; drug discovery; high-throughput screening; kinase inhibitors; natural products
    DOI:  https://doi.org/10.3389/fphar.2025.1662556
  11. Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2520310122
    Organization principles of dynamic three-dimensional genome architecture associated with centromere clustering states.
    Satya Dev Polisetty, Shuvadip Dutta, Rakesh Netha Vadnala, Dimple Notani, Ranjith Padinhateeri, Kaustuv Sanyal.
      Fungal centromeres are clustered near microtubule organizing centers to help adopt the Rabl chromosomal organization. The role of centromere clustering in driving large-scale changes in structural and functional chromatin assembly remains unclear. Here, using Hi-C and superresolution microscopy, we show that cell cycle-dependent centromere declustering and clustering states in Cryptococcus neoformans drive global changes in the 3D genome architecture. Centromeres and telomeres are scattered around the nuclear periphery at interphaseG1, and this arrangement constrains the interarm interactions within a chromosome, providing a unique interphaseG1 chromosome organization. Moreover, centromeres and telomeres are organized as separate compartments, segregating them from active euchromatic regions. Polymer modeling reveals that the transition from the unclustered to clustered centromere state during the cell cycle involves changes from a globular to an elongated chromosome architecture. Strikingly, while clustered centromeric regions replicate early in most yeasts, C. neoformans centromeres replicate late in S-phase, hinting at a possible link between centromere clustering dynamics and CEN DNA replication timing. Overall, our study uncovers several unique organizational principles governing the dynamic genome architecture in an evolutionarily diverged basidiomycete yeast.
    Keywords:  3D genome; DNA replication timing; Rabl configuration; centromere clustering
    DOI:  https://doi.org/10.1073/pnas.2520310122
  12. Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2528526122
    Mutations and mitotic recombination events in nondividing cells.
    Martin Kupiec.
      
    DOI:  https://doi.org/10.1073/pnas.2528526122
  13. EMBO Rep. 2025 Dec 08.
    A low-level Cdkn1c/p57kip2 expression in spinal progenitors drives the transition from proliferative to neurogenic modes of division.
    Baptiste Mida, Nathalie Lehmann, Rosette Goïame, Fanny Coulpier, Kamal Bouhali, Isabelle Barbosa, Hervé le Hir, Morgane Thomas-Chollier, Evelyne Fischer, Xavier Morin.
      During vertebrate neurogenesis, a transition from symmetric proliferative to asymmetric neurogenic divisions is critical to balance growth and differentiation. Using single-cell RNA-seq data from the chick embryonic neural tube, we identify the cell cycle regulator Cdkn1c as a key regulator of this transition. While Cdkn1 is classically associated with neuronal cell cycle exit, we show that its expression initiates at low levels in neurogenic progenitors. Functionally targeting the onset of this expression impacts the course of neurogenesis: Cdkn1c knockdown impairs neuron production by favoring proliferative symmetric divisions. Conversely, inducing a low-level Cdkn1c misexpression in self-expanding progenitors forces them to prematurely undergo neurogenic divisions. Cdkn1c exerts this effect primarily by inhibiting the CyclinD1-CDK4/6 complex and G1 phase lengthening. We propose that Cdkn1c acts as a dual driver of the neurogenic transition whose low level of expression first controls the progressive entry of progenitors into neurogenic modes of division before higher expression mediates cell cycle exit in daughter cells. This highlights that the precise control of neurogenesis regulators' expression sequentially imparts distinct functions essential for proper neural development.
    Keywords:  Cdkn1c; Cell Cycle; Modes of Division; Neurogenesis; Single-cell Transcriptomics
    DOI:  https://doi.org/10.1038/s44319-025-00653-9
  14. Mol Cells. 2025 Dec 10. pii: S1016-8478(25)00126-8. [Epub ahead of print] 100302
    Cellular Dynamics and Molecular Signaling Networks of Plant Cytokinesis.
    Jiwon Choi, Geert De Jaeger, Hoo Sun Chung.
      Cytokinesis, the final stage of cell division, physically partitions cytoplasm between daughter cells through mechanisms evolved to accommodate unique cellular constraints. Plant cells divide by the formation of rigid cell walls using the phragmoplast-a specialized structure guiding centrifugal cell plate formation from the cell center outward. Despite structural differences from the animal contractile ring mechanism, plant and animal cytokinesis share fundamental similarities in division plane determination, vesicle trafficking, and conserved proteins, including kinesins and microtubule-associated proteins. This conservation alongside kingdom-specific adaptations makes plant cytokinesis an excellent model for understanding evolutionary divergence. Recent technological advances have enabled detailed characterization of molecular components and regulatory networks controlling spatiotemporal progression through post-translational modifications. In this review, we provide an integrated perspective of plant cytokinesis, examining cellular dynamics from division plane determination to cell plate maturation, molecular machinery driving these processes, and kinase-mediated regulatory networks ensuring precise coordination of this complex process.
    Keywords:  Cell division; Phragmoplast dynamics; Plant cytokinesis; Protein kinase signaling; Spatiotemporal regulation
    DOI:  https://doi.org/10.1016/j.mocell.2025.100302
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