bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2022–12–25
eight papers selected by
Valentina Piano, Uniklinik Köln
  1. Fission yeast CENP-S/X regulates the spindle assembly checkpoint and faithful chromosome segregation.
  2. SWR1 Chromatin Remodeling Complex Prevents Mitotic Slippage during Spindle Position Checkpoint Arrest.
  3. Adaptation to high rates of chromosomal instability and aneuploidy through multiple pathways in budding yeast.
  4. BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms.
  5. The mitotic role of Adenomatous Polyposis Coli requires its bilateral interaction with tubulin and microtubules.
  6. Does the nuclear envelope retain its identity during mitosis?
  7. Lipid Polarization during Cytokinesis.
  8. Cdk1-mediated threonine phosphorylation of Sam68 modulates its RNA binding, alternative splicing activity and cellular functions.
  1. J Cell Sci. 2022 Dec 20. pii: jcs.260124. [Epub ahead of print]
    Fission yeast CENP-S/X regulates the spindle assembly checkpoint and faithful chromosome segregation.
    Yanze Jian, Lingyun Nie, Sikai Liu, Yueyue Jiang, Zhen Dou, Xing Liu, Xuebiao Yao, Chuanhai Fu.
      The outer kinetochore serves as a platform for initiating the spindle assembly checkpoint and for mediating kinetochore-microtubule attachments. How the inner kinetochore subcomplex CENP-S/CENP-X is involved in regulating the spindle assembly checkpoint and kinetochore-microtubule attachments has not been well characterized. Employing live-cell microscopy and yeast genetics, we found that the fission yeast CENP-S/CENP-X counterpart Mhf1/Mhf2 plays crucial roles in promoting the spindle assembly checkpoint and regulating chromosome segregation. The absence of Mhf2 attenuates the spindle assembly checkpoint, impairs the kinetochore localization of most of the components in the constitutive centromere-associated network (CCAN), and alters the localization of the kinase Aurora-B/Ark1 to the kinetochore. Hence, our findings constitute a model in which Mhf1/Mhf2 ensures faithful chromosome segregation by regulating the accurate organization of the CCAN complex that is required for promoting SAC signaling and for regulating kinetochore-microtubule attachments.
    Keywords:  Fission yeast; Kinetochore; Mhf2; Mitosis; Spindle assembly checkpoint
    DOI:  https://doi.org/10.1242/jcs.260124
  2. Mol Biol Cell. 2022 Dec 21. mbcE20030179
    SWR1 Chromatin Remodeling Complex Prevents Mitotic Slippage during Spindle Position Checkpoint Arrest.
    Ayse Koca Caydasi, Anton Khmelinskii, Zoulfia Darieva, Bahtiyar Kurtulmus, Michael Knop, Gislene Pereira.
      Faithful chromosome segregation in budding yeast requires correct positioning of the mitotic spindle along the mother to daughter cell polarity axis. When the anaphase spindle is not correctly positioned, a surveillance mechanism, named as the spindle position checkpoint (SPOC), prevents the progression out of mitosis until correct spindle positioning is achieved. How SPOC works on a molecular level is not well understood. Here, we performed a genome-wide genetic screen to search for components required for SPOC. We identified the SWR1 chromatin-remodeling complex (SWR1-C) among several novel factors that are essential for SPOC integrity. Cells lacking SWR1-C were able to activate SPOC upon spindle misorientation but underwent mitotic slippage upon prolonged SPOC arrest. This mitotic slippage required the Cdc14-early anaphase release pathway and other factors including the SAGA histone acetyltransferase complex, proteasome components and the mitotic cyclin-dependent kinase inhibitor Sic1. Together, our data establish a novel link between SWR1-C chromatin remodeling and robust checkpoint arrest in late anaphase.
    DOI:  https://doi.org/10.1091/mbc.E20-03-0179
  3. EMBO J. 2022 Dec 19. e111500
    Adaptation to high rates of chromosomal instability and aneuploidy through multiple pathways in budding yeast.
    Matthew N Clarke, Theodor Marsoner, Manuel Alonso Y Adell, Madhwesh C Ravichandran, Christopher S Campbell.
      Both an increased frequency of chromosome missegregation (chromosomal instability, CIN) and the presence of an abnormal complement of chromosomes (aneuploidy) are hallmarks of cancer. To better understand how cells are able to adapt to high levels of chromosomal instability, we previously examined yeast cells that were deleted of the gene BIR1, a member of the chromosomal passenger complex (CPC). We found bir1Δ cells quickly adapted by acquiring specific combinations of beneficial aneuploidies. In this study, we monitored these yeast strains for longer periods of time to determine how cells adapt to high levels of both CIN and aneuploidy in the long term. We identify suppressor mutations that mitigate the chromosome missegregation phenotype. The mutated proteins fall into four main categories: outer kinetochore subunits, the SCFCdc4 ubiquitin ligase complex, the mitotic kinase Mps1, and the CPC itself. The identified suppressor mutations functioned by reducing chromosomal instability rather than alleviating the negative effects of aneuploidy. Following the accumulation of suppressor point mutations, the number of beneficial aneuploidies decreased. These experiments demonstrate a time line of adaptation to high rates of CIN.
    Keywords:  Aurora B; SCF complex; aneuploidy; chromosomal instability; kinetochore
    DOI:  https://doi.org/10.15252/embj.2022111500
  4. Oncogene. 2022 Dec 22.
    BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms.
    Anita Singh, Sara Busacca, Aarti Gaba, Michael Sheaff, Charlotte Poile, Apostolos Nakas, Joanna Dzialo, Aleksandra Bzura, Alan G Dawson, Dean A Fennell, Andrew M Fry.
      The tumour suppressor BRCA1-associated protein 1 (BAP1) is the most frequently mutated cancer gene in mesothelioma. Here we report novel functions for BAP1 in mitotic progression highlighting the relationship between BAP1 and control of genome stability in mesothelioma cells with therapeutic implications. Depletion of BAP1 protein induced proteasome-mediated degradation of BRCA1 in mesothelioma cells while loss of BAP1 correlated with BRCA1 loss in mesothelioma patient tumour samples. BAP1 loss also led to mitotic defects that phenocopied the loss of BRCA1 including spindle assembly checkpoint failure, centrosome amplification and chromosome segregation errors. However, loss of BAP1 also led to additional mitotic changes that were not observed upon BRCA1 loss, including an increase in spindle length and enhanced growth of astral microtubules. Intriguingly, these consequences could be explained by loss of expression of the KIF18A and KIF18B kinesin motors that occurred upon depletion of BAP1 but not BRCA1, as spindle and astral microtubule defects were rescued by re-expression of KIF18A and KIF18B, respectively. We therefore propose that BAP1 inactivation causes mitotic defects through BRCA1-dependent and independent mechanisms revealing novel routes by which mesothelioma cells lacking BAP1 may acquire genome instability and exhibit altered responses to microtubule-targeted agents.
    DOI:  https://doi.org/10.1038/s41388-022-02577-3
  5. J Cell Sci. 2022 Dec 21. pii: jcs.260152. [Epub ahead of print]
    The mitotic role of Adenomatous Polyposis Coli requires its bilateral interaction with tubulin and microtubules.
    Laurence Serre, Julie Delaroche, Angélique Vinit, Guy Schoehn, Eric Denarier, Anne Fourest-Lieuvin, Isabelle Arnal.
      Adenomatous Polyposis Coli (APC) is a scaffold protein with tumour suppressor properties. Mutations causing the loss of its C-terminal domain (APC-C) - bearing cytoskeleton-regulating sequences - correlate with colorectal cancer. The cellular roles of APC in mitosis are widely studied, but the molecular mechanisms of its interaction with the cytoskeleton are poorly understood. Here, we investigated how APC-C regulates microtubule properties, and found it to promote both microtubule growth and shrinkage. Strikingly, APC-C accumulates at shrinking microtubule extremities, a common characteristic of depolymerases. Cryo-electron microscopy revealed that APC-C adopts an extended conformation along the protofilament crest and shows the presence of ring-like tubulin oligomers around microtubules which required the presence of two APC-C sub-domains. A mutant of APC-C incompetent to decorate microtubules with ring-like tubulin oligomers exhibited a reduced effect on microtubule dynamics. Finally, whereas native APC-C rescued defective chromosome alignment in metaphase cells silenced for APC, the ring-incompetent mutant failed to correct mitotic defects. Thus, the bilateral interaction of APC-C with tubulin and microtubules likely contributes to its mitotic functions.
    Keywords:  APC; Depolymerase; Microtubule; Mitosis; Tubulin
    DOI:  https://doi.org/10.1242/jcs.260152
  6. FEBS Lett. 2022 Dec 17.
    Does the nuclear envelope retain its identity during mitosis?
    Natsumi Tsuda, Ryohei Fukagawa, Shinji Sueda.
      During mitosis in metazoan species, the nuclear envelope (NE) undergoes breakdown, and its fragments are absorbed within the membranous network of the endoplasmic reticulum (ER). Past observations by fluorescence microscopy led researchers to think that the NE loses its identity when it is absorbed within the ER membrane. However, in our previous work, we developed a more specific labeling method and found evidence that the NE does not completely lose its identity during mitosis. In the present work, we conduct further experiments, the results of which support the idea that the NE partially retains its identity during mitosis.
    Keywords:  NE breakdown; NE marker; NE reformation; biotinylation; fluorescent labeling; mitosis; nuclear envelope
    DOI:  https://doi.org/10.1002/1873-3468.14568
  7. Cells. 2022 Dec 08. pii: 3977. [Epub ahead of print]11(24):
    Lipid Polarization during Cytokinesis.
    Govind Kunduri, Usha Acharya, Jairaj K Acharya.
      The plasma membrane of eukaryotic cells is composed of a large number of lipid species that are laterally segregated into functional domains as well as asymmetrically distributed between the outer and inner leaflets. Additionally, the spatial distribution and organization of these lipids dramatically change in response to various cellular states, such as cell division, differentiation, and apoptosis. Division of one cell into two daughter cells is one of the most fundamental requirements for the sustenance of growth in all living organisms. The successful completion of cytokinesis, the final stage of cell division, is critically dependent on the spatial distribution and organization of specific lipids. In this review, we discuss the properties of various lipid species associated with cytokinesis and the mechanisms involved in their polarization, including forward trafficking, endocytic recycling, local synthesis, and cortical flow models. The differences in lipid species requirements and distribution in mitotic vs. male meiotic cells will be discussed. We will concentrate on sphingolipids and phosphatidylinositols because their transbilayer organization and movement may be linked via the cytoskeleton and thus critically regulate various steps of cytokinesis.
    Keywords:  PUFA; aging; cancer; cataract; ceramide phosphoethanolamine; cholesterol; cortical flow; cytokinesis; disease; endocytic recycling; forward trafficking; lipid polarization; lipids; lowe syndrome; male meiotic cytokinesis; membrane bending; membrane curvature; membrane traffic; multivesicular bodies; multivesicular endosomes; phosphatidic acid; phosphatidyl serine; phosphatidylethanolamine; phosphatidylinositol; phosphatidylinositol phosphates; rab GTPase; sphingolipidoses; sphingolipids; sphingomyelin; transbilayer coupling; triacylglycerols; very long chain fatty acids; very long chain polyunsaturated fatty acids
    DOI:  https://doi.org/10.3390/cells11243977
  8. Nucleic Acids Res. 2022 Dec 20. pii: gkac1181. [Epub ahead of print]
    Cdk1-mediated threonine phosphorylation of Sam68 modulates its RNA binding, alternative splicing activity and cellular functions.
    Idir Malki, Inara Liepina, Nora Kogelnik, Hollie Watmuff, Sue Robinson, Adam Lightfoot, Oksana Gonchar, Andrew Bottrill, Andrew M Fry, Cyril Dominguez.
      Sam68, also known as KHDRBS1, is a member of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins and its role is modulated by post-translational modifications, including serine/threonine phosphorylation, that differ at various stages of the cell cycle. However, the molecular basis and mechanisms of these modulations remain largely unknown. Here, we combined mass spectrometry, nuclear magnetic resonance spectroscopy and cell biology techniques to provide a comprehensive post-translational modification mapping of Sam68 at different stages of the cell cycle in HEK293 and HCT116 cells. We established that Sam68 is specifically phosphorylated at T33 and T317 by Cdk1, and demonstrated that these phosphorylation events reduce the binding of Sam68 to RNA, control its cellular localization and reduce its alternative splicing activity, leading to a reduction in the induction of apoptosis and an increase in the proliferation of HCT116 cells.
    DOI:  https://doi.org/10.1093/nar/gkac1181
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