bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2022–12–04
seven papers selected by
Valentina Piano, Uniklinik Köln
  1. Kinetochore- and chromosome-driven transition of microtubules into bundles promotes spindle assembly.
  2. The second half of mitosis and its implications in cancer biology.
  3. Spatial separation of phosphatase and kinase activity within the Bub complex is required for proper mitosis.
  4. Autocleavage of separase suppresses its premature activation by promoting binding to cyclin B1.
  5. Revisiting degron motifs in human AURKA required for its targeting by APC/CFZR1.
  6. Engineering metaphase spindles: Construction site and building blocks.
  7. Fission yeast Dis1 is an unconventional TOG/XMAP215 that induces microtubule catastrophe to drive chromosome pulling.
  1. Nat Commun. 2022 Nov 27. 13(1): 7307
    Kinetochore- and chromosome-driven transition of microtubules into bundles promotes spindle assembly.
    Jurica Matković, Subhadip Ghosh, Mateja Ćosić, Susana Eibes, Marin Barišić, Nenad Pavin, Iva M Tolić.
      Mitotic spindle assembly is crucial for chromosome segregation and relies on bundles of microtubules that extend from the poles and overlap in the middle. However, how these structures form remains poorly understood. Here we show that overlap bundles arise through a network-to-bundles transition driven by kinetochores and chromosomes. STED super-resolution microscopy reveals that PRC1-crosslinked microtubules initially form loose arrays, which become rearranged into bundles. Kinetochores promote microtubule bundling by lateral binding via CENP-E/kinesin-7 in an Aurora B-regulated manner. Steric interactions between the bundle-associated chromosomes at the spindle midplane drive bundle separation and spindle widening. In agreement with experiments, theoretical modeling suggests that bundles arise through competing attractive and repulsive mechanisms. Finally, perturbation of overlap bundles leads to inefficient correction of erroneous kinetochore-microtubule attachments. Thus, kinetochores and chromosomes drive coarsening of a uniform microtubule array into overlap bundles, which promote not only spindle formation but also chromosome segregation fidelity.
    DOI:  https://doi.org/10.1038/s41467-022-34957-4
  2. Semin Cancer Biol. 2022 Nov 24. pii: S1044-579X(22)00246-2. [Epub ahead of print]88 1-17
    The second half of mitosis and its implications in cancer biology.
    Daniel Moreno-Andrés, Kristin Holl, Wolfram Antonin.
      The nucleus undergoes dramatic structural and functional changes during cell division. With the entry into mitosis, in human cells the nuclear envelope breaks down, chromosomes rearrange into rod-like structures which are collected and segregated by the spindle apparatus. While these processes in the first half of mitosis have been intensively studied, much less is known about the second half of mitosis, when a functional nucleus reforms in each of the emerging cells. Here we review our current understanding of mitotic exit and nuclear reformation with spotlights on the links to cancer biology.
    Keywords:  Chromatin decondensation; Chromatin segregation defects; Chromosomal instability; Cytokinesis; Genetic instability; Micronuclei; Mitotic exit; Nuclear reformation
    DOI:  https://doi.org/10.1016/j.semcancer.2022.11.013
  3. J Mol Cell Biol. 2022 Nov 28. pii: mjac062. [Epub ahead of print]
    Spatial separation of phosphatase and kinase activity within the Bub complex is required for proper mitosis.
    Lei Wang, Thomas Kruse, Blanca López-Méndez, Yuqing Zhang, Chunlin Song, Lei Zhu, Bing Li, Jing Fang, Zhimin Lu, Jakob Nilsson, Gang Zhang.
      The Bub1 and BubR1 kinetochore proteins support proper chromosome segregation and mitotic checkpoint activity. Bub1 and BubR1 are paralogues with Bub1 being a kinase while BubR1 localizes the PP2A-B56 protein phosphatase to kinetochores in humans. Whether this spatial separation of kinase and phosphatase activity is important is unclear as some organisms integrate both activities into one Bub protein. Here we engineer human Bub1 and BubR1 proteins integrating kinase and phosphatase activities into one protein and show that these do not support normal mitotic progression. A Bub1-PP2A-B56 complex can supports chromosome alignment but results in impairment of the checkpoint due to dephosphorylation of the Mad1 binding site in Bub1. Furthermore, a chimeric BubR1 protein containing the Bub1 kinase domain induces delocalized H2ApT120 phosphorylation, resulting in reduction of centromeric hSgo2 and chromosome segregation errors. Collectively, these results argue that the spatial separation of kinase and phosphatase activities within the Bub complex is required for balancing its functions in the checkpoint and chromosome alignment.
    Keywords:  Bub1; BubR1; PP2A/B56; kinetochores; mitosis; spindle assembly checkpoint
    DOI:  https://doi.org/10.1093/jmcb/mjac062
  4. Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01601-1. [Epub ahead of print]41(9): 111723
    Autocleavage of separase suppresses its premature activation by promoting binding to cyclin B1.
    Norihisa Shindo, Kazuki Kumada, Kenji Iemura, Jun Yasuda, Haruna Fujimori, Mai Mochizuki, Keiichi Tamai, Kozo Tanaka, Toru Hirota.
      Accurate chromosome segregation requires timely activation of separase, a protease that cleaves cohesin during the metaphase-to-anaphase transition. However, the mechanism that maintains the inactivity of separase prior to this event remains unclear. We provide evidence that separase autocleavage plays an essential role in this process. We show that the inhibition of separase autocleavage results in premature activity before the onset of anaphase, accompanied by the formation of chromosomal bridges and spindle rocking. This deregulation is attributed to the reduced binding of cyclin B1 to separase that occurs during the metaphase-to-anaphase transition. Furthermore, when separase is mutated to render the regulation by cyclin B1 irrelevant, which keeps separase in securin-binding form, the deregulation induced by autocleavage inhibition is rescued. Our results reveal a physiological role of separase autocleavage in regulating separase, which ensures faithful chromosome segregation.
    Keywords:  CP: Cell biology; CP: Molecular biology; cell division; chromosomal instability; chromosome segregation; cyclin B1; enzyme activity; mitosis; securin; separase
    DOI:  https://doi.org/10.1016/j.celrep.2022.111723
  5. Life Sci Alliance. 2023 Feb;pii: e202201372. [Epub ahead of print]6(2):
    Revisiting degron motifs in human AURKA required for its targeting by APC/CFZR1.
    Ahmed Abdelbaki, Camilla Ascanelli, Cynthia N Okoye, H Begum Akman, Giacomo Janson, Mingwei Min, Chiara Marcozzi, Anja Hagting, Rhys Grant, Maria De Luca, Italia Anna Asteriti, Giulia Guarguaglini, Alessandro Paiardini, Catherine Lindon.
      Mitotic kinase Aurora A (AURKA) diverges from other kinases in its multiple active conformations that may explain its interphase roles and the limited efficacy of drugs targeting the kinase pocket. Regulation of AURKA activity by the cell is critically dependent on destruction mediated by the anaphase-promoting complex (APC/CFZR1) during mitotic exit and G1 phase and requires an atypical N-terminal degron in AURKA called the "A-box" in addition to a reported canonical D-box degron in the C-terminus. Here, we find that the reported C-terminal D-box of AURKA does not act as a degron and instead mediates essential structural features of the protein. In living cells, the N-terminal intrinsically disordered region of AURKA containing the A-box is sufficient to confer FZR1-dependent mitotic degradation. Both in silico and in cellulo assays predict the QRVL short linear interacting motif of the A-box to be a phospho-regulated D-box. We propose that degradation of full-length AURKA also depends on an intact C-terminal domain because of critical conformational parameters permissive for both activity and mitotic degradation of AURKA.
    DOI:  https://doi.org/10.26508/lsa.202201372
  6. Curr Opin Cell Biol. 2022 Nov 24. pii: S0955-0674(22)00096-5. [Epub ahead of print]79 102143
    Engineering metaphase spindles: Construction site and building blocks.
    Tobias Kletter, Abin Biswas, Simone Reber.
      In an active, crowded cytoplasm, eukaryotic cells construct metaphase spindles from conserved building blocks to segregate chromosomes. Yet, spindles execute their function in a stunning variety of cell shapes and sizes across orders of magnitude. Thus, the current challenge is to understand how unique mesoscale spindle characteristics emerge from the interaction of molecular collectives. Key components of these collectives are tubulin dimers, which polymerise into microtubules. Despite all conservation, tubulin is a genetically and biochemically complex protein family, and we only begin to uncover how tubulin diversity affects microtubule dynamics and thus spindle assembly. Moreover, it is increasingly appreciated that spindles are dynamically intertwined with the cytoplasm that itself exhibits cell-type specific emergent properties with yet mostly unexplored consequences for spindle construction. Therefore, on our way toward a quantitative picture of spindle function, we need to understand molecular behaviour of the building blocks and connect it to the entire cellular context.
    Keywords:  Active cytoplasm; Macromolecular crowding; Mass density; Meiotic; Microtubule; Mitotic; Spindle; Tubulin; Tubulin PTMs; Tubulin isoforms; Viscoelasticity
    DOI:  https://doi.org/10.1016/j.ceb.2022.102143
  7. Commun Biol. 2022 Nov 26. 5(1): 1298
    Fission yeast Dis1 is an unconventional TOG/XMAP215 that induces microtubule catastrophe to drive chromosome pulling.
    Yuichi Murase, Masahiko Yamagishi, Naoyuki Okada, Mika Toya, Junichiro Yajima, Takahiro Hamada, Masamitsu Sato.
      The shortening of microtubules attached to kinetochores is the driving force of chromosome movement during cell division. Specific kinesins are believed to shorten microtubules but are dispensable for viability in yeast, implying the existence of additional factors responsible for microtubule shortening. Here, we demonstrate that Dis1, a TOG/XMAP215 ortholog in fission yeast, promotes microtubule shortening to carry chromosomes. Although TOG/XMAP215 orthologs are generally accepted as microtubule polymerases, Dis1 promoted microtubule catastrophe in vitro and in vivo. Notably, microtubule catastrophe was promoted when the tip was attached to kinetochores, as they steadily anchored Dis1 at the kinetochore-microtubule interface. Engineered Dis1 oligomers artificially tethered at a chromosome arm region induced the shortening of microtubules in contact, frequently pulling the chromosome arm towards spindle poles. This effect was not brought by oligomerised Alp14. Thus, unlike Alp14 and other TOG/XMAP215 orthologs, Dis1 plays an unconventional role in promoting microtubule catastrophe, thereby driving chromosome movement.
    DOI:  https://doi.org/10.1038/s42003-022-04271-2
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