bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–06–22
thirteen papers selected by
Valentina Piano, Uniklinik Köln
  1. IRF3-p300 axis controls global acetylation and mitotic progression.
  2. Cell state-specific cytoplasmic density controls spindle architecture and scaling.
  3. Non-canonical roles of mitotic proteins in cortical neurons.
  4. Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape.
  5. Cell cycle dependent methylation of Dam1 contributes to kinetochore integrity and faithful chromosome segregation.
  6. Blocking mutant IDH1 phosphorylation triggers APC/C CDH1-dependent ubiquitination in mitotic cells.
  7. Nuances in the control of separase activity between mitosis and meiosis.
  8. Loss of the Aspergillus fumigatus spindle assembly checkpoint components, SldA or SldB, generates triazole heteroresistant conidial populations.
  9. OsBRK1-mediated phosphorylation of OsPFN2 regulates meiotic spindle actin assembly and rice fertility.
  10. Histone deacetylation as a landmark for Sgo2 relocation from centromeres to subtelomeres during interphase.
  11. Cytoplasmic control of spindle architecture.
  12. Nuclear biophysics: Spatial coordination of transcriptional dynamics?
  13. A self-assembling surface layer flattens the cytokinetic furrow to aid cell division in an archaeon.
  1. Biochem Biophys Res Commun. 2025 Jun 14. pii: S0006-291X(25)00926-X. [Epub ahead of print]776 152211
    IRF3-p300 axis controls global acetylation and mitotic progression.
    Won-Joo Kim, Abdul Basit, Eun-Bi Ko, Yungyeong Heo, Jaehyun Shim, Su-Bin Lim, Jae-Ho Lee.
      Accurate mitotic progression depends on precisely regulated post-translational modifications, including lysine acetylation, but the upstream mechanisms governing acetylation during mitosis remain unclear. Here, we identify the IRF3-p300 axis as a major regulator of global protein acetylation during mitosis. We show that p300 serves as the major lysine acetyltransferase active during mitosis, and its enzymatic activity is essential for proper cell division. Notably, p300 activation during mitosis requires phosphorylation and dimerization of IRF3, a transcription factor known for its role in innate immunity. IRF3 interacts with and activates p300, and depletion of either IRF3 or p300 reduces global mitotic protein acetylation and delays mitotic progression. These defects are rescued by wild-type IRF3 or p300, but not by phosphorylation- or dimerization-deficient IRF3 mutants or catalytically inactive p300. Mass spectrometry analysis reveals that the mitotic acetylome is substantially altered upon loss of IRF3 or p300, with widely overlapping subsets of non-histone proteins-many involved in RNA biogenesis and processing-being affected. These findings reveal a non-canonical role for IRF3 as an upstream activator of p300 and establish the IRF3-p300 axis as a key signaling pathway that ensures proper mitotic progression through global regulation of protein acetylation.
    Keywords:  Global acetylation; IRF3; Mitosis; p300
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152211
  2. Nat Cell Biol. 2025 Jun;27(6): 959-971
    Cell state-specific cytoplasmic density controls spindle architecture and scaling.
    Tobias Kletter, Omar Muñoz, Sebastian Reusch, Abin Biswas, Aliaksandr Halavatyi, Beate Neumann, Benno Kuropka, Vasily Zaburdaev, Simone Reber.
      Mitotic spindles are dynamically intertwined with the cytoplasm they assemble in. How the physicochemical properties of the cytoplasm affect spindle architecture and size remains largely unknown. Using quantitative biochemistry in combination with adaptive feedback microscopy, we investigated mitotic cell and spindle morphology during neural differentiation of embryonic stem cells. While tubulin biochemistry and microtubule dynamics remained unchanged, spindles changed their scaling behaviour; in differentiating cells, spindles were considerably smaller than those in equally sized undifferentiated stem cells. Integrating quantitative phase imaging, biophysical perturbations and theory, we found that as cells differentiated, their cytoplasm became more dilute. The concomitant decrease in free tubulin activated CPAP (centrosomal P4.1-associated protein) to enhance the centrosomal nucleation capacity. As a consequence, in differentiating cells, microtubule mass shifted towards spindle poles at the expense of the spindle bulk, explaining the differentiation-associated switch in spindle architecture. This study shows that cell state-specific cytoplasmic density tunes mitotic spindle architecture. Thus, we reveal physical properties of the cytoplasm as a major determinant in organelle size control.
    DOI:  https://doi.org/10.1038/s41556-025-01678-x
  3. Trends Neurosci. 2025 Jun 14. pii: S0166-2236(25)00105-5. [Epub ahead of print]
    Non-canonical roles of mitotic proteins in cortical neurons.
    Joana Cavaco, Sara Carvalhal.
      Mitotic proteins are traditionally studied for their role in chromosome segregation during cell division. However, research increasingly highlights the important non-canonical roles of mitotic proteins beyond mitosis, particularly in the mammalian cerebral cortex. Alterations in the expression levels or mutations of mitotic proteins are increasingly linked to brain disorders such as primary microcephaly and Alzheimer's disease. A central, unresolved question remains: how do mitotic proteins contribute to neuronal pathogenesis? Here, we review emerging literature on the non-canonical roles of mitotic proteins in mature neurons. Additionally, we discuss how these contribute to the complex mechanisms underlying neurodevelopmental and neurodegenerative disorders. We also discuss their potential for identifying therapeutic strategies and as biomarkers in brain pathologies.
    Keywords:  brain; mitosis; neurodegenerative disorders; neuronal migration; synapsis, neurodevelopmental disorders
    DOI:  https://doi.org/10.1016/j.tins.2025.05.010
  4. iScience. 2025 Jun 20. 28(6): 112731
    Aurora B and INCENP co-overexpression severely disrupts mitosis and distinctly modifies the global transcriptional landscape.
    María Galindo-Moreno, Marta Muñoz-Barrera, Chiara Marcozzi, Federica Bruno, Cristina Maya-Álvarez, Felipe Cortés-Ledesma, Rosa María Ríos, Cristina González-Aguilera, Fernando Monje-Casas.
      Aurora B kinase, as part of the chromosomal passenger complex (CPC), controls key processes during the cell cycle such as DNA compaction, genome partitioning, or cytokinesis. Nonetheless, increased Aurora B levels are a potential threat for the cells and have been linked to different tumor types. We have carried out an exhaustive characterization of the global consequences of the overexpression of Aurora B and INCENP, the scaffold of the CPC and an activator of Aurora B kinase activity, in non-transformed human cells. Our data demonstrate not only that an individual increase in the levels of Aurora B or INCENP have a different impact on the cells, but more importantly that their simultaneous overexpression stabilizes both CPC components, exacerbates Aurora B activity, severely impairs mitotic progression and chromosome dynamics, and has a distinctive and more dramatic effect on the transcriptional landscape of the cells.
    Keywords:  Cell biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.112731
  5. PLoS Genet. 2025 Jun 16. 21(6): e1011760
    Cell cycle dependent methylation of Dam1 contributes to kinetochore integrity and faithful chromosome segregation.
    Prashant K Mishra, Wei-Chun Au, John S Choy, Pedro G Castineira, Afsa Khawar, Chloé Tessier, Sudipto Das, Andresson Thorkell, Peter H Thorpe, Elaine Yeh, Kerry S Bloom, Munira A Basrai.
      The kinetochore, a megadalton structure composed of centromeric (CEN) DNA and protein complexes, is required for faithful chromosome segregation in eukaryotes. The evolutionarily conserved Dam1/DASH complex (Ska1 in metazoans) is one of the essential protein sub-complexes of the budding yeast kinetochore. Previous studies showed that methylation of lysine residue 233 in Dam1 by Set1 is important for haploid growth as mutation of lysine 233 to alanine results in lethality. In this study, we report that Set1-mediated cell cycle dependent Dam1 lysine methylation contributes to kinetochore assembly and chromosomal stability. Our results show that Dam1 methylation is cell cycle regulated with the highest levels of methylation in metaphase. Consistent with these results, co-immunoprecipitation experiments revealed an interaction between Dam1 with Set1 in metaphase cells. Set1 has been shown to colocalize with Jhd2, a histone lysine demethylase which demethylates Set1-methylated histones. Affinity purification-based mass spectroscopy of Jhd2 associated proteins identified seven of the ten subunits of the Dam1 complex; an association of Jhd2 with non-histone proteins, such as Dam1 has not been previously reported. We confirmed the interaction of Jhd2 with Dam1 and showed that cells overexpressing JHD2 exhibit reduced levels of methylated lysine in Dam1 in wild type and UBP8 deletion strains, growth defects in kinetochore mutants, reduced levels of kinetochore proteins at CEN chromatin, defects in kinetochore biorientation and chromosome missegregation. In summary, we have shown that cell cycle dependent methylation of Dam1 plays a crucial role in the maintenance of kinetochore assembly for faithful chromosome segregation.
    DOI:  https://doi.org/10.1371/journal.pgen.1011760
  6. Biochim Biophys Acta Mol Cell Res. 2025 Jun 11. pii: S0167-4889(25)00107-7. [Epub ahead of print]1872(7): 120002
    Blocking mutant IDH1 phosphorylation triggers APC/C CDH1-dependent ubiquitination in mitotic cells.
    Sonam Swain, Nishant Jain.
      IDH1 mutation occurs early in glioma development; thus, mutant IDH1-specific inhibitors are being developed as glioma therapy. But, recent reports suggest that mutant IDH1 inhibitors treatments result in loss of therapeutic vulnerabilities and makes cells resistant to anticancer agents. To overcome resistance, the new paradigm in drug discovery is to develop molecules that can degrade oncogenes by harnessing cellular ubiquitination machinery. Therefore, it is imperative to identify strategies for degrading mutant IDH1 employing cellular ubiquitination machinery. To address this, we found that concerted action of the mitotic kinases Cdk1/Cyclin B1 and Plk1 increases mutant IDH1 enzyme activity. It is known that phosphorylation is linked to protein stability, phosphorylation of a short linear degron motif or phosphodegron can trigger target protein ubiquitination. By contrast, phosphorylation of constitutively active degron motifs can block target protein ubiquitination - phospho-inactivated degron. As phosphorylation can trigger or block ubiquitination, it is unknown if phosphorylation affects mutant IDH1 ubiquitination in mitosis. Therefore, in this study, we asked if phosphorylation of mutant IDH1 is linked to ubiquitination. To answer this question, we examined ubiquitination of phosphomutants and phosphomimetics of mutant IDH1 in mitosis. We found that blocking IDH1R132H phosphorylation is linked to ubiquitination. We observed that APC/C CDH1 ubiquitinates IDH1R132H-T77A-S94A. Further, we show that APC/C CDH1 ubiquitinates lysines 301 and 321 in C-terminal domain of IDH1R132H-T77A-S94A. Thus, blocking mutant IDH1 phosphorylation triggers APC/C CDH1-dependent ubiquitination in mitotic cells. We suggest employing mitotic inhibitors that also block phosphorylation of mutant IDH1 can ubiquitinate mutant IDH1 in cancer cells.
    Keywords:  APC/C; CDC20; CDH1; IDH1(R132H-T77A-S94A); Mitosis; Ubiquitination
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120002
  7. PLoS Biol. 2025 Jun;23(6): e3003206
    Nuances in the control of separase activity between mitosis and meiosis.
    Martin Anger.
      Mammalian oocytes are prone to chromosome segregation errors, which frequently lead into aneuploidy and pregnancy loss. A new study in PLOS Biology addresses the role of the Mad2/SGO2 complex in the control of separase activity in these cells during meiosis.
    DOI:  https://doi.org/10.1371/journal.pbio.3003206
  8. Microbiol Spectr. 2025 Jun 16. e0053625
    Loss of the Aspergillus fumigatus spindle assembly checkpoint components, SldA or SldB, generates triazole heteroresistant conidial populations.
    Ashley V Nywening, Harrison I Thorn, Jinhong Xie, Adela Martin-Vicente, Xabier Guruceaga, Wenbo Ge, John G Gibbons, Jarrod R Fortwendel.
      The opportunistic pathogen Aspergillus fumigatus is the chief causative agent of human invasive filamentous fungal infections. Triazoles, the primary therapeutic options to combat invasive aspergillosis (IA), target the biosynthesis of ergosterol, a vital component of the fungal cell membrane. Unfortunately, resistance to this class of medical therapeutics has arisen globally and now threatens the future usefulness of these compounds for antifungal treatment. Infection with A. fumigatus with acquired triazole resistance increases an already high associated mortality rate and reduces the limited arsenal of therapeutic options to combat IA. How this specific fungal pathogen obtains resistance remains poorly understood. In this study, we show that loss of the previously uncharacterized A. fumigatus spindle assembly checkpoint (SAC) components, SldA or SldB, resulted in a heteroresistance phenotype to multiple mold active medical triazoles and to compounds inhibiting ergosterol biosynthesis at points upstream of the triazole target, Cyp51A. Consistent with conserved roles in mitotic fidelity, loss of either component resulted in the production of conidia characterized by an increased genome size, suggestive of potential aneuploidy development. Interestingly, we find that heteroresistance of the ∆sldA or ∆sldB conidial populations was only evident in response to ergosterol biosynthesis pathway inhibition and not seen with other external stress. Our findings support the hypothesis that specific links exist between SAC function and resistance to ergosterol biosynthesis perturbation in A. fumigatus.IMPORTANCEThe rising threat of antifungal resistance in Aspergillus fumigatus, a filamentous fungal species which remains one of the leading causes of human invasive infections, is an increasingly relevant concern to public health worldwide. The mode and mechanism of triazole resistance acquisition remain an understudied issue for this opportunistic pathogen. This work uncovers a novel role for a functional spindle assembly checkpoint in maintaining susceptibility to ergosterol biosynthesis inhibitors, including the triazole antifungal drug class.
    Keywords:  Aspergillus fumigatus; aneuploidy; antifungal susceptibility; antifungal tolerance; ergosterol biosynthesis; spindle assembly checkpoint; triazole resistance
    DOI:  https://doi.org/10.1128/spectrum.00536-25
  9. Plant Commun. 2025 Jun 13. pii: S2590-3462(25)00179-8. [Epub ahead of print] 101417
    OsBRK1-mediated phosphorylation of OsPFN2 regulates meiotic spindle actin assembly and rice fertility.
    Hai Zheng, Zhigang Zhao, Shanshan Zhu, Yulong Ren, Jiangfeng Shen, Ziqi Xun, Xiaowen Yu, Chaolong Wang, Bowen Yao, Siqi Cheng, Yang Hu, Shihao Zhang, Qiming Wang, Jiayu Lu, Zhenwei Xie, Dekun Lei, Anqi Jian, Minrui Chen, Keyi Chen, Shijia Liu, Xi Liu, Yunlu Tian, Lin Jiang, Zhijun Cheng, Cailin Lei, Qibing Lin, Xiupin Guo, Xin Wang, Chuanyin Wu, Haiyang Wang, Shanjin Huang, Jianmin Wan.
      The formation of a meiotic spindle structure is crucial for chromosome segregation and fertility in plants. Previous studies have shown that actin decorates spindle microtubules in mammalian oocytes, forming spindle actin, which is indispensable for genome stability and gamete segregation. However, the regulatory mechanisms underlying spindle actin assembly remain unknown. Here, we report that dysfunction of OsPFN2, a rice profilin protein, disrupts meiotic spindle actin assembly and spindle microtubule structure, and causes errors in chromosome alignment and segregation in pollen mother cells (PMCs), resulting in male sterility. Furthermore, our results demonstrate that OsPFN2 interacts with Rice Morphology Determinant (OsRMD), a formin protein in rice, whose depletion also impacts spindle actin assembly and meiotic spindle microtubule structure. Intriguingly, we identified an interaction between OsPFN2 and Bub1-Related Kinase 1 (OsBRK1) and demonstrated that OsBRK1 depletion enhances spindle actin assembly. Additionally, we found that OsBRK1 phosphorylates OsPFN2, and the resulting phospho-mimetic OsPFN2 retains its capability to bind actin. However, these phospho-mimetic actin-OsPFN2 complexes are not utilized by OsRMD. Our findings thus reveal that the OsPFN2-OsRMD module controls meiotic spindle actin assembly, and OsBRK1 fine-tunes this process through phosphorylation of OsPFN2.
    Keywords:  Rice (Oryza sativa); male sterile; pollen development; spindle actin assembly; spindle morphogenesis
    DOI:  https://doi.org/10.1016/j.xplc.2025.101417
  10. iScience. 2025 Jun 20. 28(6): 112717
    Histone deacetylation as a landmark for Sgo2 relocation from centromeres to subtelomeres during interphase.
    Miho Osaki, Yoko Otsubo, Atika Nurani, Nanoka Asano, Kota Ono, Junko Kanoh.
      Shugoshin family proteins localize to centromeres and play pivotal roles in chromosome segregation during mitosis and meiosis. In fission yeast, the Shugoshin paralog Sgo2 relocates from centromeres to subtelomeres during interphase, where it contributes to gene repression by establishing a subtelomere-specific condensed chromatin structure known as the knob. However, the mechanisms underlying subtelomere-specific Sgo2 localization and knob formation during interphase remain poorly understood. Here, we identified Nts1, a component of the histone deacetylase complex, as a key regulator of Sgo2 localization through a genetic screen. Deletion of both nts1 + and set2 + (which encodes a histone H3-K36 methyltransferase) resulted in an almost complete loss of Sgo2 localization and knob formation at subtelomeres, indicating that Nts1 and Set2 function redundantly to target Sgo2 to subtelomeres. Notably, Nts1 localizes to subtelomeres during interphase and promotes histone H4 deacetylation, suggesting that histone deacetylation serves as a landmark for subtelomere-specific Sgo2 localization and knob formation.
    Keywords:  Chromosome organization; Molecular Genetics; Molecular interaction; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2025.112717
  11. Nat Cell Biol. 2025 Jun;27(6): 884-885
    Cytoplasmic control of spindle architecture.
    Gabriel Cavin-Meza, Rebecca Heald.
      
    DOI:  https://doi.org/10.1038/s41556-025-01686-x
  12. Curr Opin Cell Biol. 2025 Jun 14. pii: S0955-0674(25)00099-7. [Epub ahead of print]95 102561
    Nuclear biophysics: Spatial coordination of transcriptional dynamics?
    Tae Yeon Yoo, Bernardo Gouveia, Daniel Needleman.
      A great deal is known about biochemical aspects of transcription, but we still lack an understanding of how transcription is causally regulated in space and time. A major unanswered question is the extent to which transcription at different locations in the nucleus are independent from each other or, instead, are spatially coordinated. We propose two classes of models of coordination: 1) the shared environment model, in which neighboring loci exhibit coordinated transcriptional dynamics due to sharing the same local biochemical environment; 2) the mechanical crosstalk model, in which forces propagate from one actively transcribing locus to affect transcription of another. Determining the prevalence of the spatial coordination of transcription, and the underlying mechanisms when it occurs, is an exciting challenge in nuclear biophysics.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102561
  13. Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2501044122
    A self-assembling surface layer flattens the cytokinetic furrow to aid cell division in an archaeon.
    Sherman Foo, Ido Caspy, Alice Cezanne, Tanmay A M Bharat, Buzz Baum.
      The surface layer or "S-layer" is a two-dimensional lattice of proteins that coats a wide range of archaea and bacteria in place of a cell wall or capsular polysaccharides. S-layers are thought to play an important role in chemically and physically insulating cells from the external environment. Here, we show that the integrity of the S-layer in Sulfolobus acidocaldarius is maintained as cells grow via a process of self-assembly as SlaA monomers fill gaps in the lattice. Although this lattice which is physically tethered to the membrane might be expected to hinder cell division, we show that the S-layer flattens the membrane at cytokinesis to accelerate ESCRT-III-dependent cell division-and is important for robust, successful cell divisions under conditions of mechanical stress. Taken together, these results define the rules governing S-layer self-assembly and show how a flexible lattice coat that is coupled to the underlying membrane can both provide a cell with mechanical support and help to drive rapid and functionally important changes in cell shape.
    Keywords:  S-layer; archaea; cell division; cell mechanics; cytokinesis
    DOI:  https://doi.org/10.1073/pnas.2501044122
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