bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–05–04
eleven papers selected by
Valentina Piano, Uniklinik Köln
  1. The Spc105/Kre28 complex promotes mitotic error correction by outer kinetochore recruitment of Ipl1/Sli15.
  2. Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.
  3. Multitasking Proteins: Exploring Noncanonical Functions of Proteins during Mitosis.
  4. Total whole-arm chromosome losses predict malignancy in human cancer.
  5. Crystal structures of Kif2A complexed with WDR5 reveal the structural plasticity of WIN-S7 sites.
  6. LINE-1 ribonucleoprotein condensates bind DNA to enable nuclear entry during mitosis.
  7. A cortical pool of LIN-5 (NuMA) controls cytokinetic furrow formation and cytokinesis completion.
  8. Stability and robustness of kinetochore dynamics under sudden perturbations and stochastic influences.
  9. Interphase cell morphology defines the mode, symmetry, and outcome of mitosis.
  10. 1H, 13C and 15N resonance assignments for the acetyltransferase domain of the kinetoplastid kinetochore protein KKT23 from Trypanosoma brucei.
  11. Marking dad's centromeres: maintaining CENP-A in sperm.
  1. EMBO J. 2025 Apr 25.
    The Spc105/Kre28 complex promotes mitotic error correction by outer kinetochore recruitment of Ipl1/Sli15.
    Alexander Dudziak, Richard Pleuger, Jasmin Schmidt, Frederik Hamm, Sharvari Tendulkar, Karolin Jänen, Ingrid R Vetter, Sylvia Singh, Josef Fischböck, Franz Herzog, Stefan Westermann.
      Kinetochores link chromosomes to dynamic microtubules of the mitotic spindle. To ensure equal chromosome segregation, sister chromatids must achieve biorientation. The conserved kinase Aurora B phosphorylates outer kinetochore proteins on attachments lacking tension, allowing the re-establishment of new connections until biorientation is achieved. Aurora B localizes to the centromere as part of the chromosomal passenger complex (CPC), but the underlying recruitment pathways can be eliminated without disrupting biorientation. It therefore remains unclear how the kinase operates during error correction. Here, we identify the conserved Spc105/Kre28 complex as an outer kinetochore receptor of the Aurora kinase Ipl1 and its activator Sli15 in Saccharomyces cerevisiae. We show that mutations in the helix bundle domain of Spc105/Kre28 impair mitotic error correction, resembling the effects of ipl1 or sli15 mutants. The defects can be suppressed by the artificial recruitment of Ipl1. In biochemical experiments, Ipl1/Sli15 directly associates with Spc105/Kre28, and a conserved segment in the Sli15 central domain is crucially involved in the binding mechanism. These results have important implications for the mechanism of tension-dependent error correction during chromosome biorientation.
    Keywords:  Chromosomal Passenger Complex; Chromosome Biorientation; Error Correction; KMN Network; Signaling
    DOI:  https://doi.org/10.1038/s44318-025-00437-w
  2. Res Sq. 2025 Apr 23. pii: rs.3.rs-6173630. [Epub ahead of print]
    Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.
    Daniel J Barrero, Sabrine Hedouin, Yizi Mao, Charles L Asbury, Andrew Stergachis, Eileen O'Toole, Sue Biggins.
      Eukaryotic chromosome segregation requires spindle microtubules to attach to chromosomes through kinetochores. The chromosomal locus that mediates kinetochore assembly is the centromere and is epigenetically specified in most organisms by a centromeric histone H3 variant called CENP-A. An exception to this is budding yeast which have short, sequenced-defined point centromeres. In S. cerevisiae , a single CENP-A nucleosome is formed at the centromere and is sufficient for kinetochore assembly. The thermophilic budding yeast Kluyveromyces marxianus also has a point centromere but its length is nearly double the S. cerevisiae centromere and the number of centromeric nucleosomes and kinetochore attachment sites is unknown. Purification of native kinetochores from K. marxianus yielded a mixed population, with one subpopulation that appeared to consist of doublets, making it unclear whether K. marxianus shares the same attachment architecture as S. cerevisiae. Here, we demonstrate that though the doublet kinetochores have a functional impact on kinetochore strength, kinetochore localization throughout the cell cycle appears conserved between these two yeasts. In addition, whole spindle electron tomography demonstrates that a single microtubule binds to each chromosome. Single-molecule nucleosome mapping analysis suggests the presence of a single centromeric nucleosome. Taken together, we propose that the K. marxianus point centromere assembles a single centromeric nucleosome that mediates attachment to one microtubule.
    DOI:  https://doi.org/10.21203/rs.3.rs-6173630/v1
  3. Biochemistry. 2025 May 02.
    Multitasking Proteins: Exploring Noncanonical Functions of Proteins during Mitosis.
    Valentina Piano.
      This review provides a comprehensive overview of how mitotic cells drive the repurposing of proteins to fulfill mitosis-specific functions. To ensure the successful completion of cell division, the cell strategically reallocates its "workforce" by assigning additional functions to available proteins. Protein repurposing occurs at multiple levels of cellular organization and involves diverse mechanisms. At the protein level, proteins may gain mitosis-specific functions through post-translational modifications. At the structural level, proteins that typically maintain cellular architecture in interphase are co-opted to participate in mitotic spindle formation, chromosome condensation, and kinetochore assembly. Furthermore, the dynamic reorganization of the nuclear envelope and other organelles relies on the temporary reassignment of enzymes, structural proteins, and motor proteins to facilitate these changes. These adaptive mechanisms underscore the remarkable versatility of the cellular proteome in responding to the stringent requirements of mitosis. By leveraging the existing proteome for dual or multiple specialized roles, cells optimize resource usage while maintaining the precision needed to preserve genomic integrity and ensure the survival of the next generation of cells.
    Keywords:  cell cycle; chromosomes; mitochondria; mitosis; mitotic spindle; organelles; protein functions; protein moonlighting
    DOI:  https://doi.org/10.1021/acs.biochem.5c00083
  4. Proc Natl Acad Sci U S A. 2025 May 06. 122(18): e2505385122
    Total whole-arm chromosome losses predict malignancy in human cancer.
    Ye Zheng, Kami Ahmad, Steven Henikoff.
      Aneuploidy is observed as gains or losses of whole chromosomes or chromosome arms and is a common hallmark of cancer. Whereas models for the generation of aneuploidy in cancer invoke mitotic chromosome segregation errors, whole-arm losses might occur simply as a result of centromere breakage. We recently showed that elevated RNA Polymerase II level over the S-phase-dependent histone genes predicts rapid recurrence of human meningioma and is correlated with total whole-arm losses relative to gains. To explain this imbalance in arm losses over gains, we have proposed that histone overexpression at S-phase competes with the histone H3 variant CENP-A, resulting in centromere breaks and whole-arm losses. To test whether centromere breaks alone can drive aneuploidy, we ask whether total whole-arm aneuploids can predict outcomes across different cancer types in large RNA and whole-genome sequencing databanks. We find that total whole-arm losses generally predict outcome, suggesting that centromere breakage is a major initiating factor leading to aneuploidy and the resulting changes in the selective landscape that drive most cancers. We also present evidence that centromere breakage alone is sufficient to account for whole-arm losses and gains, contrary to mitotic spindle error models for the generation of aneuploidy. Our results suggest that therapeutic intervention targeting histone overexpression has the potential to reduce aneuploidy and slow cancer progression.
    Keywords:  RNA sequencing; aneuploidy; centromeres; histones; whole genome sequencing
    DOI:  https://doi.org/10.1073/pnas.2505385122
  5. Acta Biochim Biophys Sin (Shanghai). 2025 Apr 30.
    Crystal structures of Kif2A complexed with WDR5 reveal the structural plasticity of WIN-S7 sites.
    Yang Yang, Shuting Zhang, Zhangyu Wu, Wenwen Li, Xuefang Sun, Yumi Xuan, Tianrong Hang, Li Xu, Xuemin Chen.
      Chromosome congression and spindle assembly are essential for genomic stability and proper cell division, with deficiencies in these processes linked to tumorigenesis. WD repeat-containing protein 5 (WDR5), a core component of the mixed lineage leukemia (MLL) methyltransferase complex, directly binds to kinesin family member 2A (Kif2A) to regulate these mitotic events. Despite the importance of this interaction, its structural basis for Kif2A recognition by WDR5 remains unclear. Here, we determine the crystal structure of WDR5 in complex with a Kif2A-derived peptide (residues 114-122) at a resolution of 1.85 Å. Structural analysis reveals that Kif2A engages both the WIN and S7 sites of WDR5 via Arg117 and Ser121, with Ser121 forming hydrogen bonds with WDR5 Tyr191 and Lys259, driving Tyr191 rotation and opening the S7 pocket. Additional structures of WDR5 complexed with truncated or mutated Kif2A peptides and a WDR5 Y191F variant highlight the dynamic nature of Tyr191. Notably, anti-WDR5 compounds exhibit a similar binding mode at the WDR5 WIN-S7 site. The results of mutagenesis combined with isothermal titration calorimetry (ITC) assays underscore the critical roles of Arg117 and Ser121 in mediating the binding of Kif2A to WDR5. In summary, our findings provide atomic-level insights into the molecular mechanisms underlying the non-canonical mitotic function of the MLL/WDR5 complex and highlight WIN-S7 sites as promising therapeutic targets for diseases associated with chromosomal instability, such as cancers.
    Keywords:  Kif2A; S7 pocket; WDR5; WIN motif; crystal structure
    DOI:  https://doi.org/10.3724/abbs.2025066
  6. Sci Adv. 2025 May 02. 11(18): eadt9318
    LINE-1 ribonucleoprotein condensates bind DNA to enable nuclear entry during mitosis.
    Sarah Zernia, Farida Ettefa, Srinjoy Sil, Cas Koeman, Joëlle Deplazes-Lauber, Marvin Freitag, Liam J Holt, Johannes Stigler.
      Long interspersed nuclear element-1 (LINE-1) is an autonomous retrotransposon that makes up a substantial portion of the human genome, contributing to genetic diversity and genome evolution. LINE-1 encodes two proteins, ORF1p and ORF2p, both essential for successful retrotransposition. ORF2p has endonuclease and reverse transcription activity, while ORF1p binds RNA. Many copies of ORF1p assemble onto the LINE-1 RNA to form a ribonucleoprotein (RNP) condensate. However, the function of these condensates in the LINE-1 life cycle remains unclear. Using reconstitution assays on DNA curtains, we show that L1 RNP condensates gain DNA binding activity only when RNA is super-saturated with ORF1p. In cells, L1 RNP condensates bind to chromosomes during mitosis. Mutational analysis reveals that DNA binding is crucial for nuclear entry and LINE-1 retrotransposition activity. Thus, a key function of ORF1p is to form an RNP condensate that gains access to the genome through DNA binding upon nuclear envelope breakdown.
    DOI:  https://doi.org/10.1126/sciadv.adt9318
  7. J Cell Biol. 2025 Jul 07. pii: e202406059. [Epub ahead of print]224(7):
    A cortical pool of LIN-5 (NuMA) controls cytokinetic furrow formation and cytokinesis completion.
    Kuheli Adhikary, Sukriti Kapoor, Sachin Kotak.
      In animal cells, cleavage furrow formation is controlled by localized activation of the GTPase RhoA at the equatorial membrane using cues transmitted from the spindle. Here, we explore the function of LIN-5, a well-studied protein known for its role in aster separation and spindle positioning in cleavage furrow formation. We show that the cortical pool of LIN-5, recruited by GPR-1/2 and important for cortical force generation, regulates cleavage furrow formation independently of its roles in aster separation and spindle positioning. Instead, our data suggest that enrichment of LIN-5/GPR-1/2 at the polar cortical region is essential to ensure the timely accumulation of contractile ring components-myosin II and Anillin at the equatorial cortex. We additionally define a late cytokinesis role of cortical LIN-5/GPR-1/2 in midbody stabilization and abscission. These results indicate that the cortical LIN-5/GPR-1/2 complex contributes to multiple aspects of cytokinesis independently of its roles in spindle positioning and elongation.
    DOI:  https://doi.org/10.1083/jcb.202406059
  8. Sci Rep. 2025 Apr 28. 15(1): 14883
    Stability and robustness of kinetochore dynamics under sudden perturbations and stochastic influences.
    Farzona Mukhamedova, Farrukh Mukhamedov.
      Understanding the dynamic behavior of kinetochores is crucial for understanding the mechanisms of accurate chromosome segregation during cell division. In this study, we introduced non-linear exponents p and q into two new systems to capture the complex movements that govern the intersister movement of kinetochores during chromosome segregation. Our analysis revealed a power-law relationship between these exponents and the maximum amplitude A of sister kinetochore 2, indicating that even small adjustments in p and q lead to significant changes in kinetochore movement. This sensitivity suggests that kinetochore dynamics are governed by scale-invariant principles, potentially reflecting intrinsic properties of the kinetochore-microtubule interface such as motor protein activity. We observed that the Type II model with perturbation functions, demonstrated stability with rapidly dampening oscillations across various forms of noise and sudden shocks. This highlights the effectiveness of adaptable regulatory mechanisms in maintaining stability during mitosis. In contrast, the Type I model without such regulatory parameters exhibited sustained, bounded oscillations that did not dampen over time and showed significant fragility under stochastic noise, potentially compromising chromosome segregation fidelity. Our findings highlight the role of the exponents p and q in modulating kinetochore behavior and suggest that enhancing or mimicking these regulatory mechanisms could be a potential strategy for improving cell division fidelity as shown in our theoretical work.
    DOI:  https://doi.org/10.1038/s41598-025-98415-z
  9. Science. 2025 May;388(6746): eadu9628
    Interphase cell morphology defines the mode, symmetry, and outcome of mitosis.
    Holly E Lovegrove, Georgia E Hulmes, Sabrina Ghadaouia, Christopher Revell, Marta Giralt-Pujol, Zain Alhashem, Andreia Pena, Damian D Nogare, Ellen Appleton, Guilherme Costa, Richard L Mort, Christoph Ballestrem, Gareth W Jones, Cerys S Manning, Ajay B Chitnis, Claudio A Franco, Claudia Linker, Katie Bentley, Shane P Herbert.
      During tissue formation, dynamic cell shape changes drive morphogenesis while asymmetric divisions create cellular diversity. We found that the shifts in cell morphology that shape tissues could concomitantly act as conserved instructive cues that trigger asymmetric division and direct core identity decisions underpinning tissue building. We performed single-cell morphometric analyses of endothelial and other mesenchymal-like cells. Distinct morphological changes switched cells to an "isomorphic" mode of division, which preserved pre-mitotic morphology throughout mitosis. In isomorphic divisions, interphase morphology appeared to provide a geometric code defining mitotic symmetry, fate determinant partitioning, and daughter state. Rab4-positive endosomes recognized this code, allowing them to respond to pre-mitotic morphology and segregate determinants accordingly. Thus, morphogenetic shape change sculpts tissue form while also generating cellular heterogeneity, thereby driving tissue assembly.
    DOI:  https://doi.org/10.1126/science.adu9628
  10. Biomol NMR Assign. 2025 May 02.
    1H, 13C and 15N resonance assignments for the acetyltransferase domain of the kinetoplastid kinetochore protein KKT23 from Trypanosoma brucei.
    Patryk Ludzia, Charlotte Nugent, Bungo Akiyoshi, Christina Redfield.
      KKT23 is a kinetoplastid-specific kinetochore protein that has a C-terminal GCN5-related histone acetyltransferase domain that acetylates the C-terminal tail of histone H2A. Here, we present the 1H, 13C and 15N resonance assignments for the C-terminal region of KKT23 (KKT23125-348) from Trypanosoma brucei in complex with known cofactors for acetyltransferases, acetyl coenzyme A and coenzyme A. These assignments provide the starting point for detailed investigation of the structure, dynamics and interactions of KKT23 in solution.
    Keywords:  Acetyl coenzyme A; Acetyltransferase; GCN5; GNAT; KKT23; Kinetochore; Kinetoplastid; NMR resonance assignments; Trypanosomes
    DOI:  https://doi.org/10.1007/s12104-025-10235-4
  11. Chromosome Res. 2025 Apr 26. 33(1): 8
    Marking dad's centromeres: maintaining CENP-A in sperm.
    Miriama Štiavnická, Rachel S Keegan, Elaine M Dunleavy.
      During spermiogenesis, histones are removed from most genomic loci and are replaced by protamines in mature sperm nuclei. Yet, centromeres appear resistant to this process. We review the experimental evidence that the centromeric histone CENP-A is maintained in mature sperm nuclei, comparing human, bovine, mouse and fly species. We also recall how the detection of centromeres in mature sperm nuclei in the 1990's contributed to the isolation of the CENP-A protein and the eventual cloning of the human CENP-A gene. Further, based on more recent genetic studies carried out in flies and in mice, we discuss the inheritance and functional importance of paternal CENP-A and how it is complemented by maternal CENP-A to give rise to a healthy embryo. Finally, we raise some unanswered questions regarding the exclusive maintenance of CENP-A on sperm, the organisation of sperm centromeric chromatin and its importance for fertility and early embryo development.
    Keywords:  CENP-A; Centromere; Gamete; Histone; Male fertility; Sperm
    DOI:  https://doi.org/10.1007/s10577-025-09766-2
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