bims-micesi 2025-09-28 papers

bims-micesi

Biomed News

on Mitotic cell signalling

Issue of 2025–09–28
twelve papers selected by
Valentina Piano, Uniklinik Köln

The kinesin motor Kif9 regulates centriolar satellite positioning during interphase.
PBK/TOPK mediates Ikaros, Aiolos and CTCF displacement from mitotic chromosomes and alters chromatin accessibility at selected C2H2-zinc finger protein binding sites.
Kinesin Spindle Protein (KIF11) in Mitosis and Cancer.
Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation.
Progressive chromosome shape changes during cell divisions.
Endomitosis: a new cell fate in the cell cycle leading to polyploidy in megakaryocytes and hepatocytes.
Differential splice isoforms of mouse CDK2 play functionally redundant roles during mitotic and meiotic division.
Mitotic Disruption and Cytoskeletal Alterations Induced by Acorus calamus Essential Oil: Implications for Bioherbicidal Potential.
Targeting Aurora A kinase: Computational discovery of potent inhibitors through integrated pharmacophore and simulation approaches.
Asymmetric centromere and gene locus positioning in Drosophila neural stem cells.
DNA binding and mitotic phosphorylation: native mechanisms preventing polyglutamine protein aggregation.
Segregation of sister chromosomes during the shape change of developing Myxococcus xanthus cells.

Curr Biol. 2025 Sep 19. pii: S0960-9822(25)01130-3. [Epub ahead of print]

The kinesin motor Kif9 regulates centriolar satellite positioning during interphase.

Juan Jesus Vicente, Michael Wagenbach, Justin Decarreau, Alex Zelter, Michael J MacCoss, Trisha N Davis, Linda Wordeman.

  Centrosomes are the principal microtubule-organizing centers of the cell, are cellular hubs for protein degradation, and play an essential role in mitotic spindle function that ultimately regulates chromosome segregation during mitosis. Centrosome maturation is achieved by strict control of protein acquisition and phosphorylation prior to mitosis. Defects in this process during interphase promote fragmentation of pericentriolar material once cells enter mitosis due to the increased forces exerted over the centrosome by the mitotic spindle, finally culminating in multipolar spindles and chromosome missegregation. Centriolar satellites, membrane-less assemblies of proteins involved in the trafficking of proteins toward and away from the centrosome, are thought to contribute to centrosome biogenesis. Moreover, centriolar satellites also regulate the quantity of proteolytic factors reaching the centrosome. Here, we show that the microtubule plus-end-directed kinesin motor Kif9 localizes to centriolar satellites and regulates their pericentrosomal localization during interphase. Lack of Kif9 leads to aggregation of satellites closer to the centrosome and increased centrosomal protein degradation that disrupts centrosome maturation and results in chromosome congression and segregation defects during mitosis. Our data show that the kinesin Kif9 controls the position of centriolar satellites relative to the centrosome and reveal roles for Kif9 and centriolar satellites in the regulation of cellular proteostasis and mitosis.

Keywords:  Kif9; PCM1; centriolar satellites; centrosome; chromosome congression; chromosome missegregation; kinesin; microtubules; mitosis; pericentriolar material

DOI:  https://doi.org/10.1016/j.cub.2025.08.064
Nat Commun. 2025 Sep 23. 16(1): 8348

PBK/TOPK mediates Ikaros, Aiolos and CTCF displacement from mitotic chromosomes and alters chromatin accessibility at selected C2H2-zinc finger protein binding sites.

Andrew Dimond, Do Hyeon Gim, Elizabeth Ing-Simmons, Chad Whilding, Holger B Kramer, Dounia Djeghloul, Alex Montoya, Bhavik Patel, Sherry Cheriyamkunnel, Karen E Brown, Pavel V Shliaha, Juan M Vaquerizas, Matthias Merkenschlager, Amanda G Fisher.

PBK/TOPK is a mitotic kinase implicated in haematological and non-haematological cancers. Here we show that the key haemopoietic regulators Ikaros and Aiolos require PBK-mediated phosphorylation to dissociate from chromosomes in mitosis. Eviction of Ikaros is rapidly reversed by addition of the PBK-inhibitor OTS514, revealing dynamic regulation by kinase and phosphatase activities. To identify more PBK targets, we analysed loss of mitotic phosphorylation events in Pbk-/- preB cells and performed proteomic comparisons on isolated mitotic chromosomes. Among a large pool of C2H2-zinc finger targets, PBK is essential for evicting the CCCTC-binding protein CTCF and zinc finger proteins encoded by Ikzf1, Ikzf3, Znf131 and Zbtb11. PBK-deficient cells were able to divide but showed altered chromatin accessibility and nucleosome positioning consistent with CTCF retention. Our studies reveal that PBK controls the dissociation of selected factors from condensing mitotic chromosomes and contributes to their compaction.

DOI: https://doi.org/10.1038/s41467-025-63740-4
Int J Mol Sci. 2025 Sep 15. pii: 8975. [Epub ahead of print]26(18):

Kinesin Spindle Protein (KIF11) in Mitosis and Cancer.

João P N Silva, Patrícia M A Silva, Hassan Bousbaa.

  Kinesin spindle protein (KSP), also known as KIF11, is a member of the kinesin superfamily of motor proteins that plays a pivotal role in mitosis by regulating spindle assembly, chromosome alignment, and segregation. Its motor activity, which is essential for the proper organization of microtubules during mitosis, is crucial for maintaining genomic stability. KSP overexpression has been observed in several cancer types, where it promotes uncontrolled cell proliferation, making it a promising target for cancer therapy. This review provides a comprehensive analysis of the molecular mechanisms underlying KSP function, including its structural features, ATPase activity, and interactions with other mitotic proteins. Additionally, we review the regulation of KSP through post-translational modifications, such as phosphorylation, as well as the therapeutic strategies currently being explored to inhibit its activity in cancer treatment.

Keywords:  KIF11; KSP; cancer; cancer therapy; mitosis; molecular motor

DOI:  https://doi.org/10.3390/ijms26188975
Dev Cell. 2025 Sep 24. pii: S1534-5807(25)00537-4. [Epub ahead of print]

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation.

Catherine A Tower, Gabriel Manske, Emily L Ferrell, Dilara N Anbarci, Kelsey Jorgensen, Binbin Ma, Mansour Aboelenain, Rajesh Ranjan, Saikat Chakraborty, Lindsay Moritz, Arunika Das, Michele Boiani, Ben E Black, Shawn Chavez, Erica E Marsh, Ariella Shikanov, Karen Schindler, Xin Chen, Saher Sue Hammoud.

  Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation during the mammalian parental-to-zygote transition is poorly understood. To address this, we generated a CENP-A-mScarlet mouse model that revealed sex-specific dynamics: mature sperm retain 10% of the CENP-A levels present in MII oocytes. However, this difference is resolved in zygotes prior to the first mitosis, using maternally inherited cytoplasmic CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on the asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in both pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization function impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts as a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity.

Keywords:  CENP-A; CENP-C; MIS18BP1; centromere; epigenetics; intergenerational; mouse; oocyte; sperm; zygote

DOI:  https://doi.org/10.1016/j.devcel.2025.08.017
EMBO Rep. 2025 Sep 23.

Progressive chromosome shape changes during cell divisions.

Yasutaka Kakui, Yoshiharu Kusano, Tereza Clarence, Maya Lopez, Todd Fallesen, Toru Hirota, Bhavin S Khatri, Frank Uhlmann.

  Mitotic chromosomes give genome portions the required compaction and mechanical stability for faithful inheritance during cell divisions. They are shaped by the chromosomal condensin complex. Here, we record human chromosome dimensions from their appearance in prophase over successive times in a mitotic arrest. Chromosomes first appear long and uniformly thin. Then, individual chromosome arms become discernible, which continuously shorten and thicken-the longer a chromosome arm, the thicker it becomes. In the search for a molecular explanation of this behavior, given uniform condensin density, the popular loop extrusion model provides no obvious means by which longer chromosome arms become thicker. Instead, we find that simulations of an alternative loop capture model recapitulate key features of our observations, with re-arranging chromatin rosettes underpinning the gradually developing arm length-to-width relationship. Our analyses portray chromosomes as out-of-equilibrium structures in the process of transitioning towards, but on biologically relevant time scales not typically reaching, steady state.

Keywords:  Chromosome Formation; Condensin; Loop Capture; Loop Extrusion; Polymer Simulations

DOI:  https://doi.org/10.1038/s44319-025-00577-4
J Zhejiang Univ Sci B. 2025 Sept 20;26(9):pii: 1673-1581(2025)09-0843-20. [Epub ahead of print]26(9): 843-862

Endomitosis: a new cell fate in the cell cycle leading to polyploidy in megakaryocytes and hepatocytes.

Qi-Hua Hua, Xuechun Zhang, Ruifeng Tian, Zhigang She, Zan Huang.

  Megakaryocytes and hepatocytes are unique cells in mammals that undergo polyploidization through endomitosis in terminal differentiation. Many polyploidization regulators and underlying mechanisms have been reported, most of which are tightly coupled with development, organogenesis, and cell differentiation. However, the nature of endomitosis, which involves successful entry into and exit from mitosis without complete cytokinesis, has not yet been fully elucidated. We highlight that endomitosis is a new cell fate in the cell cycle, and tetraploidy is a critical stage at the bifurcation of cell fate decision. This review summarizes the recent research progress in this area and provides novel insights into how cells manipulate mitosis toward endomitosis. Endomitotic cells can evade the tetraploidy restrictions and proceed to multiple rounds of the cell cycle. This knowledge not only deepens our understanding of endomitosis as a fundamental biological process but also offers new perspectives on the physiological and pathophysiological implications of polyploidization.

Keywords:  Cell cycle; Endomitosis; Hepatocyte; Megakaryocyte; Polyploidy; Tetraploidy checkpoint; Whole-genome doubling

DOI:  https://doi.org/10.1631/jzus.B2400127
J Cell Sci. 2025 Sep 22. pii: jcs.264291. [Epub ahead of print]

Differential splice isoforms of mouse CDK2 play functionally redundant roles during mitotic and meiotic division.

Nathan Palmer, Nisan Ece Kalem-Yapar, Hanna Hultén, Umur Keles, S Zakiah A Talib, Jin Rong Ow, Tommaso Tabaglio, Christine M F Goh, Li Na Zhao, Ernesto Guccione, Kui Liu, Philipp Kaldis.

  In most mammals, the cell cycle kinase; cyclin-dependent kinase 2 (CDK2) is expressed as two major isoforms due to alternative splicing. The shorter CDK2 isoform: CDK2S, is expressed constitutively during the cell cycle and can be detected in several tissues. In contrast, the longer isoform: CDK2L, shows preferential expression in meiotically dividing cells and upon S-phase entry in the mitotic cycle. Both CDK2L and CDK2S form heteromeric complexes with cyclins A2 and E1 in vitro. However, complexes comprised of each isoform differ considerably in their kinase activity towards known CDK substrates. It is currently unknown whether the long and short isoforms of CDK2 play functionally different roles in vivo during either mitotic and meiotic divisions as conventional knockout methodology deletes both of the isoforms. Therefore, we generated mice expressing only CDK2S or CDK2L and found that both CDK2L and CDK2S are sufficient to support both mitotic and meiotic division when expressed in the absence of the other. This data contributes to the explanation of the apparent tolerance of the evolutionary loss of CDK2L expression in humans.

Keywords:  CDK2; Gene function; Meiosis; Mitosis; Splicing

DOI:  https://doi.org/10.1242/jcs.264291
Int J Mol Sci. 2025 Sep 13. pii: 8933. [Epub ahead of print]26(18):

Mitotic Disruption and Cytoskeletal Alterations Induced by Acorus calamus Essential Oil: Implications for Bioherbicidal Potential.

Mateusz Wróblewski, Natalia Gocek, Aneta Żabka, Justyna T Polit.

  Essential oils are increasingly recognized as promising agents for sustainable weed control due to their selectivity and complex modes of action. This study evaluated the effects of Acorus calamus essential oil (SEO) on mitosis in two Fabaceae species (Vicia faba, Lupinus luteus) and two Brassicaceae species (Brassica napus, Arabidopsis thaliana) treated with species-specific IC50 concentrations (0.03%, 0.025%, 0.01%, and 0.005%, respectively). Previous research showed that SEO induces oxidative stress and S-phase delay via genome instability. Here, SEO consistently disrupted mitosis across all species, reducing mitotic index by 50-60%, decreasing Cdc2 (CDKA homolog) levels, and causing chromosomal aberrations, including uneven chromatin condensation, sticky chromosomes, bridges, and micronuclei. Cells accumulated in metaphase and exhibited abnormal karyokinetic and cytokinetic spindles. Immunolabeling revealed thick, tightly packed microtubules and actin filaments, indicating excessive stabilization and impaired reorganization. Epigenetic regulation was also affected: H3T3 phosphorylation was abnormally strong, widely distributed, and persistent into anaphase/telophase, while H3S10Ph intensity was weakened. These results suggest that SEO targets multiple components of mitotic machinery and epigenetic control, regardless of species. The observed selectivity depends on dosage, not mechanism. This multi-targeted action may limit the development of plant resistance, supporting the potential of SEO as a bioherbicide in sustainable agriculture.

Keywords:  CDKA; chromosomal aberrations; cytoskeleton; epigenetics; mitotic index; phytotoxicity

DOI:  https://doi.org/10.3390/ijms26188933
Comput Biol Chem. 2025 Sep 17. pii: S1476-9271(25)00351-2. [Epub ahead of print] 108690

Targeting Aurora A kinase: Computational discovery of potent inhibitors through integrated pharmacophore and simulation approaches.

Bhuvaneswari Sivaraman, Kathiravan Muthukumaradoss.

  Cancer currently ranks as the second most common cause of mortality worldwide, primarily due to uncontrolled cell growth driven by aberrant mitotic processes. Aurora A kinase (AURKA), a key regulator of mitosis involved in centrosome maturation, bipolar spindle formation, and cytokinesis, has been identified as a promising anticancer target. This study employs a comprehensive computational approach to identify new AURKA inhibitors. Using MOE software, a ligand-based pharmacophore model was developed based on six potent AURKA inhibitors. The model, consisting of three features-Aro/HydA, Acc, and Don/Acc-at an 80 % threshold, demonstrated strong discriminative power with a sensitivity of 69.8 %, specificity of 63.6 %, and accuracy of 60.4 %. Screening of the ZINC database yielded 774 hits, from which A1 (ZINC63106872) and A2 (ZINC39272872) were identified as the top candidates, with superior docking scores (-9.24 and -8.97 kcal/mol) compared to the reference MK-5108 (-7.49 kcal/mol). These hits satisfied Lipinski's rule and exhibited favourable ADMET profiles. DFT analysis revealed higher dipole moments (A1: 6.15 D, A2:6.39 D) and narrower HOMO-LUMO gaps (A1: 0.33 eV, A2: 0.38 eV), indicating enhanced polarity and reactivity. MEP plots showed defined donor-acceptor zones for both compounds, having a balanced surface. Molecular dynamics simulations over 500 ns confirmed complex stability, with protein backbone RMSD around 2.8 Å and ligand RMSD of 4.0 Å (A1) and 6.0 Å (A2). RMSF values remained below 2.4 Å. The most favourable binding energy for A1 (-75.34 kcal/mol) in MM-GBSA analysis confirms its strong interaction and therapeutic potential.

Keywords:  Aurora Kinase A; Cancer; DFT; Docking; Dynamics; MMGBSA; Mitotic signalling; Pharmacophore modelling

DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108690
bioRxiv. 2025 Sep 15. pii: 2025.09.14.676095. [Epub ahead of print]

Asymmetric centromere and gene locus positioning in Drosophila neural stem cells.

Jennifer A Taylor, Clemens Cabernard.

Chromatin organization is important for cell division, epigenetic memory, and gene regulation. It is often reflected in the non-random positioning of centromeres, but the underlying mechanisms and functions remain largely unknown. Here, we demonstrate that asymmetrically dividing Drosophila neural stem cells cluster centromeres near the nuclear envelope, adjacent to the apical centrosome. This asymmetric centromere positioning is regulated through microtubules, originating from the apical centrosome that connect to apical nuclear pore complexes. The minus-end directed motor protein Dynein, its binding partner Mushroom body defect, and Lamin are also required. Asymmetric centromere positioning persists throughout interphase in neural stem cells but is lost in more differentiated progeny. We also reveal that the genes hunchback ( hb ) and pendulin ( pen ) occupy specific nuclear regions, correlating with polarized centromere localization. We propose that fly neural stem cells translate their inherent polarity into stereotypical chromatin organization, potentially influencing cell fate decisions and stem cell behavior.

DOI: https://doi.org/10.1101/2025.09.14.676095
Sci China Life Sci. 2025 Sep 23.

DNA binding and mitotic phosphorylation: native mechanisms preventing polyglutamine protein aggregation.

Haiyan Yan, Xinyu Zhou, Junyue Tao, Fangwei Wang.

DOI: https://doi.org/10.1007/s11427-025-3058-6
J Bacteriol. 2025 Sep 26. e0032825

Segregation of sister chromosomes during the shape change of developing Myxococcus xanthus cells.

Y Hoang, Yann S Dufour, Lee Kroos.

  Chromosome organization is critical for the maintenance of genetic integrity. Most studies of bacterial nucleoids have focused on growing rod-shaped organisms. Studying nucleoid dynamics during Myxococcus xanthus development offers the unique opportunity to investigate the localization of two sister chromosomes as rod-shaped cells transition into round spores. During starvation-induced multicellular development, DNA replication is required for M. xanthus rods to transition into spores with two copies of the chromosome. Here, we report novel approaches using confocal fluorescence microscopy to observe the chromosome number and arrangement, and nucleoid localization in developing cells in situ. We discovered that sister chromosomes are present in some rods and transitioning cells (TCs) early in development. The arrangement of the two chromosomes in developing cells was novel compared to predivisional growing cells studied previously. We observed segregated nucleoids in ~40% of TCs and spores. The majority of TCs contained a crescent-shaped nucleoid along one side, perhaps due to ongoing chromosome segregation, whereas most spores appeared to have undergone nucleoid decondensation. During unicellular glycerol-induced sporulation of M. xanthus, we observed segregated nucleoids in only ~10%-20% of TCs and spores. In addition, early in starvation-induced development, we discovered a subpopulation of cells that may be spheroplasts destined for lysis, which is the fate of most cells under these conditions. Chromosome segregation in developing M. xanthus may be a bet-hedging strategy to increase survival under different conditions and/or an evolutionary remnant of ancestral events that included cell division to produce spores with one copy of the chromosome.IMPORTANCEThe cell cycle normally involves DNA replication, chromosome segregation, and cell division. During starvation-induced Myxococcus xanthus development, DNA replication is necessary for progression to spore formation, which occurs without cell division, resulting in spores with two copies of the chromosome. The organization of sister chromosomes during the morphological change of rod-shaped cells into round spores was unknown. We discovered that the two nucleoids often segregate during the transition from rods to spores. Mature spores contained decondensed nucleoids. Our observations raise important questions about the mechanism of chromosome segregation during M. xanthus development and the reason for its existence. We also discovered a subpopulation of developing cells with characteristics suggesting they are spheroplasts on the verge of cell death.

Keywords:  Myxococcus xanthus; bacterial development; cell shape change; chromosome segregation; nucleoid; sister chromosomes; sporulation

DOI:  https://doi.org/10.1128/jb.00328-25