bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–02–16
ten papers selected by
Valentina Piano, Uniklinik Köln
  1. Independence of Centromeric and Pericentromeric Chromatin Stability on CCAN Components.
  2. NuMA is a mitotic adaptor protein that activates dynein and connects it to microtubule minus ends.
  3. Three-dimensional memory of nuclear organization through cell cycles.
  4. The spatiotemporal distribution of LIN-5/NuMA regulates spindle orientation in the C. elegans germ line.
  5. Functionalized Docetaxel Probes for Refined Visualization of Mitotic Spindles by Expansion Microscopy.
  6. A biallelic variant in GORASP1 causes a novel Golgipathy with glycosylation and mitotic defects.
  7. Adaptive evolution of CENP-T modulates centromere binding.
  8. Mitosis - predicting primary tumour and metastatic lymph node behaviour and beyond in OSCC - A pilot study.
  9. Chromosomal localization of PHOX2B during M-phase is disrupted in disease-associated mutants.
  10. NUDC Is Critical for Mitosis and Postmitotic Cell Maintenance Through Its Modulation of Dynein and Actin Cytoskeletal Reorganization.
  1. Mol Biol Cell. 2025 Feb 12. mbcE24020066
    Independence of Centromeric and Pericentromeric Chromatin Stability on CCAN Components.
    Ronald J Biggs, Kousik Sundararajan, Mingxuan Sun, Eline Hendrix, Aaron F Straight, John F Marko.
      The chromatin of the centromere provides the assembly site for the mitotic kinetochore that couples microtubule attachment and force production to chromosome movement in mitosis. The chromatin of the centromere is specified by nucleosomes containing the histone H3 variant CENP-A. The constitutive centromeric-associated network (CCAN) and kinetochore are assembled on CENP-A chromatin to enable chromosome separation. CENP-A chromatin is surrounded by pericentromeric heterochromatin and bound by the sequence specific binding protein CENP-B. We performed mechanical experiments on mitotic chromosomes while tracking CENP-A and CENP-B to observe the centromere's stiffness and the role of the CCAN. We degraded CENP-C and CENP-N using auxin-inducible degrons, which we verified compromises the CCAN via observation of CENP-T loss. Chromosome stretching revealed that the CENP-A domain does not visibly stretch, even in the absence of CENP-C and/or CENP-N. Pericentromeric chromatin deforms upon force application, stretching approximately 3-fold less than the entire chromosome. CENP-C and/or CENP-N loss has no impact on pericentromere stretching. Chromosome-disconnecting nuclease treatments showed no structural effects on CENP-A. Our experiments show that the core-centromeric chromatin is more resilient and likely mechanically disconnected from the underlying pericentromeric chromatin, while the pericentric chromatin is deformable yet stiffer than the chromosome arms.
    DOI:  https://doi.org/10.1091/mbc.E24-02-0066
  2. J Cell Biol. 2025 Apr 07. pii: e202408118. [Epub ahead of print]224(4):
    NuMA is a mitotic adaptor protein that activates dynein and connects it to microtubule minus ends.
    Sabina Colombo, Christel Michel, Silvia Speroni, Felix Ruhnow, Maria Gili, Cláudia Brito, Thomas Surrey.
      Nuclear mitotic apparatus protein (NuMA) is indispensable for the mitotic functions of the major microtubule minus-end directed motor cytoplasmic dynein 1. NuMA and dynein are both essential for correct spindle pole organization. How these proteins cooperate to gather microtubule minus ends at spindle poles remains unclear. Here, we use microscopy-based in vitro reconstitutions to demonstrate that NuMA is a dynein adaptor, activating processive dynein motility together with dynein's cofactors dynactin and Lissencephaly-1 (Lis1). Additionally, we find that NuMA binds and stabilizes microtubule minus ends, allowing dynein/dynactin/NuMA to transport microtubule minus ends as cargo to other minus ends. We further show that the microtubule-nucleating γ-tubulin ring complex (γTuRC) hinders NuMA binding and that NuMA only caps minus ends of γTuRC-nucleated microtubules after γTuRC release. These results provide new mechanistic insight into how dynein, dynactin, NuMA, and Lis1 together with γTuRC and uncapping proteins cooperate to organize spindle poles in cells.
    DOI:  https://doi.org/10.1083/jcb.202408118
  3. J Chem Phys. 2025 Feb 14. pii: 065103. [Epub ahead of print]162(6):
    Three-dimensional memory of nuclear organization through cell cycles.
    Shin Fujishiro, Masaki Sasai.
      The genome in the cell nucleus is organized by a dynamic process influenced by structural memory from mitosis. In this study, we develop a model of human genome dynamics through cell cycles by extending the previously developed whole-genome model to cover the mitotic phase. With this extension, we focus on the role of mitotic and cell cycle memory in genome organization. The simulation progresses from mitosis to interphase and the subsequent mitosis, leading to successive cell cycles. During mitosis, our model describes microtubule dynamics, showing how forces orchestrate the assembly of chromosomes into a rosette ring structure at metaphase. The model explains how the positioning of chromosomes depends on their size in metaphase. The memory of the metaphase configuration persists through mitosis and into interphase in dimensions perpendicular to the cell division axis, effectively guiding the distribution of chromosome territories over multiple cell cycles. At the onset of each G1 phase, phase separation of active and inactive chromatin domains occurs, leading to A/B compartmentalization. Our cycling simulations show that the compartments are unaffected by structural memory from previous cycles and are consistently established in each cell cycle. The genome model developed in this study highlights the interplay between chromosome dynamics and structural memory across cell cycles, providing insights for the analyses of cellular processes.
    DOI:  https://doi.org/10.1063/5.0242859
  4. Cell Rep. 2025 Feb 12. pii: S2211-1247(25)00067-1. [Epub ahead of print]44(2): 115296
    The spatiotemporal distribution of LIN-5/NuMA regulates spindle orientation in the C. elegans germ line.
    Réda M Zellag, Vincent Poupart, Takefumi Negishi, Jean-Claude Labbé, Abigail R Gerhold.
      Mitotic spindle orientation contributes to tissue organization and shape by setting the cell division plane. How spindle orientation is coupled to diverse tissue architectures is incompletely understood. The C. elegans gonad is a tube-shaped organ with germ cells forming a circumferential monolayer around a common cytoplasmic lumen. How this organization is maintained during development is unclear, as germ cells lack the canonical cell-cell junctions that ensure spindle orientation in other tissue types. Here, we show that the microtubule force generator dynein and its conserved regulator LIN-5/NuMA regulate germ cell spindle orientation and are required for germline tissue organization. We uncover a cyclic, polarized pattern of LIN-5/NuMA cortical localization that predicts centrosome positioning throughout the cell cycle, providing a means to align spindle orientation with the tissue plane. This work reveals a new mechanism by which oriented cell division can be achieved to maintain tissue organization during animal development.
    Keywords:  CP: Cell biology; CP: Developmental biology; Caenorhabditis elegans; LIN-5/NuMA; dynein; germ cells; germline development; gonad explants; in situ live-cell imaging; mitotic spindle orientation; oriented cell division; tissue organization
    DOI:  https://doi.org/10.1016/j.celrep.2025.115296
  5. J Am Chem Soc. 2025 Feb 11.
    Functionalized Docetaxel Probes for Refined Visualization of Mitotic Spindles by Expansion Microscopy.
    Gang Wen, Xiong Chen, Patrick Eiring, Volker Leen, Johan Hofkens, Markus Sauer.
      Visualizing the ultrastructure of mitotic spindles, the macromolecular machines that segregate chromosomes during mitosis, by fluorescence imaging remains challenging. Here we introduce an azido- and amino-functionalized docetaxel probe, which upon labeling of microtubules can be fixed, click-labeled and linked into hydrogels. The new probe is particularly useful for super-resolution imaging of dense microtubule structures in mitotic spindles. Multicolor expansion microscopy of mitotic cells allowed us to visualize the different phases of mitosis with unprecedented spatial resolution.
    DOI:  https://doi.org/10.1021/jacs.4c15608
  6. Life Sci Alliance. 2025 Apr;pii: e202403065. [Epub ahead of print]8(4):
    A biallelic variant in GORASP1 causes a novel Golgipathy with glycosylation and mitotic defects.
    Sophie Lebon, Arnaud Bruneel, Séverine Drunat, Alexandra Albert, Zsolt Csaba, Monique Elmaleh, Alexandra Ntorkou, Yann Ténier, François Fenaille, Pierre Gressens, Sandrine Passemard, Odile Boespflug-Tanguy, Imen Dorboz, Vincent El Ghouzzi.
      GRASP65 is a Golgi-associated peripheral protein encoded by the GORASP1 gene and required for Golgi cisternal stacking in vitro. A key role of GRASP65 in the regulation of cell division has also been suggested. However, depletion of GRASP65 in mice has little effect on the Golgi structure and the gene has not been associated with any human phenotype to date. Here, we report the identification of the first human pathogenic variant of GORASP1 (c.1170_1171del; p.Asp390Glufs*18) in a patient combining a neurodevelopmental disorder with neurosensory, neuromuscular, and skeletal abnormalities. Functional analysis revealed that the variant leads to a total absence of GRASP65. The structure of the Golgi apparatus did not show fragmentation, but glycosylation anomalies such as hyposialylation were detected. Mitosis analyses revealed an excess of prometaphases and metaphases with polar chromosomes, suggesting a delay in the cell cycle. These phenotypes were recapitulated in RPE cells in which a similar mutation was introduced by CRISPR/Cas9. These results indicate that loss of GRASP65 in humans causes a novel Golgipathy associated with defects in glycosylation and mitotic progression.
    DOI:  https://doi.org/10.26508/lsa.202403065
  7. Curr Biol. 2025 Feb 10. pii: S0960-9822(25)00046-6. [Epub ahead of print]
    Adaptive evolution of CENP-T modulates centromere binding.
    Damian Dudka, Alexandra L Nguyen, Katelyn G Boese, Océane Marescal, R Brian Akins, Ben E Black, Iain M Cheeseman, Michael A Lampson.
      Centromeric DNA and proteins evolve rapidly despite conserved function in mediating kinetochore-microtubule attachments during cell division. This paradox is explained by selfish DNA sequences preferentially binding centromeric proteins to disrupt attachments and bias their segregation into the egg (drive) during female meiosis. Adaptive centromeric protein evolution is predicted to prevent preferential binding to these sequences and suppress drive. Here, we test this prediction by defining the impact of adaptive evolution of the DNA-binding histone fold domain of CENP-T, a major link between centromeric DNA and microtubules. We reversed adaptive changes by creating chimeric variants of mouse CENP-T with the histone fold domain from closely related species, expressed exogenously in mouse oocytes or in a transgenic mouse model. We show that adaptive evolution of mouse CENP-T reduced centromere binding, which supports robust female gametogenesis. However, this innovation is independent of the centromeric DNA sequence, as shown by comparing the binding of divergent CENP-T variants to distinct centromere satellite arrays in mouse oocytes and in somatic cells from other species. Overall, our findings support a model in which selfish sequences drive to fixation, disrupting attachments of all centromeres to the spindle. DNA sequence-specific innovations are not needed to mitigate fitness costs in this model, so centromeric proteins adapt by modulating their binding to all centromeres in the aftermath of drive.
    Keywords:  CENP-T; adaptive evolution; centromere; centromere drive; female meiosis; mouse oocytes
    DOI:  https://doi.org/10.1016/j.cub.2025.01.017
  8. J Oral Maxillofac Pathol. 2024 Oct-Dec;28(4):28(4): 602-611
    Mitosis - predicting primary tumour and metastatic lymph node behaviour and beyond in OSCC - A pilot study.
    Soumya Makarla, Radhika M Bavle, Satyajit Topajiche.
       Background and Objectives: In the evaluation of oral cancer, mitotic index/mitotic figures are of paramount importance in histopathology. The number of mitoses in tumour cells is directly proportional to the activity of the tumour cells. In this novel study, we evaluated the status of the mitotic figures found in the metastatic deposit of the lymph nodes in addition to the primary tumour. A great deal of significance is given to this parameter in the evaluation of progress of the primary tumours in a state of distant metastasis. Therefore, we propose to analyse the lymph node mitotic index (LMI) in metastatic deposits and its relation to the primary tumour by assessing the relation between primary: LN mitosis ratio (PLMR). This also can provide an insight into the concept of understanding the dynamic state of lymph node deposits in oral squamous cell carcinoma (OSCC).
    Materials and Methods: A total of 510 lymph nodes from 17 cases of surgically treated OSCC were analysed, of which 40 lymph nodes were found to be positive. These 40 lymph nodes were examined histopathologically for the presence of mitotic figures in ten randomly selected fields (x400) and compared to the mitotic activity of the primary tumour by two observers independently, along with other histopathological features. LMI and PLMR were further determined for these cases.
    Observations and Results: The mitotic index was significantly higher in the metastatic deposits than in the primary tumour (P = 0.004). A higher percentage of abnormal mitoses was observed in metastatic lymph nodes, but no statistical significance (P = 0.27) was found when compared with primary tumour. Statistically significant correlation (P = 0.001) was observed between abnormal mitoses (%) and presence of ECS as well as size of the metastatic deposits. The LMI ratio showed a high mitotic rate in close to 80% of the cases. PLMR showed 58-60% cases with mitotically more active lymph nodes.
    Interpretation and Conclusion: This study is the first of its kind, which examines a level further than the nature of the primary tumour. Mitotic index/numbers in lymph nodes (LMI) might be considered an important parameter to evaluate the disease spread, revealing the nature of transiently indolent and mitotically active metastatic lymph nodes. The PLMR adds a further dimension on the lymph node's dynamic status in the progression of the disease.
    Keywords:  Abnormal mitosis; increased mitosis; lymph node mitotic index (LMI); metastatic lymph nodes; modified Anneroth’s grading system; oral squamous cell carcinoma; primary and lymph node mitosis ratio (PLMR)
    DOI:  https://doi.org/10.4103/jomfp.jomfp_292_24
  9. Dev Growth Differ. 2025 Feb 11.
    Chromosomal localization of PHOX2B during M-phase is disrupted in disease-associated mutants.
    Yuki Sato, Shinichi Hayashi, Souichi Oe, Taro Koike, Yousuke Nakano, Ryohei Seki-Omura, Hikaru Iwashita, Yukie Hirahara, Masaaki Kitada.
      In the M-phase, the nuclear membrane is broken down, nucleosomes are condensed as mitotic chromosomes, and transcription factors are generally known to be dislocated from their recognition sequences and dispersed to the cytoplasm. However, some transcription factors have recently been reported to remain on mitotic chromosomes and facilitate the rapid re-activation of the target genes in early G1-phase. Paired-like homeobox 2B (PHOX2B) is a transcription factor exhibiting chromosomal localization during M-phase. PHOX2B mutations are associated with congenital central hypoventilation syndrome, Hirschsprung disease, and neuroblastoma. In this study, we investigated PHOX2B chromosomal localization during M-phase through immunostaining and fluorescence recovery after photobleaching analysis to determine whether the chromosomal localization of disease-associated PHOX2B mutants is altered during M-phase. Missense mutations in the homeodomain and the frameshift mutation in the C-terminal domain disrupted the chromosomal localization of PHOX2B in M-phase, leading to its dispersion in the cell. Furthermore, a PHOX2B mutant with polyalanine expansion showed a line-shaped localization to the restricted region of mitotic chromosomes. Our findings suggest an association between the disease-associated mutations and defective chromosomal localization of transcription factors during M-phase. Further investigations of PHOX2B chromosomal localization during M-phase could reveal pathogenic mechanisms of such diseases.
    Keywords:  Hirschsprung disease; PHOX2B; chromosomal localization; congenital central hypoventilation syndrome; neuroblastoma
    DOI:  https://doi.org/10.1111/dgd.70001
  10. Adv Exp Med Biol. 2025 ;1468 453-457
    NUDC Is Critical for Mitosis and Postmitotic Cell Maintenance Through Its Modulation of Dynein and Actin Cytoskeletal Reorganization.
    Mary Anne Garner, Alecia K Gross.
      Nuclear Distribution Protein C (NUDC) has been studied extensively for its role in mitosis. In addition to its well-established role in dynein-mediated nuclear migration, NUDC also plays a role in postmitotic cells. NUDC affects dynein-mediated protein and organelle trafficking and also stabilizes the actin-modulating protein, cofilin (CFL1), thereby affecting cytoskeletal reorganization. This mini-review will cover the known role of NUDC in mitosis as well as its role in actin cytoskeletal reorganization and in protein and organelle trafficking in nondividing cells, as well as update findings on the effect of a loss of NUDC on rod photoreceptors.
    Keywords:  Cofilin 1 (CFL1); Dynein; Mitosis; NUDC; Photoreceptor; Retinal degeneration; Rod
    DOI:  https://doi.org/10.1007/978-3-031-76550-6_74
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