bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–02–09
twenty-one papers selected by
Valentina Piano, Uniklinik Köln



  1. Sci Adv. 2025 Feb 07. 11(6): eadq4033
      Proper chromosome segregation during cell division is essential for genomic integrity and organismal development. This process is monitored by the spindle assembly checkpoint (SAC), which delays anaphase onset until all chromosomes are properly attached to the mitotic spindle. The kinetochore protein KNL1 plays a critical role in recruiting SAC proteins. Here, we reveal that Arabidopsis KNL1 regulates SAC silencing through the direct recruitment of type one protein phosphatase (TOPP) to kinetochores. We show that KNL1 interacts with all nine TOPPs via a conserved RVSF motif in its N terminus, and this interaction is required for the proper localization of TOPPs to kinetochores during mitosis. Disrupting KNL1-TOPP interaction leads to persistent SAC activation, resulting in a severe metaphase arrest and defects in plant growth and development. Our findings highlight the evolutionary conservation of KNL1 in coordinating kinetochore-localized phosphatase to ensure timely SAC silencing and faithful chromosome segregation in Arabidopsis.
    DOI:  https://doi.org/10.1126/sciadv.adq4033
  2. Life Sci Alliance. 2025 Apr;pii: e202403140. [Epub ahead of print]8(4):
      Either inhibiting or stabilizing SUMOylation in mitosis causes defects in chromosome segregation, suggesting that dynamic mitotic SUMOylation of proteins is critical to maintain integrity of the genome. Polo-like kinase 1-interacting checkpoint helicase (PICH), a mitotic chromatin remodeling enzyme, interacts with SUMOylated chromosomal proteins via three SUMO-interacting motifs (SIMs) to control their association with chromosomes. Using cell lines with conditional PICH depletion/PICH replacement, we revealed mitotic defects associated with compromised PICH functions toward SUMOylated chromosomal proteins. Defects in either remodeling activity or SIMs of PICH delayed mitotic progression caused by activation of the spindle assembly checkpoint (SAC) indicated by extended duration of Mad1 foci at centromeres. Proteomics analysis of chromosomal SUMOylated proteins whose abundance is controlled by PICH activity identified candidate proteins to explain the SAC activation phenotype. Among the identified candidates, Bub1 kinetochore abundance is increased upon loss of PICH. Our results demonstrated a novel relationship between PICH and the SAC, where PICH directly or indirectly affects Bub1 association at the kinetochore and impacts SAC activity to control mitosis.
    DOI:  https://doi.org/10.26508/lsa.202403140
  3. Front Cell Dev Biol. 2024 ;12 1491394
      The spindle assembly checkpoint (SAC) is a surveillance mechanism that prevents uneven segregation of sister chromatids between daughter cells during anaphase. This essential regulatory checkpoint prevents aneuploidy which can lead to various congenital defects observed in newborns. Many studies have been carried out to elucidate the role of proteins involved in the SAC as well as the function of the checkpoint during gametogenesis and embryogenesis. In this review, we discuss the role of SAC proteins in regulating both meiotic and mitotic cell division along with several factors that influence the SAC strength in various species. Finally, we outline the role of SAC proteins and the consequences of their absence or insufficiency on proper gametogenesis and embryogenesis in vivo.
    Keywords:  embryogenesis; gametogenesis; mitosis; mitotic checkpoint; spindle assembly checkpoint
    DOI:  https://doi.org/10.3389/fcell.2024.1491394
  4. Front Cell Dev Biol. 2024 ;12 1510019
      Faithful chromosome segregation is crucial for cell division in eukaryotes, facilitated by the kinetochore, a multi-subunit protein complex that connects chromosomes to the spindle microtubules. Recent research has significantly advanced our understanding of kinetochore function in plants, including surprising findings about spindle assembly checkpoint, the composition of the inner kinetochore and unique kinetochore arrangement in holocentric Cuscuta species. Additionally, some kinetochore proteins in plants have been implicated in roles beyond chromosome segregation, such as cytokinesis regulation and involvement in developmental processes. This review summarizes recent insights into plant kinetochore biology, compares plant kinetochores with those of animals and fungi, and highlights key open questions and potential future directions in the field.
    Keywords:  cell division; chromosome; kinetochore; mitosis; plant; spindle
    DOI:  https://doi.org/10.3389/fcell.2024.1510019
  5. J Cell Biol. 2025 Mar 03. pii: e202311194. [Epub ahead of print]224(3):
      The Ras homolog (Rho) small GTPases coordinate diverse cellular functions including cell morphology, adhesion and motility, cell cycle progression, survival, and apoptosis via their role in regulating the actin cytoskeleton. The upstream regulators for many of these functions are unknown. ARHGEF17 (also known as TEM4) is a Rho family guanine nucleotide exchange factor (GEF) implicated in cell migration, cell-cell junction formation, and the mitotic checkpoint. In this study, we characterize the regulation of the cell cycle by TEM4. We demonstrate that TEM4-depleted cells exhibit multiple defects in mitotic entry and duration, spindle morphology, and spindle orientation. In addition, TEM4 insufficiency leads to excessive cortical actin polymerization and cell rounding defects. Mechanistically, we demonstrate that TEM4-depleted cells delay in G1 as a consequence of decreased expression of the proproliferative transcriptional co-activator YAP. TEM4-depleted cells that progress through to mitosis do so with decreased levels of cyclin B as a result of attenuated expression of CCNB1. Importantly, cyclin B overexpression in TEM4-depleted cells largely rescues mitotic progression and chromosome segregation defects in anaphase. Our study thus illustrates the consequences of Rho signaling imbalance on cell cycle progression and identifies TEM4 as the first GEF governing Rho GTPase-mediated regulation of G1/S.
    DOI:  https://doi.org/10.1083/jcb.202311194
  6. PLoS Genet. 2025 Feb 04. 21(2): e1011576
      Aneuploidy typically poses challenges for cell survival and growth. However, recent studies have identified exceptions where aneuploidy is beneficial for cells with mutations in certain regulatory genes. Our research reveals that cells lacking the spindle checkpoint gene BUB3 exhibit aneuploidy of select chromosomes. While the spindle checkpoint is not essential in budding yeast, the loss of BUB3 and BUB1 increases the probability of chromosome missegregation compared to wildtype cells. Contrary to the prevailing assumption that the aneuploid cells would be outcompeted due to growth defects, our findings demonstrate that bub3Δ cells consistently maintained aneuploidy of specific chromosomes over many generations. We investigated whether the persistence of these additional chromosomes in bub3Δ cells resulted from the beneficial elevated expression of certain genes, or mere tolerance. We identified several genes involved in chromosome segregation and cell cycle regulation that confer an advantage to Bub3-depleted cells. Overall, our results suggest that the gain of specific genes through aneuploidy may provide a survival advantage to strains with poor chromosome segregation fidelity.
    DOI:  https://doi.org/10.1371/journal.pgen.1011576
  7. Comput Struct Biotechnol J. 2025 ;27 321-332
      Mitotic checkpoints orchestrate cell division through intricate molecular networks that ensure genomic stability. While experimental research has uncovered key aspects of checkpoint function, the complexity of protein interactions and spatial dynamics necessitates computational modeling for a deeper, system-level understanding. This review explores mathematical frameworks-from ordinary differential equations to stochastic simulations, which reveal checkpoint dynamics across multiple scales, encompassing models ranging from simple protein interactions to whole-system simulations with thousands of parameters. These approaches have elucidated fundamental properties, including bistable switches driving spindle assembly checkpoint (SAC) activation, spatial organization principles underlying spindle position checkpoint (SPOC) signaling, and critical system-level features ensuring checkpoint robustness. This study evaluates diverse modeling approaches, from rule-based models to chemical organization theory, highlighting their successful application in predicting protein localization patterns and checkpoint response dynamics validated through live-cell imaging. Contemporary challenges persist in integrating spatial and temporal scales, refining parameter estimation, and enhancing spatial modeling fidelity. However, recent advances in single-molecule imaging, data-driven algorithms, and machine learning techniques, particularly deep learning for parameter optimization, present transformative opportunities for improving model accuracy and predictive power. By bridging molecular mechanisms with system-level behaviors through validated computational frameworks, this review offers a comprehensive perspective on the mathematical modeling of cell cycle control, with practical implications for cancer research and therapeutic development.
    Keywords:  34C60; 37N25; 92C37; 92C42; Modeling techniques; Simulations; Spindle assembly checkpoint; Spindle positioning checkpoint; Tools
    DOI:  https://doi.org/10.1016/j.csbj.2024.12.021
  8. Sci Adv. 2025 Feb 07. 11(6): eadq9549
      Mitotic centrosomes assemble when centrioles recruit large amounts of pericentriolar material (PCM) around themselves. The PCM comprises hundreds of proteins, and there is much debate about its physical nature. Here, we show that Drosophila Spd-2 (human CEP192) fluxes out from centrioles, recruiting Polo and Aurora A kinases to catalyze the assembly of two distinct mitotic-PCM scaffolds: a Polo-dependent Cnn scaffold, and an Aurora A-dependent TACC scaffold, which exhibit solid- and liquid-like behaviors, respectively. Both scaffolds can independently recruit PCM proteins, but both are required for proper centrosome assembly, with the Cnn scaffold providing mechanical strength, and the TACC scaffold concentrating centriole and centrosome proteins. Recruiting Spd-2 to synthetic beads injected into early embryos reconstitutes key aspects of mitotic centrosome assembly on the bead surface, and this depends on Spd-2's ability to recruit Polo and Aurora A. Thus, Spd-2 orchestrates the assembly of two scaffolds, with distinct biophysical properties, that cooperate to build mitotic centrosomes in flies.
    DOI:  https://doi.org/10.1126/sciadv.adq9549
  9. Nat Plants. 2025 Jan 31.
      The nuclear pore complex (NPC) is a cornerstone of eukaryotic cell functionality, orchestrating the nucleocytoplasmic shuttling of macromolecules. Here we report that Plant Nuclear Envelope Transmembrane 1 (PNET1), a transmembrane nucleoporin, is an adaptable NPC component that is mainly expressed in actively dividing cells. PNET1's selective incorporation into the NPC is required for rapid cell growth in highly proliferative meristem and callus tissues in Arabidopsis. We demonstrate that the cell cycle-dependent phosphorylation of PNET1 coordinates mitotic disassembly and post-mitotic reassembly of NPCs during the cell cycle. PNET1 hyperphosphorylation disrupts its interaction with the NPC scaffold, facilitating NPC dismantling and nuclear membrane breakdown to trigger mitosis. In contrast, nascent, unphosphorylated PNET1 is incorporated into the nuclear pore membrane in the daughter cells, where it restores interactions with scaffolding nucleoporins for NPC reassembly. The expression of the human PNET1 homologue is required for and markedly upregulated during cancer cell growth, suggesting that PNET1 plays a conserved role in facilitating rapid cell division during open mitosis in highly proliferative tissues.
    DOI:  https://doi.org/10.1038/s41477-025-01908-y
  10. Cancer Lett. 2025 Feb 03. pii: S0304-3835(25)00090-4. [Epub ahead of print] 217526
      High Myc phenotypes are extensively documented in the hyperproliferative cell cycle of cancer cells, as well as non-proliferative endoreplication cycles engaged during normal development and stress response. Notably, endoreplication in cancer produces chemotherapy resistant polyploid cells, necessitating a clearer understanding of altered cell cycle regulation that uncouples DNA replication and mitotic cell division. The c-Myc oncogene is a well-established transcriptional regulator of cell cycle progression and has been extensively published as an essential driver of the G1/S transition. Beyond S phase, Myc transcriptionally activates the proteins that drive mitotic entry. Sustained activation of Myc through the cell cycle transcriptionally couples DNA replication and mitotic cell division. Based on the literature in this field, we propose a new model of temporal regulation of Myc activity that serves to either couple or uncouple these two processes, determining cell cycle fate - proliferation or polyploidy. The mitotic cell cycle requires two pulses of Myc activity - the first driving the G1/S transition and the second driving the G2/M transition. During mitosis, Myc activity must be silenced to achieve high-fidelity division. Absence of the second activity pulse during G2 results in the downregulation of the proteins essential for mitotic entry and permits premature activation of APC/C, inducing mitotic bypass. A subsequent rise of Myc activity following mitotic bypass permits genome re-replication, driving polyploid phenotypes. This model serves to provide a new level of understanding to the global regulation of S phase-mitosis coupling, as well as a new lens to view low Myc phenotypes.
    DOI:  https://doi.org/10.1016/j.canlet.2025.217526
  11. MicroPubl Biol. 2025 ;2025
      In C. elegans , dhc-1 ( or283 ); mel-28 ( t1684 ) double mutants have a severely reduced brood size compared with each single mutant and compared to the wild type. To determine if this synthetic low-fecundity phenotype is due to reduced potential to produce gametes, we studied gonad length and distal gonad mitotic activity in dhc-1 ( or283 ) mutants, mel-28 ( t1684 ) mutants, wild-type animals, and dhc-1 ( or283 ); mel-28 ( t1684 ) double mutants. Gonad length in dhc-1 ; mel-28 double mutants was the same as the wild type. Using an antibody against phosphorylated histone H3 (PH3), we tracked mitotic activity in mutant and wild-type gonads. We found no significant difference in mitotic activity between the double mutant and the wild-type. These observations suggest that the reduced brood size in dhc-1 ; mel-28 double mutants is not caused by a mitotically-inactive gonad and instead has a different and yet-to-be-determined basis.
    DOI:  https://doi.org/10.17912/micropub.biology.001445
  12. Curr Biol. 2025 Feb 03. pii: S0960-9822(24)01639-7. [Epub ahead of print]35(3): R91-R93
      Spatiotemporal control of subcellular events is crucial for embryogenesis. A new study in fruit flies reports that the speed of chromosome segregation upon nuclear division robustly scales with spindle size and cell-cycle duration, both of which change during development.
    DOI:  https://doi.org/10.1016/j.cub.2024.11.072
  13. Genetics. 2025 Feb 01. pii: iyaf020. [Epub ahead of print]
      Asymmetric cell division is essential for the creation of cell types with different identities and functions. The EMS blastomere of the four-cell Caenorhabditis elegans embryo undergoes an asymmetric division in response to partially redundant signaling pathways. One pathway involves a Wnt signal from the neighboring P2 cell, while the other pathway is defined by the receptor-like MES-1 transmembrane protein localized at the EMS-P2 cell contact, and the cytoplasmic kinase SRC-1. In response to these signals, the EMS nuclear-centrosome complex rotates so that the spindle forms on the anterior-posterior axis; after division, the daughter cell contacting P2 becomes the endodermal precursor cell. Here we identify the Rac1 homolog CED-10 as a new component of the MES-1/SRC-1 pathway. Loss of CED-10 affects both spindle positioning and endoderm specification in the EMS cell. SRC-1 dependent phosphorylation at the EMS-P2 contact is reduced. However, the asymmetric division of the P2 cell, which is also MES-1 and SRC-1 dependent, appears normal in ced-10 mutants. These and other results suggest that CED-10 acts upstream of, or at the level of, SRC-1 activity in the EMS cell. In addition, we find that the branched actin regulator ARX-2 is enriched at the EMS-P2 cell contact site, in a CED-10 dependent manner. Loss of ARX-2 results in EMS spindle orientation defects, suggesting that CED-10 acts through branched actin to promote spindle orientation in the EMS cell.
    Keywords:   C. elegans ; Rac; Src; Wnt; branched actin; spindle orientation
    DOI:  https://doi.org/10.1093/genetics/iyaf020
  14. J Cell Sci. 2025 Feb 07. pii: jcs.263747. [Epub ahead of print]
      Evolutionarily conserved Mis4 establishes cohesion between replicated sister chromatids in vegetatively proliferating cells. In the fission yeast, Schizosaccharomyces pombe, defects in Mis4 lead to premature separation of sister chromatids, resulting in fatal chromosome mis-segregation during mitosis. In humans, NIPBL, an ortholog of Mis4, is responsible for a multisystem disorder called Cornelia de Lange syndrome. We reported that Mis4 is also essential in non-proliferating quiescent cells. Whereas wild-type fission yeast cells can maintain high viability for long periods without cell division in the quiescent G0 phase, mis4-450 mutant cells cannot. Here, we show that Mis4 is not required for cells to enter G0 phase, but is essential for them to exit from it. When resuming mitosis after passage of G0, mis4 mutant cells segregated sister chromatid successfully, but failed to separate daughter nuclei completely and consequently formed dikaryon-like cells. These findings suggest a novel role for Mis4/NIPBL in quiescent cells, which is prerequisite for full nuclear separation upon resumed mitosis. As most human cells are in a quiescent state, this study may facilitate development of novel therapies for human diseases caused by Mis4/NIPBL deficiency.
    Keywords:  Cohesin; Dikaryon; Fission yeast; Quiescence
    DOI:  https://doi.org/10.1242/jcs.263747
  15. Circulation. 2025 Feb 06.
       BACKGROUND: Cytokinesis is the last step in the eukaryotic cell cycle, which physically separates a mitotic cell into 2 daughter cells. A few days after birth in mouse cardiomyocytes, DNA synthesis occurs without cytokinesis, leading to the majority of cardiomyocytes becoming binucleated instead of generating 2 daughter cells with 1 nucleus each. This results in cell cycle arrest of cardiomyocytes, and the mouse heart is no longer able to regenerate. A longstanding unanswered question is whether binucleation of cardiomyocytes is a result of cytokinesis failure.
    METHODS: To address this, we generated several transgenic mouse models to determine whether forced induction of cardiomyocyte cytokinesis generates mononucleated cardiomyocytes and restores the endogenous regenerative properties of the myocardium. We focused on 2 complementary regulators of cytokinesis: Plk1 (polo-like kinase 1) and Ect2 (epithelial cell-transformation sequence 2).
    RESULTS: We found that cardiomyocyte-specific transgenic overexpression of constitutively active Plk1(T210D) promotes mitosis and cytokinesis in adult hearts, whereas overexpression of Ect2 alone promotes only cytokinesis. Cardiomyocyte-specific overexpression of both Plk1(T210D) and Ect2 concomitantly (double transgenic) prevents binucleation of cardiomyocytes postnatally and results in widespread cardiomyocyte mitosis, cardiac enlargement, contractile failure, and death before 2 weeks of age. Similarly, doxycycline-inducible cardiomyocyte-specific overexpression of both proteins (inducible double transgenic) in the adult heart results in reversible widespread cardiomyocyte mitosis and contractile failure. Transient induction of both genes in adult mice improves left ventricular systolic function after myocardial infarction.
    CONCLUSIONS: These results collectively demonstrate that cytokinesis failure mediates cardiomyocyte multinucleation and cell cycle exit of postnatal cardiomyocytes, but may be a protective mechanism to preserve the contractile function of the myocardium.
    Keywords:  cytokinesis; myocardium; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.065763
  16. Clin Pharmacol Ther. 2025 Feb 05.
      Aurora kinases are a family of serine/threonine kinases that includes Aurora kinase A, Aurora kinase B, and Aurora kinase C. These kinases play crucial roles in mitotic spindle formation and cell proliferation. Over the past several decades, extensive research has elucidated the multifaceted roles of Aurora kinases in cancer development and progression. Recent studies have also highlighted the significant involvement of Aurora kinases in various kidney diseases, such as renal cell carcinoma, diabetic nephropathy, chronic kidney disease, and polycystic kidney disease. The mechanisms by which Aurora kinases contribute to renal diseases are complex and influenced by both specific pathological conditions and environmental factors. In this review, we comprehensively summarize the role and mechanisms through which Aurora kinases operate in kidney diseases and discuss the efficacy and application of existing inhibitors targeting these kinases in managing renal disorders in animal models.
    DOI:  https://doi.org/10.1002/cpt.3584
  17. Nat Cell Biol. 2025 Jan 31.
      During early embryogenesis, fast mitotic cycles without interphase lead to a decrease in cell size, while scaling mechanisms must keep cellular structures proportional to cell size. For instance, as cells become smaller, if the position of nuclear envelope reformation (NER) did not adapt, NER would have to occur beyond the cell boundary. Here we found that NER position in anaphase scales with cell size via changes in chromosome motility, mediated by cytoplasmic flows that themselves scale with cell size. Flows are a consequence of friction between viscous cytoplasm and bulky cargo transported by dynein on astral microtubules. As an emerging property, confinement in cells of different sizes yields scaling of cytoplasmic flows. Thus, flows behave like a cell geometry sensor: astral microtubules approach the boundary causing flow velocity changes, which then affect the velocity of chromosome separation, thus scaling NER.
    DOI:  https://doi.org/10.1038/s41556-024-01605-6
  18. Theriogenology. 2025 Mar 15. pii: S0093-691X(25)00018-4. [Epub ahead of print]235 254-261
      KIFC1 is a motor protein of the Kinesin family and it is involved in spindle apparatus assembly, chromosome arrangement, and microfilament-mediated biological processes in mitosis. However, the specific function of KIFC1 in pig oocytes remains unclear. Here, in order to explore the function of KIFC1 in porcine oocytes, the AZ82 inhibitor was used to inhibit the activity of KIFC1. Our results showed when KIFC1 was inhibited, the polar body extrusion rate was obviously decreased, indicating that KIFC1 plays a crucial role in porcine oocytes. We next measured the spindle structure and chromosome arrangement via immunofluorescent staining and found both the rates of abnormal spindle and chromosome disorder increased significantly. By further analyzing the causes of the abnormal spindle, we found the acetylation of tubulin was disrupted. In addition, we also found the spindle position was impaired after KIFC1 inhibition, declaring the spindle migration was affected. Further analysis found cortex actin decreased and cytoplasmic actin increased after KIFC1 inhibition. In summary, we found that KIFC1 played a critical role in porcine oocytes maturation by controlling spindle apparatus via mediating the acetylation of microtubule and regulating the spindle migration via affecting actin dynamics.
    Keywords:  KIFC1; Meiosis; Oocyte; actin; spindle
    DOI:  https://doi.org/10.1016/j.theriogenology.2025.01.012
  19. Adv Sci (Weinh). 2025 Feb 04. e2409769
      Immune checkpoint inhibitor (ICI) therapy is a promising anti-tumor therapeutic strategy; however, its efficacy in solid tumors is limited. Chromosome missegregation is common in various solid tumors; however, its role in tumor progression remains poorly understood, and its correlation with ICI is yet to be explored. Here, it is found that increased chromosome missegregation promotes tumor immune microenvironment, and eventually immunotherapeutic efficacy, by triggering pyroptosis. yin yang 2 (YY2) is identified as a mitotic checkpoint regulator, which promotes chromosome missegregation by upregulating BUB1B transcription. Increased chromosome missegregation promoted the formation of micronuclei and release of double-stranded DNA (dsDNA) into the cytosol, triggering an AIM2-mediated cytosolic dsDNA response. The subsequent pyroptosis strengthened the tumor immune microenvironment, thereby enhancing immunoinfiltration and cytotoxicity of CD8+ T cells, while preventing their exhaustion. Finally, through in vitro and in vivo experiments, it is demonstrated that combining YY2 overexpression-induced chromosome missegregation/cytosolic dsDNA response and PD-1 inhibitor significantly enhanced the efficacy of ICI immunotherapy in microsatellite instable and microsatellite stable colorectal cancer cells. Together, these findings provide new insights on the role of chromosome missegregation in triggering cytosolic dsDNA response-mediated pyroptosis and modulating the tumor immune microenvironment, suggesting a novel strategy for improving ICI therapeutic efficacy in colorectal cancer.
    Keywords:  CD8+ T cell; anti‐tumor immunotherapy; chromosome missegregation; cytosolic dsDNA response; micronucleus; pyroptosis; yin yang 2
    DOI:  https://doi.org/10.1002/advs.202409769