bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2022–11–13
nine papers selected by
Valentina Piano, Uniklinik Köln
  1. MCRS1 modulates the heterogeneity of microtubule minus-end morphologies in mitotic spindles.
  2. Mitotic Antipairing of Homologous Chromosomes.
  3. PRL stimulates mitotic errors by suppressing kinetochore-localized activation of AMPK during mitosis.
  4. PARP10 Mediates Mono-ADP-Ribosylation of Aurora-A Regulating G2/M Transition of the Cell Cycle.
  5. Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle.
  6. Aurora A phosphorylates Ndel1 to reduce the levels of Mad1 and NuMA at spindle poles.
  7. The first mitotic division of human embryos is highly error prone.
  8. CENP-A: A Histone H3 Variant with Key Roles in Centromere Architecture in Healthy and Diseased States.
  9. Arrest of Cell Cycle by Avian Reovirus p17 through Its Interaction with Bub3.
  1. Mol Biol Cell. 2022 Nov 09. mbcE22080306T
    MCRS1 modulates the heterogeneity of microtubule minus-end morphologies in mitotic spindles.
    Alejandra Laguillo-Diego, Robert Kiewisz, Carlos Martí-Gómez, Daniel Baum, Thomas Müller-Reichert, Isabelle Vernos.
      Faithful chromosome segregation requires the assembly of a bipolar spindle, consisting of two antiparallel microtubule (MT) arrays having most of their minus ends focused at the spindle poles and their plus ends overlapping in the spindle midzone. Spindle assembly, chromosome alignment and segregation require highly dynamic MTs. The plus ends of MTs have been extensively investigated; instead, their minus end structure remains poorly characterized. Here, we used large-scale electron tomography to study the morphology of the MT minus ends in 3D-reconstructed metaphase spindles in HeLa cells. In contrast to the homogeneous open morphology of the MT plus ends at the kinetochores, we found that MT minus ends are heterogeneous showing either open or closed morphologies. Silencing the minus-end specific stabilizer, MCRS1 increased the proportion of open MT minus ends. Altogether, these data suggest a correlation between the morphology and the dynamic state of the MT ends. Taking this heterogeneity of the MT minus end morphologies into account, our work indicates an unsynchronized behavior of MTs at the spindle poles, thus laying the ground for further studies on the complexity of MT dynamics regulation. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E22-08-0306-T
  2. Results Probl Cell Differ. 2022 ;70 191-220
    Mitotic Antipairing of Homologous Chromosomes.
    Lisa L Hua, Christian J Casas, Takashi Mikawa.
      Chromosome organization is highly dynamic and plays an essential role during cell function. It was recently found that pairs of the homologous chromosomes are continuously separated at mitosis and display a haploid (1n) chromosome set, or "antipairing," organization in human cells. Here, we provide an introduction to the current knowledge of homologous antipairing in humans and its implications in human disease.
    Keywords:  Antipairing; Homologous chromosomes; Mitosis; Nuclear organization
    DOI:  https://doi.org/10.1007/978-3-031-06573-6_6
  3. Cell Struct Funct. 2022 Nov 05.
    PRL stimulates mitotic errors by suppressing kinetochore-localized activation of AMPK during mitosis.
    Kajung Ryu, Atsushi Yoshida, Yosuke Funato, Daisuke Yamazaki, Hiroaki Miki.
      Phosphatase of regenerating liver (PRL) is frequently overexpressed in various malignant cancers and is known to be a driver of malignancy. Here, we demonstrated that PRL overexpression causes mitotic errors that accompany spindle misorientation and aneuploidy, which are intimately associated with cancer progression. Mechanistic analyses of this phenomenon revealed dysregulation of the energy sensor kinase, AMP-activated protein kinase (AMPK), in PRL-induced mitotic errors. Specifically, immunofluorescence analysis showed that levels of phosphorylated AMPK (P-AMPK), an activated form of AMPK, at the kinetochore were reduced by PRL expression. Moreover, artificial activation of AMPK using chemical activators, such as A769662 and AICAR, in PRL-expressing cells restored P-AMPK signals at the kinetochore and normalized spindle orientation. Collectively, these results indicate the crucial importance of the activation of kinetochore-localized AMPK in the normal progression of mitosis, which is specifically perturbed by PRL overexpression.Key words: cancer, AMPK, PRL, kinetochore, mitotic errors.
    Keywords:  AMPK; PRL; cancer; kinetochore; mitotic errors
    DOI:  https://doi.org/10.1247/csf.22034
  4. Cancers (Basel). 2022 Oct 24. pii: 5210. [Epub ahead of print]14(21):
    PARP10 Mediates Mono-ADP-Ribosylation of Aurora-A Regulating G2/M Transition of the Cell Cycle.
    Simone Di Paola, Maria Matarese, Maria Luisa Barretta, Nina Dathan, Antonino Colanzi, Daniela Corda, Giovanna Grimaldi.
      Intracellular mono-ADP-ribosyltransferases (mono-ARTs) catalyze the covalent attachment of a single ADP-ribose molecule to protein substrates, thus regulating their functions. PARP10 is a soluble mono-ART involved in the modulation of intracellular signaling, metabolism and apoptosis. PARP10 also participates in the regulation of the G1- and S-phase of the cell cycle. However, the role of this enzyme in G2/M progression is not defined. In this study, we found that genetic ablation, protein depletion and pharmacological inhibition of PARP10 cause a delay in the G2/M transition of the cell cycle. Moreover, we found that the mitotic kinase Aurora-A, a previously identified PARP10 substrate, is actively mono-ADP-ribosylated (MARylated) during G2/M transition in a PARP10-dependent manner. Notably, we showed that PARP10-mediated MARylation of Aurora-A enhances the activity of the kinase in vitro. Consistent with an impairment in the endogenous activity of Aurora-A, cells lacking PARP10 show a decreased localization of the kinase on the centrosomes and mitotic spindle during G2/M progression. Taken together, our data provide the first evidence of a direct role played by PARP10 in the progression of G2 and mitosis, an event that is strictly correlated to the endogenous MARylation of Aurora-A, thus proposing a novel mechanism for the modulation of Aurora-A kinase activity.
    Keywords:  Aurora-A; G2/M transition; MARylation; Mono-ADP-ribosylation; NAD; PARP10; PARPs; cell cycle; mitosis; post-translational modification
    DOI:  https://doi.org/10.3390/cancers14215210
  5. Elife. 2022 Nov 08. pii: e79558. [Epub ahead of print]11
    Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle.
    Pooja Suresh, Vahe Galstyan, Rob Phillips, Sophie Dumont.
      During cell division, the spindle generates force to move chromosomes. In mammals, microtubule bundles called kinetochore-fibers (k-fibers) attach to and segregate chromosomes. To do so, k-fibers must be robustly anchored to the dynamic spindle. We previously developed microneedle manipulation to mechanically challenge k-fiber anchorage, and observed spatially distinct response features revealing the presence of heterogeneous anchorage (Suresh et al., 2020). How anchorage is precisely spatially regulated, and what forces are necessary and sufficient to recapitulate the k-fiber's response to force remain unclear. Here, we develop a coarse-grained k-fiber model and combine with manipulation experiments to infer underlying anchorage using shape analysis. By systematically testing different anchorage schemes, we find that forces solely at k-fiber ends are sufficient to recapitulate unmanipulated k-fiber shapes, but not manipulated ones for which lateral anchorage over a 3 μm length scale near chromosomes is also essential. Such anchorage robustly preserves k-fiber orientation near chromosomes while allowing pivoting around poles. Anchorage over a shorter length scale cannot robustly restrict pivoting near chromosomes, while anchorage throughout the spindle obstructs pivoting at poles. Together, this work reveals how spatially regulated anchorage gives rise to spatially distinct mechanics in the mammalian spindle, which we propose are key for function.
    Keywords:  cell biology; chromosome segregation; coarse-grained modeling; mechanics; microtubules; p. tridactylis; physics of living systems; spindle
    DOI:  https://doi.org/10.7554/eLife.79558
  6. Mol Biol Cell. 2022 Nov 09. mbcE21090438
    Aurora A phosphorylates Ndel1 to reduce the levels of Mad1 and NuMA at spindle poles.
    Paweł Ł Janczyk, Eliza Żyłkiewicz, Henry De Hoyos, Thomas West, Daniel R Matson, Won-Chan Choi, Heather M Raimer Young, Zygmunt S Derewenda, P Todd Stukenberg.
      Dynein inactivates the spindle assembly checkpoint (SAC) by transporting checkpoint proteins away from kinetochores towards spindle poles in a process known as "stripping." We find that inhibition of Aurora A kinase, which is localized to spindle poles, enables the accumulation of the spindle checkpoint activator Mad1 at poles where it is normally absent. Aurora kinases phosphorylate the dynein activator Ndel1 on Ser285 and Mad1 accumulates at poles when Ndel1 is replaced by a non-phosphorylatable mutant in human cells. The pole focusing protein NuMA, transported to poles by dynein, also accumulates at poles in cells harboring a mutant Ndel1. Phosphorylation of Ndel1 on Ser285 is required for robust spindle checkpoint activity and regulates the poles of asters in Xenopus extracts. Our data suggest that dynein/SAC complexes that are generated at kinetochores and then transported directionally toward poles on microtubules are inhibited by Aurora A before they reach spindle poles. These data suggest that Aurora A generate a spatial signal at spindle poles that controls dynein transport and spindle function.
    DOI:  https://doi.org/10.1091/mbc.E21-09-0438
  7. Nat Commun. 2022 Nov 08. 13(1): 6755
    The first mitotic division of human embryos is highly error prone.
    Cerys E Currie, Emma Ford, Lucy Benham Whyte, Deborah M Taylor, Bettina P Mihalas, Muriel Erent, Adele L Marston, Geraldine M Hartshorne, Andrew D McAinsh.
      Human beings are made of ~50 trillion cells which arise from serial mitotic divisions of a single cell - the fertilised egg. Remarkably, the early human embryo is often chromosomally abnormal, and many are mosaic, with the karyotype differing from one cell to another. Mosaicism presumably arises from chromosome segregation errors during the early mitotic divisions, although these events have never been visualised in living human embryos. Here, we establish live cell imaging of chromosome segregation using normally fertilised embryos from an egg-share-to-research programme, as well as embryos deselected during fertility treatment. We reveal that the first mitotic division has an extended prometaphase/metaphase and exhibits phenotypes that can cause nondisjunction. These included multipolar chromosome segregations and lagging chromosomes that lead to formation of micronuclei. Analysis of nuclear number and size provides evidence of equivalent phenotypes in 2-cell human embryos that gave rise to live births. Together this shows that errors in the first mitotic division can be tolerated in human embryos and uncovers cell biological events that contribute to preimplantation mosaicism.
    DOI:  https://doi.org/10.1038/s41467-022-34294-6
  8. Results Probl Cell Differ. 2022 ;70 221-261
    CENP-A: A Histone H3 Variant with Key Roles in Centromere Architecture in Healthy and Diseased States.
    Daniel Jeffery, Marina Lochhead, Geneviève Almouzni.
      Centromeres are key architectural components of chromosomes. Here, we examine their construction, maintenance, and functionality. Focusing on the mammalian centromere- specific histone H3 variant, CENP-A, we highlight its coevolution with both centromeric DNA and its chaperone, HJURP. We then consider CENP-A de novo deposition and the importance of centromeric DNA recently uncovered with the added value from new ultra-long-read sequencing. We next review how to ensure the maintenance of CENP-A at the centromere throughout the cell cycle. Finally, we discuss the impact of disrupting CENP-A regulation on cancer and cell fate.
    Keywords:  Alpha-satellite; CENP-A; Cancer; Cell cycle; Centromere; Genome architecture; HJURP; Histone variant
    DOI:  https://doi.org/10.1007/978-3-031-06573-6_7
  9. Viruses. 2022 Oct 28. pii: 2385. [Epub ahead of print]14(11):
    Arrest of Cell Cycle by Avian Reovirus p17 through Its Interaction with Bub3.
    Junyu Tang, Mengjiao Fu, Xiang Chen, Yimeng Zhao, Li Gao, Hong Cao, Xiaoqi Li, Shijun J Zheng, Yongqiang Wang.
      Avian reoviruses (ARV) are a group of poultry pathogens that cause runting and stunting syndrome (RSS), a condition otherwise known as "frozen chicken", which are characterized by dramatically delayed growth in broilers. It has been known that p17, a nonstructural protein encoded by ARV, prohibits cellular proliferation by halting the cell cycle at the G2/M phase, the result of which is directly associated with the typical clinical sign of RSS. Nevertheless, the mechanism by which p17 modulates cell-cycle progression remains largely unknown. Here, we screened the interactome of ectopically expressed p17 through a yeast two-hybrid assay and identified Bub3, a cellular mitotic checkpoint protein, as a binding partner of p17. The infection of the Vero cells by ARV downregulated the Bub3 expression, while the knockdown of Bub3 alleviated the p17-modulated cell-cycle arrest during ARV infection. Remarkably, the suppression of Bub3 by RNAi in the Vero cells significantly reduced the viral mRNA and protein abundance, which eventually led to diminished virus replication. Altogether, our findings reveal that ARV p17 impedes host cell proliferation through a Bub3-dependent cell-cycle arrest, which eventually contributes to efficient virus replication. These results also unveil a hitherto unknown therapeutic target for RSS.
    Keywords:  Bub3; avian reovirus; cell-cycle arrest; mitotic checkpoint; p17; viral replication
    DOI:  https://doi.org/10.3390/v14112385
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