bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–05–18
twelve papers selected by
Valentina Piano, Uniklinik Köln
  1. N6-Methyladenosine Reader Protein YTHDC1 Supports Proper Mitotic Progression Partly through Regulation of TPX2-Aurora A Signaling.
  2. Nanoscale-folding of mitotic chromosomes.
  3. Mechanical Coupling With the Nuclear Envelope Shapes the Schizosaccharomyces pombe Mitotic Spindle.
  4. Condensation-dependent multivalent interactions of EB1 and CENP-R regulate chromosome oscillations in mitosis.
  5. The Drosophila nucleoporin ELYS is required for parental chromosome arrangement at fertilization.
  6. CDC6 Inhibits CDK1 Activity in MII-Arrested Oocyte Cell-Free Extract.
  7. KIF2A stabilizes intercellular bridge microtubules to maintain mouse embryonic stem cell cytokinesis.
  8. Phosphorylation by Aurora kinase A facilitates cortical-cytoplasmic dynamics of Par-3 in asymmetric division of radial glia progenitors.
  9. Cancer cells' chamber of secrets: the link between micronuclei, chromothripsis and malignancy.
  10. Mechanistic insight into anaphase bridge signaling to the abscission checkpoint.
  11. Binding of CEP152 to PLK4 stimulates kinase activity to promote centriole assembly.
  12. Intermediate Filament Protein BFSP1 Maintains Oocyte Asymmetric Division by Modulating Spindle Length.
  1. Biol Pharm Bull. 2025 ;48(5): 613-621
    N6-Methyladenosine Reader Protein YTHDC1 Supports Proper Mitotic Progression Partly through Regulation of TPX2-Aurora A Signaling.
    Rina Michimori, Ryuzaburo Yuki, Junna Tanaka, Youhei Saito, Yuji Nakayama.
      Chemical modification of mRNA regulates its stability and translation efficiency. The most prevalent modification is the N6-methyladenosine (m6A) modification. YT521-B homology domain-containing proteins (YTHDCs) are "reader" proteins of m6A modification and contribute to various cell functions by regulating their target m6A-containing mRNAs. Although m6A modification dynamically changes throughout the cell cycle, the role of the m6A pathway in cell division remains unclear. In this study, we found that YTHDC1, one of the YTHDCs, is important for cell division. Mitotic progression is delayed in YTHDC1-knockdown cells, and the mitotic delay is mitigated by the re-expression of wild-type YTHDC1, indicating the YTHDC1 function in mitotic progression. Time-lapse imaging analysis showed that prolonged mitotic duration caused by YTHDC1 knockdown is due to the retardation of chromosome alignment and segregation. Treatment of AZ3146, an inhibitor of the spindle assembly checkpoint (SAC), mitigates the mitotic delay in YTHDC1-knockdown cells, suggesting that YTHDC1 knockdown results in SAC activation, leading to a slowdown of mitotic progression. Furthermore, increased TPX2 protein expression and the subsequent overabundance of Aurora A at the centrosomes is partly involved in YTHDC1 knockdown-induced mitotic delay. Since YTHDC1 knockdown does not affect the TPX2 mRNA level and the inhibition of protein synthesis by cycloheximide treatment impairs the YTHDC1-knockdown effect on the TPX2 protein level, YTHDC1 may post-transcriptionally regulate the TPX2 expression. Considering that TPX2 or Aurora A overexpression causes mitotic failure, these results suggest that YTHDC1 contributes to mitotic progression partly through the precise regulation of TPX2-Aurora A signaling.
    Keywords:  N6-methyladenosine reader; TPX2; YT521-B homology domain-containing protein 1 (YTHDC1); aurora A kinase; mitosis; spindle assembly checkpoint
    DOI:  https://doi.org/10.1248/bpb.b24-00542
  2. Nat Genet. 2025 May;57(5): 1061
    Nanoscale-folding of mitotic chromosomes.
    Petra Gross.
      
    DOI:  https://doi.org/10.1038/s41588-025-02213-2
  3. Cytoskeleton (Hoboken). 2025 May 10.
    Mechanical Coupling With the Nuclear Envelope Shapes the Schizosaccharomyces pombe Mitotic Spindle.
    Marcus A Begley, Taylor Mahoney, Christian Pagán Medina, Parsa Zareiesfandabadi, Matthew B Rapp, Mastawal Tirfe, Sharonda J LeBlanc, Meredith D Betterton, Mary Williard Elting.
      The fission yeast Schizosaccharomyces pombe divides via closed mitosis, meaning that spindle elongation and chromosome segregation transpire entirely within the closed nuclear envelope. Both the spindle and nuclear envelope must undergo shape changes and exert varying forces on each other during this process. Previous work has demonstrated that nuclear envelope expansion (Yam, He, Zhang, Chiam, & Oliferenko, 2011; Mori & Oliferenko, 2020) and spindle pole body (SPB) embedding in the nuclear envelope are required for normal S. pombe mitosis, and mechanical modeling has described potential contributions of the spindle to nuclear morphology (Fang et al., 2020; Zhu et al., 2016). However, it is not yet fully clear how and to what extent the nuclear envelope and mitotic spindle each directly shape each other during closed mitosis. Here, we investigate this relationship by observing the behaviors of spindles and nuclei in live mitotic fission yeast following laser ablation. First, we characterize these dynamics in mitotic S. pombe nuclei with increased envelope tension, finding that nuclear envelope tension can both bend the spindle and slow elongation. Next, we directly probe the mechanical connection between spindles and nuclear envelopes by ablating each structure. We demonstrate that envelope tension can be relieved by severing spindles and that spindle compression can be relieved by rupturing the envelope. We interpret our experimental data via two quantitative models that demonstrate that fission yeast spindles and nuclear envelopes are a mechanical pair that can each shape the other's morphology.
    Keywords:  closed mitosis; cytoskeleton; fission yeast; mitotic spindle; nuclear mechanics
    DOI:  https://doi.org/10.1002/cm.22035
  4. Cell Rep. 2025 May 09. pii: S2211-1247(25)00331-6. [Epub ahead of print]44(5): 115560
    Condensation-dependent multivalent interactions of EB1 and CENP-R regulate chromosome oscillations in mitosis.
    Chengcheng Hu, Qing Hu, Tongtong Yang, Panpan Xu, Fangyuan Xiong, Xinyang Wang, Chao Wang, Kai Jiang, Donald L Hill, Lin Xue, Changlu Tao, Chuanhai Fu, Liang Zhang, Dan Liu, Shengqi Xiang, Jianye Zang, Zhikai Wang, Xuebiao Yao, Xing Liu.
      Mitotic chromosomes oscillate between the spindle poles upon the establishment of bi-orientation, which is essential for chromosome alignment and subsequent synchronous segregation. However, the molecular mechanisms underlying the oscillatory movement remain unclear. Recent studies revealed that phase separation of the end-binding protein 1 (EB1) is essential for eukaryotic cell division. Here, we show that EB1 interacts with CENP-R and that the phase separation-defective EB1 mutant fails to power the chromosome oscillations. Biochemical analyses reveal a co-condensation of EB1 and CENP-R, a subunit of the constitutive centromere-associated network. Nuclear magnetic resonance assays reveal that the interaction and co-condensation are largely mediated by the structured end-binding homology domain of EB1 and the non-structured N-terminal intrinsic disorder region of CENP-R. Chromosome oscillation is perturbed in cells expressing the EB1-binding-defective CENP-R mutant. Thus, phase-separated EB1 binding to CENP-R forms a physical link between inner kinetochore and dynamic spindle microtubule plus-ends to guide accurate chromosome oscillations.
    Keywords:  CENP-R; CP: Cell biology; EB1; chromosome oscillations; condensation; multivalent interactions
    DOI:  https://doi.org/10.1016/j.celrep.2025.115560
  5. G3 (Bethesda). 2025 May 13. pii: jkaf104. [Epub ahead of print]
    The Drosophila nucleoporin ELYS is required for parental chromosome arrangement at fertilization.
    Kazuyuki Hirai, Hiroki Sakamoto, Yoko Keira, Mika Ozaki, Kanta Yamazoe, Hiroyuki O Ishikawa, Yoshihiro H Inoue, Kyoichi Sawamura.
      One key aspect of fertilization is the unification of the maternal and paternal genomes driven by the first mitotic spindle. However, little is known about the mechanisms that underlie the formation of a bipolar spindle that interacts with the two discrete chromosome sets in juxtaposition. We here show that, in Drosophila, the maternally provided ELYS-an evolutionarily conserved subunit of the nuclear pore complex-localizes to female and male pronuclei and then redistributes to the interior of the spindle and the resulting zygotic nuclei. Both Elys loss-of-function mutations and ELYS overexpression in the female germline were associated with maternal-effect lethality. Our cytological studies of fertilized eggs revealed that ELYS is primarily involved in the apposition of female and male pronuclei, potentially impacting the parental genome configuration of the first mitotic spindle. We propose that pronuclear apposition is essential for centrosome localization at the emergent pronuclear junction to promote bipolar spindle formation for the first mitosis. In addition, we discuss the possible involvement of ELYS in interspecific hybrid incompatibility.
    Keywords:  centrosomes; early embryos; maternal effects; pronuclear apposition; spindle bipolarity; the first mitosis; zygotes
    DOI:  https://doi.org/10.1093/g3journal/jkaf104
  6. Int J Mol Sci. 2025 May 01. pii: 4309. [Epub ahead of print]26(9):
    CDC6 Inhibits CDK1 Activity in MII-Arrested Oocyte Cell-Free Extract.
    Louis Dillac, Klaudia Porębska, Malgorzata Kloc, Rafal P Piprek, Jean-Pierre Tassan, Jacek Z Kubiak.
      The control of cyclin-dependent kinase 1 (CDK1) kinase activity is crucial for cell cycle progression. Cell division cycle 6 (CDC6) inhibits this activity in embryonic mitoses, and thus regulates the timing of cell division progression. The meiotic cell cycle differs greatly from the mitotic one. Metaphase II (MII)-arrested oocytes remain in prolonged M-phase state due to the high activity of CDK1 in the presence of CytoStatic Factor (CSF). The role of CDC6 in the control of CDK1 during MII and oocyte activation remains unknown. Here, we studied the role of CDC6/CDK1 interactions in Xenopus laevis cell-free extracts arrested in MII (CSF extract) and upon calcium activation leading to meiotic-to-mitotic transition. The CSF extract allows analysis of biochemical processes based on immunodepletion of selected proteins and facilitates manipulations using addition of recombinant proteins. We show by glutathione S-transferase (GST)-CDC6 pull-down that CDC6 associates with CDK1 in CSF extract and by histone H1 kinase assay that it downregulates CDK1 activity. Thus, CDC6-dependent inhibition of CDK1 is involved in the homeostasis of the MII-arrest. Upon CSF extract activation with calcium exogenous GST-CDC6 provokes accelerated transition from MII to interphase, while the depletion of endogenous CDC6 results in a slower transition to interphase. We demonstrate this by following both the phosphorylation state of CDK1 substrate cell division cycle 27 (CDC27) and histone H1 kinase assay. Importantly, increasing doses of GST-CDC6 proportionally accelerate CDK1 inactivation showing that CDC6 controls the dynamics of MII to interphase transition in a dose-dependent manner. Thus, CDC6 is a CDK1 silencer acting upon both the MII arrest and CSF extract activation by assuring the physiological activity of CDK1 during this meiotic arrest and correct timely inactivation of this kinase during the second process. Thus, we show that CDC6 controls CDK1 not only during mitotic divisions, but also in MII-arrest and the meiotic-to-mitotic transition in Xenopus laevis cell-free extracts. This study aims to bridge that gap by investigating CDC6 function using a biochemically controlled system.
    Keywords:  Xenopus laevis; calcium; cell cycle; cell division cycle 27 (CDC27); cell division cycle 6 (CDC6); cyclin-dependent kinase 1 (CDK1); embryo; histone H1 kinase; meiotic-to-mitotic transition; metaphase II (MII) arrest; oocyte; oocyte activation
    DOI:  https://doi.org/10.3390/ijms26094309
  7. J Cell Biol. 2025 Jul 07. pii: e202409157. [Epub ahead of print]224(7):
    KIF2A stabilizes intercellular bridge microtubules to maintain mouse embryonic stem cell cytokinesis.
    Lieke Stockmann, Hélène Kabbech, Gert-Jan Kremers, Brent van Herk, Bas Dille, Mirjam van den Hout, Wilfred F J van IJcken, Dick H W Dekkers, Jeroen A A Demmers, Ihor Smal, Danny Huylebroeck, Sreya Basu, Niels Galjart.
      Cytokinesis, the final stage of cell division, serves to physically separate daughter cells. In cultured naïve mouse embryonic stem cells, cytokinesis lasts unusually long. Here, we describe a novel function for the kinesin-13 member KIF2A in this process. In genome-engineered mouse embryonic stem cells, we find that KIF2A localizes to spindle poles during metaphase and regulates spindle length in a manner consistent with its known role as a microtubule minus-end depolymerase. In contrast, during cytokinesis we observe tight binding of KIF2A to intercellular bridge microtubules. At this stage, KIF2A maintains microtubule length and number and controls microtubule acetylation. We propose that the conversion of KIF2A from a depolymerase to a stabilizer is driven by both the inhibition of its ATPase activity, which increases lattice affinity, and a preference for compacted lattices. In turn, KIF2A might maintain the compacted microtubule state at the intercellular bridge, thereby dampening acetylation. As KIF2A depletion causes pluripotency problems and affects mRNA homeostasis, our results furthermore indicate that KIF2A-mediated microtubule stabilization prolongs cytokinesis to maintain pluripotency.
    DOI:  https://doi.org/10.1083/jcb.202409157
  8. Sci Adv. 2025 May 16. 11(20): eadq3858
    Phosphorylation by Aurora kinase A facilitates cortical-cytoplasmic dynamics of Par-3 in asymmetric division of radial glia progenitors.
    Jason Q Garcia, Vincent Mouilleau, Henry Ng, Xiang Zhao, David O Morgan, Su Guo.
      During asymmetric cell division (ACD) of radial glia progenitors (RGPs), the cortical polarity regulator Par-3 is detected in the cytoplasm colocalizing with dynein and Notch ligand DeltaD (Dld). What drives Par-3 to the cytoplasm and its impact on RGP ACD remain unknown. Here, we visualize cytoplasmic Par-3 using in vivo time-lapse imaging and find that Ser954 of zebrafish Par-3 is phosphorylated by Aurora kinase A (AurkA) in vitro. Expression of the nonphosphorylated mutant Par-3S954A dominant negatively affects embryonic development, reduces cytoplasmic Par-3, and disrupts the anteroposterior asymmetry of cortical Par-3 and Dld endosomes and, in turn, daughter cell fate. AurkA in mitotic RGPs shows dynamic pericentrosomal distribution that transiently colocalizes with cortical Par-3 preferentially on the posterior side. AurkA is both necessary and sufficient to increase cytoplasmic while decreasing cortical Par-3, disrupts Par-3 cortical asymmetry, and perturbs polarized Dld endosome dynamics. These findings suggest that AurkA regulates Par-3 cortical-cytoplasmic dynamics that is critical for ACD and daughter cell fate.
    DOI:  https://doi.org/10.1126/sciadv.adq3858
  9. Open Biol. 2025 May;15(5): 240388
    Cancer cells' chamber of secrets: the link between micronuclei, chromothripsis and malignancy.
    Truman Raleigh Mcneil, Sweta Sikder, Yamini Dalal.
      Micronuclei exhibit defective proteomes rendering their chromatin vulnerable to fragmentation. This fragmentation process, known as chromothripsis, promotes tumorigenesis by catalysing the activation of oncogenes and the silencing of tumor suppressors. With this role in mind, micronuclei serve as promising targets for therapeutic intervention. This review will explore recent discoveries regarding how micronuclei form, their function in catalysing chromothripsis and how chromothripsis provides a selective advantage for cancer cells.
    Keywords:  cancer; chromosomal instability; chromothripsis; micronuclei; mitotic defects; tumorigenesis
    DOI:  https://doi.org/10.1098/rsob.240388
  10. EMBO J. 2025 May 12.
    Mechanistic insight into anaphase bridge signaling to the abscission checkpoint.
    Manika I Singh, Girish Rajendraprasad, Vasileios Katopodis, Rui Cui, Marin Barisic, Rahul Bhowmick, Ian D Hickson.
      During cytokinesis in human cells, a failure to resolve persistent DNA bridges that span the cell-division plane maintains the Aurora B-dependent abscission checkpoint in an active state. However, the molecular mechanism by which unresolved sister-chromatid bridging signals to this checkpoint is poorly defined. Here, we define an essential role for the Bloom's syndrome helicase, BLM, in signaling to the abscission-checkpoint machinery in response to replication stress through the conversion of dsDNA bridges into RPA-coated ssDNA. RPA then promotes ATR-CHK1 signaling to Aurora B, utilizing a kinase cascade shared with the S-phase checkpoint. BLM-deficient cells ultimately abandon cytokinesis in response to replication stress, which promotes binucleation and hence aneuploidy. Considering that aneuploidy is a hallmark of cancer, we propose that this role for BLM in cytokinesis is a plausible reason for cancer predisposition in Bloom's syndrome individuals. Consistent with this, BLM deficiency promotes anchorage-independent growth of non-cancer cells.
    Keywords:  ATR-CHK1 Signaling; Anchorage Independent Growth; Aneuploidy; Chromosome Missegregation; Cytokinesis Failure
    DOI:  https://doi.org/10.1038/s44318-025-00453-w
  11. Mol Biol Cell. 2025 May 15. mbcE24120581
    Binding of CEP152 to PLK4 stimulates kinase activity to promote centriole assembly.
    Hazal Kübra Gürkaşlar, Ingrid Hoffmann.
      Centriole duplication is regulated by polo-like kinase 4 (PLK4) and several conserved initiator proteins. The precise timing and regulation of PLK4 activation are critical for ensuring that centriole duplication occurs only once per cell cycle. While significant progress has been made in understanding how PLK4 is activated, many aspects remain unclear. Here, we show how CEP152 contributes to the activation of PLK4. We utilize human cell lines that have been genetically engineered to rapidly degrade CEP152. Upon degradation of CEP152, localization of PLK4 at the proximal end of the centriole is disrupted. We show that binding of CEP152 N-terminal part to PLK4 increases phosphorylation and kinase activation. CEP152 controls the localization and levels of phosphorylated PLK4 at the proximal end of the centriole. CEP152 binding to PLK4 leads to phosphorylation and activation of PLK4 which might stabilize PLK4 dimer formation, thus allowing autophosphorylation. We propose that CEP152 activates PLK4 to ensure proper centriole duplication at the onset of S-phase.
    DOI:  https://doi.org/10.1091/mbc.E24-12-0581
  12. Adv Sci (Weinh). 2025 May 11. e2504066
    Intermediate Filament Protein BFSP1 Maintains Oocyte Asymmetric Division by Modulating Spindle Length.
    Yu Li, Hanwen Zhang, Wenjun Zeng, Yilong Miao, Shaochen Sun, Yu Zhang, Bo Xiong.
      The cytoskeleton is composed of microtubules, microfilaments, and intermediate filaments in cells. While the functions of microtubules and microfilaments have been well elucidated, the roles of intermediate filaments and associated proteins remain largely unknown, especially in meiosis. BFSP1 is an intermediate filament protein mainly expressed in the eye lens to play important roles in the development of congenital cataract. Here, we document that BFSP1 functions as a spindle regulator to drive the oocyte asymmetric division. Specifically, we found that BFSP1 distributed on the spindle apparatus during oocyte meiotic maturation. Depletion of BFSP1 resulted in symmetric division of oocytes, accompanied by the formation of elongated spindles at metaphase I and anaphase/telophase I stages. In addition, immunoprecipitation combined with mass spectrometry analysis identified MAP1B, a microtubule-associated protein, as an interacting partner of BFSP1. Depletion or mutation of MAP1B phenocopied the meiotic defects observed in BFSP1-depleted oocytes, and expression of exogenous MAP1B-EGFP in BFSP1-depleted oocytes recovered the spindle length and asymmetric division. We further determined that BFSP1 recruited molecular chaperone HSP90α on the spindle to stabilize MAP1B, thereby controlling the spindle length. To sum up, our findings reveal a unique meiotic role for BFSP1 in the regulation of spindle dynamics and oocyte asymmetric division.
    Keywords:  BFSP1; asymmetric division; intermediate filament protein; oocyte meiosis; spindle length
    DOI:  https://doi.org/10.1002/advs.202504066
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