bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2024–12–29
nine papers selected by
Valentina Piano, Uniklinik Köln
  1. Non-autonomous insulin signaling delays mitotic progression in C. elegans germline stem and progenitor cells.
  2. Prolonged mitosis: A key indicator for detecting stressed and damaged cells.
  3. A Microtubule-Associated Protein Functions in Preventing Oocytes from Evading the Spindle Assembly Checkpoint.
  4. Ki-67 and CDK1 Control the Dynamic Association of Nuclear Lipids with Mitotic Chromosomes.
  5. Sequestration of ribosomal subunits as inactive 80S by targeting eIF6 limits mitotic exit and cancer progression.
  6. Chromosome architecture and low cohesion bias acrocentric chromosomes towards aneuploidy during mammalian meiosis.
  7. The histone H3.3 K27M mutation suppresses Ser31phosphorylation and mitotic fidelity, which can directly drive gliomagenesis.
  8. Kinetochores get a grip!
  9. Molecular architectures of centrosomes in C. elegans embryos visualized by cryo-electron tomography.
  1. PLoS Genet. 2024 Dec 23. 20(12): e1011351
    Non-autonomous insulin signaling delays mitotic progression in C. elegans germline stem and progenitor cells.
    Eric Cheng, Ran Lu, Abigail R Gerhold.
      Stem and progenitor cell mitosis is essential for tissue development and homeostasis. How these cells ensure proper chromosome segregation, and thereby maintain mitotic fidelity, in the complex physiological environment of a living animal is poorly understood. Here we use in situ live-cell imaging of C. elegans germline stem and progenitor cells (GSPCs) to ask how the signaling environment influences stem and progenitor cell mitosis in vivo. Through a candidate screen we identify a new role for the insulin/IGF receptor (IGFR), daf-2, during GSPC mitosis. Mitosis is delayed in daf-2/IGFR mutants, and these delays require canonical, DAF-2/IGFR to DAF-16/FoxO insulin signaling, here acting cell non-autonomously from the soma. Interestingly, mitotic delays in daf-2/IGFR mutants depend on the spindle assembly checkpoint but are not accompanied by a loss of mitotic fidelity. Correspondingly, we show that caloric restriction, which delays GSPC mitosis and compromises mitotic fidelity, does not act via the canonical insulin signaling pathway, and instead requires AMP-activated kinase (AMPK). Together this work demonstrates that GSPC mitosis is influenced by at least two genetically separable signaling pathways and highlights the importance of signaling networks for proper stem and progenitor cell mitosis in vivo.
    DOI:  https://doi.org/10.1371/journal.pgen.1011351
  2. Curr Opin Cell Biol. 2024 Dec 24. pii: S0955-0674(24)00128-5. [Epub ahead of print]92 102449
    Prolonged mitosis: A key indicator for detecting stressed and damaged cells.
    Carmen Sparr, Franz Meitinger.
      During mitosis, chromosomes condense, align to form a metaphase plate and segregate to the two daughter cells. Mitosis is one of the most complex recurring transformations in the life of a cell and requires a high degree of reliability to ensure the error-free transmission of genetic information to the next cell generation. An abnormally prolonged mitosis indicates potential defects that compromise genomic integrity. The mitotic stopwatch pathway detects even moderately prolonged mitoses by integrating memories of mitotic durations, ultimately leading to p53-mediated cell cycle arrest or death. This mechanism competes with mitogen signaling to stop the proliferation of damaged and potentially dangerous cells at a pre-oncogenic stage. Mitosis is a highly vulnerable phase, which is affected by multiple types of cellular damages and diverse stresses. We discuss the hypothesis that the duration of mitosis serves as an indicator of cell health.
    Keywords:  53BP1; Cancer; Cell integrity; Genome stability; Microcephaly; Mitogen-activated protein kinases; Mitotic quality control; Mitotic stopwatch; Mitotic surveillance; Prolonged mitosis; Tumor suppressor; USP28; p53
    DOI:  https://doi.org/10.1016/j.ceb.2024.102449
  3. Adv Sci (Weinh). 2024 Dec 25. e2413097
    A Microtubule-Associated Protein Functions in Preventing Oocytes from Evading the Spindle Assembly Checkpoint.
    Changyin Zhou, Xue Zhang, Genlu Xu, Yuting Ran, Hui Wang, Xuefeng Xie, Ang Li, Fei Li, Xiaozhen Li, Jinlong Ding, Mianqun Zhang, Qing-Yuan Sun, Xiang-Hong Ou.
      Aneuploidy eggs are a common cause of human infertility, spontaneous abortion, or trisomy syndromes. The spindle assembly checkpoint (SAC) plays a crucial role in preventing aneuploidy in oocytes, yet it is unclear if additional mechanisms exist to ensure oocyte adherence to this checkpoint. It is now revealed that the microtubule-associated protein NUSAP can prevent oocytes from evading the SAC and regulate the speed of the cell cycle. Mechanistically, the study identifies NUSAP as a novel stabilizer of the E3 ubiquitin ligase APC/CCDH1, protecting CDH1 from SCFBTRC-mediated degradation. Depletion of NUSAP reduces CDH1 protein level, leading to abnormal spindle assembly and chromosome alignment, and disrupting the balance of cell cycle proteins. This misregulated balance causes oocytes to evade the SAC. Consequently, these abnormal oocytes not only fail to arrest at metaphase but also accelerate the cell process, ultimately resulting in the production of aneuploid eggs. Together, the findings not only clarify the existence of mechanisms that ensure oocytes compliance with the spindle assembly checkpoint but also expand the new functions of NUSAP beyond its role as a microtubule- associated protein.
    Keywords:  aneuploid eggs; microtubule‐associated protein; oocyte meiosis; spindle assembly checkpoint
    DOI:  https://doi.org/10.1002/advs.202413097
  4. J Lipid Res. 2024 Dec 18. pii: S0022-2275(24)00236-0. [Epub ahead of print] 100731
    Ki-67 and CDK1 Control the Dynamic Association of Nuclear Lipids with Mitotic Chromosomes.
    Hsiao-Tang Hu, Ueh-Ting Tim Wang, Bi-Chang Chen, Yi-Ping Hsueh, Ting-Fang Wang.
      Nuclear lipids play roles in regulatory processes such as signaling, transcriptional regulation, and DNA repair. In this report, we demonstrate that nuclear lipids may contribute to Ki-67-regulated chromosome integrity during mitosis. In COS-7 cells, nuclear lipids are enriched at the perichromosomal layer and excluded from intrachromosomal regions during early mitosis, but are then detected in intrachromosomal regions during late mitosis, as revealed by TT-ExM, an improved expansion microscopy technique that enables high-sensitivity, super-resolution imaging of proteins, lipids, and nuclear DNA. The nuclear non-histone protein Ki-67 acts as a surfactant to form a repulsive molecular brush around fully condensed sister chromatids in early mitosis, preventing the diffusion or penetration of nuclear lipids into intrachromosomal regions. Ki-67 is phosphorylated during mitosis by cyclin-dependent kinase 1 (CDK1), the best-known master regulator of the cell cycle. Both Ki-67 knockdown and reduced Ki-67 phosphorylation by CDK1 inhibitors allow nuclear lipids to penetrate chromosomal regions. Thus, both Ki-67 protein level and phosphorylation status during mitosis appear to influence the perichromosomal distribution of nuclear lipids. Ki-67 knockdown and CDK1 inhibition also lead to uneven chromosome disjunction between daughter cells, highlighting the critical role of this regulatory mechanism in ensuring accurate chromosome segregation. Given that Ki-67 has been proposed to promote chromosome individualization and establish chromosome-cytoplasmic compartmentalization during open mitosis in vertebrates, our results reveal that nuclear lipid enrichment at the perichromosomal layer enhances Ki-67's ability to form a protective perichromosomal barrier (chromosome envelope), which is critical for correct chromosome segregation and maintenance of genome integrity during mitosis.
    Keywords:  Biotin-DHPE; Cell cycle; Cell cycle-dependent kinase 1; Expansion microscopy; Ki-67; Nuclear lipid; Perichromosomal layer; Phosphatidylserine; TT-ExM
    DOI:  https://doi.org/10.1016/j.jlr.2024.100731
  5. Nucleic Acids Res. 2024 Dec 27. pii: gkae1272. [Epub ahead of print]
    Sequestration of ribosomal subunits as inactive 80S by targeting eIF6 limits mitotic exit and cancer progression.
    Poonam Roshan, Aparna Biswas, Sinthyia Ahmed, Stella Anagnos, Riley Luebbers, Kavya Harish, Megan Li, Nicholas Nguyen, Gao Zhou, Frank Tedeschi, Vivian Hathuc, Zhenguo Lin, Zachary Hamilton, Sofia Origanti.
      Moderating the pool of active ribosomal subunits is critical for maintaining global translation rates. A factor crucial for modulating the 60S ribosomal subunit is eukaryotic translation initiation factor-6 (eIF6). Release of eIF6 from the 60S subunit is essential to permit 60S interactions with the 40S subunit. Here, using the eIF6-N106S mutant, we show that disrupting eIF6 interaction with the 60S subunit leads to an increase in vacant 80S ribosomes. It further highlights a dichotomy in the anti-association activity of eIF6 that is distinct from its role in 60S subunit biogenesis and shows that nucleolar localization of eIF6 is not dependent on BCCIP chaperone and uL14. Limiting active ribosomal pools markedly deregulates translation especially in mitosis and leads to chromosome segregation defects, mitotic exit delays and mitotic catastrophe. Ribo-seq analysis of eIF6-N106S mutant shows a significant downregulation in the translation efficiencies of mitotic factors and specifically transcripts with long 3' untranslated regions. eIF6-N106S mutation also limits cancer invasion, and this role is correlated with overexpression of eIF6 only in high-grade invasive cancers suggesting that deregulation of eIF6 is probably not an early event in cancers. Thus, this study highlights the segregation of eIF6 functions and its role in moderating 80S ribosome availability for translation, mitosis and cancer progression.
    DOI:  https://doi.org/10.1093/nar/gkae1272
  6. Nat Commun. 2024 Dec 23. 15(1): 10713
    Chromosome architecture and low cohesion bias acrocentric chromosomes towards aneuploidy during mammalian meiosis.
    Eirini Bellou, Agata P Zielinska, Eike Urs Mönnich, Nina Schweizer, Antonio Z Politi, Antonina Wellecke, Claus Sibold, Andreas Tandler-Schneider, Melina Schuh.
      Aneuploidy in eggs is a leading cause of miscarriages or viable developmental syndromes. Aneuploidy rates differ between individual chromosomes. For instance, chromosome 21 frequently missegregates, resulting in Down Syndrome. What causes chromosome-specific aneuploidy in meiosis is unclear. Chromosome 21 belongs to the class of acrocentric chromosomes, whose centromeres are located close to the chromosome end, resulting in one long and one short chromosome arm. We demonstrate that acrocentric chromosomes are generally more often aneuploid than metacentric chromosomes in porcine eggs. Kinetochores of acrocentric chromosomes are often partially covered by the short chromosome arm during meiosis I in human and porcine oocytes and orient less efficiently toward the spindle poles. These partially covered kinetochores are more likely to be incorrectly attached to the spindle. Additionally, sister chromatids of acrocentric chromosomes are held together by lower levels of cohesin, making them more vulnerable to age-dependent cohesin loss. Chromosome architecture and low cohesion therefore bias acrocentric chromosomes toward aneuploidy during mammalian meiosis.
    DOI:  https://doi.org/10.1038/s41467-024-54659-3
  7. Curr Biol. 2024 Dec 19. pii: S0960-9822(24)01575-6. [Epub ahead of print]
    The histone H3.3 K27M mutation suppresses Ser31phosphorylation and mitotic fidelity, which can directly drive gliomagenesis.
    Charles A Day, Florina Grigore, Faruck L Hakkim, Souren Paul, Alyssa Langfald, Molly Weberg, Sela Fadness, Paiton Schwab, Leslie Sepaniac, Jason Stumpff, Kevin T Vaughan, David J Daniels, James P Robinson, Edward H Hinchcliffe.
      Serine 31 is a phospho-site unique to the histone H3.3 variant; mitotic phospho-Ser31 is restricted to pericentromeric heterochromatin, and disruption of phospho-Ser31 results in chromosome segregation defects and loss of p53-dependant G1 cell-cycle arrest.1,2,3,4 Ser31 is proximal to the H3.3 lysine 27-to-methionine (K27M) mutation that drives ∼80% of pediatric diffuse midline gliomas.5,6,7,8,9,10,11,12 Here, we show that expression of the H3.3 K27M mutant in normal, diploid cells results in increased chromosome missegregation and failure to arrest in the following G1. Expression of a non-phosphorylatable S31A mutant also drives chromosome missegregation, while the expression of a double K27M + phosphomimetic S31E mutant restores mitotic fidelity and the p53 response to chromosome missegregation. We show that patient-derived H3.3 K27M tumor cells have decreased mitotic Ser31 phosphorylation and increased frequency of chromosome missegregation. CRISPR reversion of the K27M mutation to wild type (WT) restores phospho-Ser31 levels and results in a decrease in chromosome missegregation. However, inserting an S31A mutation by CRISPR into these revertant cells disrupts mitotic fidelity. In vitro and in vivo analyses reveal that Chk1-the mitotic Ser31 kinase-is preferentially retained at pericentromeres in K27M-expressing tumor cells, compared with MLysine27-to-methionine mutation (M27K) isogenic revertants, correlating with both diminished phospho-Ser31 and mitotic defects. Interestingly, whereas M27K revertant cells do not form xenograft tumors in mice, H3.3 S31A cells do, similar to those formed by H3.3 K27M cells. Replication-competent avian leukosis virus splice-acceptor (RCAS)/cellular receptor for subgroup A avian sarcoma and leukosis virus (TVA) mice expressing S31A also form diffuse midline gliomas morphologically indistinguishable from K27M tumors. Together, our results reveal that the H3.3 K27M mutant alters H3.3 Ser31 phosphorylation, which, in turn, has profound impacts on chromosome segregation/cell-cycle regulation.
    Keywords:  Chk1 kinase; DIPG; K27M mutation; cell cycle; chromosome instability; diffuse midline glioma; histone H3.3; p53
    DOI:  https://doi.org/10.1016/j.cub.2024.11.035
  8. J Cell Biol. 2025 Jan 06. pii: e202411040. [Epub ahead of print]224(1):
    Kinetochores get a grip!
    Christian Cozma, Stefan Westermann.
      A new study by Larson and colleagues (2025. J. Cell Biol.https://doi.org/10.1083/jcb.202405176) reveals that kinetochores are biased to bind to microtubule plus-ends due to an interplay between subcomplex organization and the intrinsic polarity of microtubules.
    DOI:  https://doi.org/10.1083/jcb.202411040
  9. Dev Cell. 2024 Dec 21. pii: S1534-5807(24)00724-X. [Epub ahead of print]
    Molecular architectures of centrosomes in C. elegans embryos visualized by cryo-electron tomography.
    Fergus Tollervey, Manolo U Rios, Evgenia Zagoriy, Jeffrey B Woodruff, Julia Mahamid.
      Centrosomes organize microtubules that are essential for mitotic divisions in animal cells. They consist of centrioles surrounded by pericentriolar material (PCM). Questions related to mechanisms of centriole assembly, PCM organization, and spindle microtubule formation remain unanswered, partly due to limited availability of molecular-resolution structural data inside cells. Here, we use cryo-electron tomography to visualize centrosomes across the cell cycle in cells isolated from C. elegans embryos. We describe a pseudo-timeline of centriole assembly and identify distinct structural features in both mother and daughter centrioles. We find that centrioles and PCM microtubules differ in protofilament number (13 versus 11), which could be explained by atypical γ-tubulin ring complexes with 11-fold symmetry identified at the minus ends of short PCM microtubule segments. We further characterize a porous and disordered network that forms the interconnected PCM. Thus, our work builds a three-dimensional structural atlas that helps explain how centrosomes assemble, grow, and achieve function.
    Keywords:  CLEM; Cryo-ET; FIB; SPD-5; centriole; cryo-correlative light and electron microscopy; cryo-focused ion beam; microtubule; mitosis; peri-centriolar material; γ-tubulin ring complex
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.002
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