bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2022–03–20
twelve papers selected by
Valentina Piano, Max Planck Institute of Molecular Physiology
  1. Mitotic spindle formation in the absence of Polo kinase.
  2. Mitosis: Kinetochores determined against random search-and-capture.
  3. Microtubule rescue at midzone edges promotes overlap stability and prevents spindle collapse during anaphase B.
  4. Dictyostelium spastin is involved in nuclear envelope dynamics during semi-closed mitosis.
  5. Mre11 exonuclease activity promotes irreversible mitotic progression under replication stress.
  6. Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe.
  7. The TFIIH complex is required to establish and maintain mitotic chromosome structure.
  8. The multifaceted roles of cohesin in cancer.
  9. Rab11 endosomes and Pericentrin coordinate centrosome movement during pre-abscission in vivo.
  10. In Vivo Photocontrol of Microtubule Dynamics and Integrity, Migration and Mitosis, by the Potent GFP-Imaging-Compatible Photoswitchable Reagents SBTubA4P and SBTub2M.
  11. Microtubule Organization Is Essential for Maintaining Cellular Morphology and Function.
  12. The expanding role of WEE1.
  1. Proc Natl Acad Sci U S A. 2022 Mar 22. 119(12): e2114429119
    Mitotic spindle formation in the absence of Polo kinase.
    Juyoung Kim, Gohta Goshima.
      SignificanceMitosis is an essential process in all eukaryotes, but paradoxically, genes required for mitosis vary among species. The essentiality of many mitotic genes was bypassed by activating alternative mechanisms during evolution. However, bypass events have rarely been recapitulated experimentally. Here, using the fission yeast Schizosaccharomyces pombe, the essentiality of a kinase (Plo1) required for bipolar spindle formation was bypassed by other mutations, many of which are associated with glucose metabolism. The Plo1 bypass by the reduction in glucose uptake was dependent on another kinase (casein kinase I), which potentiated spindle microtubule formation. This study illustrates a rare experimental bypass of essentiality for mitotic genes and provides insights into the molecular diversity of mitosis.
    Keywords:  Polo-like kinase; Schizosaccharomyces pombe; experimental evolution; microtubule nucleation; mitotic spindle
    DOI:  https://doi.org/10.1073/pnas.2114429119
  2. Curr Biol. 2022 Mar 14. pii: S0960-9822(22)00225-1. [Epub ahead of print]32(5): R231-R234
    Mitosis: Kinetochores determined against random search-and-capture.
    Joana Soares-de-Oliveira, Helder Maiato.
      The mechanism of chromosome biorientation during mitotic spindle assembly remains a century-old mystery. In contrast to the stochastic models that have dominated the field for decades, a new study now proposes that chromosome biorientation is instead deterministic and driven by microtubule self-organization at kinetochores.
    DOI:  https://doi.org/10.1016/j.cub.2022.02.003
  3. Elife. 2022 Mar 16. pii: e72630. [Epub ahead of print]11
    Microtubule rescue at midzone edges promotes overlap stability and prevents spindle collapse during anaphase B.
    Manuel Lera-Ramirez, François J Nédélec, Phong T Tran.
      During anaphase B, molecular motors slide interpolar microtubules to elongate the mitotic spindle, contributing to the separation of chromosomes. However, sliding of antiparallel microtubules reduces their overlap, which may lead to spindle breakage, unless microtubules grow to compensate sliding. How sliding and growth are coordinated is still poorly understood. In this study, we have used the fission yeast S. pombe to measure microtubule dynamics during anaphase B. We report that the coordination of microtubule growth and sliding relies on promoting rescues at the midzone edges. This makes microtubules stable from pole to midzone, while their distal parts including the plus ends alternate between assembly and disassembly. Consequently, the midzone keeps a constant length throughout anaphase, enabling sustained sliding without the need for a precise regulation of microtubule growth speed. Additionally, we found that in S. pombe, which undergoes closed mitosis, microtubule growth speed decreases when the nuclear membrane wraps around the spindle midzone.
    Keywords:  S. pombe; cell biology
    DOI:  https://doi.org/10.7554/eLife.72630
  4. Nucleus. 2022 Dec;13(1): 144-154
    Dictyostelium spastin is involved in nuclear envelope dynamics during semi-closed mitosis.
    Ulrike Schweigel, Petros Batsios, Annette Müller-Taubenberger, Ralph Gräf, Marianne Grafe.
      Dictyostelium amoebae perform a semi-closed mitosis, in which the nuclear envelope is fenestrated at the insertion sites of the mitotic centrosomes and around the central spindle during karyokinesis. During late telophase the centrosome relocates to the cytoplasmic side of the nucleus, the central spindle disassembles and the nuclear fenestrae become closed. Our data indicate that Dictyostelium spastin (DdSpastin) is a microtubule-binding and severing type I membrane protein that plays a role in this process. Its mitotic localization is in agreement with a requirement for the removal of microtubules that would hinder closure of the fenestrae. Furthermore, DdSpastin interacts with the HeH/ LEM-family protein Src1 in BioID analyses as well as the inner nuclear membrane protein Sun1, and shows subcellular co-localizations with Src1, Sun1, the ESCRT component CHMP7 and the IST1-like protein filactin, suggesting that the principal pathway of mitotic nuclear envelope remodeling is conserved between animals and Dictyostelium amoebae.
    Keywords:  ESCRT; LEM-domain; Spastin; dictyostelium; mitosis; nuclear envelope; sun1
    DOI:  https://doi.org/10.1080/19491034.2022.2047289
  5. Life Sci Alliance. 2022 Jun;pii: e202101249. [Epub ahead of print]5(6):
    Mre11 exonuclease activity promotes irreversible mitotic progression under replication stress.
    Yoshitami Hashimoto, Hirofumi Tanaka.
      Mre11 is a versatile exo-/endonuclease involved in multiple aspects of DNA replication and repair, such as DSB end processing and checkpoint activation. We previously demonstrated that forced mitotic entry drives replisome disassembly at stalled replication forks in Xenopus egg extracts. Here, we examined the effects of various chemical inhibitors using this system and discovered a novel role of Mre11 exonuclease activity in promoting mitotic entry under replication stress. Mre11 activity was necessary for the initial progression of mitotic entry in the presence of stalled forks but unnecessary in the absence of stalled forks or after mitotic entry. In the absence of Mre11 activity, mitotic CDK was inactivated by Wee1/Myt1-dependent phosphorylation, causing mitotic exit. An inhibitor of Wee1/Myt1 or a nonphosphorylatable CDK1 mutant was able to partially bypass the requirement of Mre11 for mitotic entry. These results suggest that Mre11 exonuclease activity facilitates the processing of stalled replication forks upon mitotic entry, which attenuates the inhibitory pathways of mitotic CDK activation, leading to irreversible mitotic progression and replisome disassembly.
    DOI:  https://doi.org/10.26508/lsa.202101249
  6. J Med Chem. 2022 Mar 14.
    Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe.
    Nuria A Tamayo, Matthew P Bourbeau, Jennifer R Allen, Kate S Ashton, Jian Jeffrey Chen, Matthew R Kaller, Thomas T Nguyen, Nobuko Nishimura, Liping H Pettus, Mary Walton, Brian Belmontes, Jodi Moriguchi, Kui Chen, John D McCarter, Kelly Hanestad, Grace Chung, Maria Stefania S Ninniri, Jan Sun, Leszek Poppe, Chris Spahr, John Hui, Lei Jia, Tian Wu, Upendra P Dahal, Katheryne Z Edson, Marc Payton.
      Chromosomal instability (CIN) is a hallmark of cancer that results from errors in chromosome segregation during mitosis. Targeting of CIN-associated vulnerabilities is an emerging therapeutic strategy in drug development. KIF18A, a mitotic kinesin, has been shown to play a role in maintaining bipolar spindle integrity and promotes viability of CIN cancer cells. To explore the potential of KIF18A, a series of inhibitors was identified. Optimization of an initial hit led to the discovery of analogues that could be used as chemical probes to interrogate the role of KIF18A inhibition. Compounds 23 and 24 caused significant mitotic arrest in vivo, which was sustained for 24 h. This would be followed by cell death either in mitosis or in the subsequent interphase. Furthermore, photoaffinity labeling experiments reveal that this series of inhibitors binds at the interface of KIF18A and tubulin. This study represents the first disclosure of KIF18A inhibitors with in vivo activity.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c02030
  7. Elife. 2022 Mar 16. pii: e75475. [Epub ahead of print]11
    The TFIIH complex is required to establish and maintain mitotic chromosome structure.
    Julian Haase, Richard Chen, Wesley M Parker, Mary Kate Bonner, Lisa M Jenkins, Alexander E Kelly.
      Condensins compact chromosomes to promote their equal segregation during mitosis, but the mechanism of condensin engagement with and action on chromatin is incompletely understood. Here, we show that the general transcription factor TFIIH complex is continuously required to establish and maintain a compacted chromosome structure in transcriptionally silent Xenopus egg extracts. Inhibiting the DNA-dependent ATPase activity of the TFIIH complex subunit XPB rapidly and reversibly induces a complete loss of chromosome structure and prevents the enrichment of condensins I and II, but not topoisomerase II, on chromatin. In addition, inhibiting TFIIH prevents condensation of both mouse and Xenopus nuclei in Xenopus egg extracts, which suggests an evolutionarily conserved mechanism of TFIIH action. Reducing nucleosome density through partial histone depletion restores chromosome structure and condensin enrichment in the absence of TFIIH activity. We propose that the TFIIH complex promotes mitotic chromosome condensation by dynamically altering the chromatin environment to facilitate condensin loading and condensin-dependent loop extrusion.
    Keywords:  cell biology; chromosomes; gene expression; mouse; xenopus
    DOI:  https://doi.org/10.7554/eLife.75475
  8. J Exp Clin Cancer Res. 2022 Mar 14. 41(1): 96
    The multifaceted roles of cohesin in cancer.
    Maddalena Di Nardo, Maria M Pallotta, Antonio Musio.
      The cohesin complex controls faithful chromosome segregation by pairing sister chromatids after DNA replication until mitosis. In addition, it is crucial for hierarchal three-dimensional organization of the genome, transcription regulation and maintaining DNA integrity. The core complex subunits SMC1A, SMC3, STAG1/2, and RAD21 as well as its modulators, have been found to be recurrently mutated in human cancers. The mechanisms by which cohesin mutations trigger cancer development and disease progression are still poorly understood. Since cohesin is involved in a range of chromosome-related processes, the outcome of cohesin mutations in cancer is complex. Herein, we discuss recent discoveries regarding cohesin that provide new insight into its role in tumorigenesis.
    Keywords:  Cancer; Chromosome aneuploidy; Cohesin; DNA repair; Gene expression regulation; Genome instability; Replication stress; Topologically associated domains
    DOI:  https://doi.org/10.1186/s13046-022-02321-5
  9. Life Sci Alliance. 2022 Jul;pii: e202201362. [Epub ahead of print]5(7):
    Rab11 endosomes and Pericentrin coordinate centrosome movement during pre-abscission in vivo.
    Nikhila Krishnan, Maxx Swoger, Lindsay I Rathbun, Peter J Fioramonti, Judy Freshour, Michael Bates, Alison E Patteson, Heidi Hehnly.
      The last stage of cell division involves two daughter cells remaining interconnected by a cytokinetic bridge that is cleaved during abscission. Conserved between the zebrafish embryo and human cells, we found that the oldest centrosome moves in a Rab11-dependent manner towards the cytokinetic bridge sometimes followed by the youngest. Rab11-endosomes are organized in a Rab11-GTP dependent manner at the mother centriole during pre-abscission, with Rab11 endosomes at the oldest centrosome being more mobile compared with the youngest. The GTPase activity of Rab11 is necessary for the centrosome protein, Pericentrin, to be enriched at the centrosome. Reduction in Pericentrin expression or optogenetic disruption of Rab11-endosome function inhibited both centrosome movement towards the cytokinetic bridge and abscission, resulting in daughter cells prone to being binucleated and/or having supernumerary centrosomes. These studies suggest that Rab11-endosomes contribute to centrosome function during pre-abscission by regulating Pericentrin organization resulting in appropriate centrosome movement towards the cytokinetic bridge and subsequent abscission.
    DOI:  https://doi.org/10.26508/lsa.202201362
  10. J Am Chem Soc. 2022 Mar 15.
    In Vivo Photocontrol of Microtubule Dynamics and Integrity, Migration and Mitosis, by the Potent GFP-Imaging-Compatible Photoswitchable Reagents SBTubA4P and SBTub2M.
    Li Gao, Joyce C M Meiring, Adam Varady, Iris E Ruider, Constanze Heise, Maximilian Wranik, Cecilia D Velasco, Jennifer A Taylor, Beatrice Terni, Tobias Weinert, Jörg Standfuss, Clemens C Cabernard, Artur Llobet, Michel O Steinmetz, Andreas R Bausch, Martin Distel, Julia Thorn-Seshold, Anna Akhmanova, Oliver Thorn-Seshold.
      Photoswitchable reagents are powerful tools for high-precision studies in cell biology. When these reagents are globally administered yet locally photoactivated in two-dimensional (2D) cell cultures, they can exert micron- and millisecond-scale biological control. This gives them great potential for use in biologically more relevant three-dimensional (3D) models and in vivo, particularly for studying systems with inherent spatiotemporal complexity, such as the cytoskeleton. However, due to a combination of photoswitch isomerization under typical imaging conditions, metabolic liabilities, and insufficient water solubility at effective concentrations, the in vivo potential of photoswitchable reagents addressing cytosolic protein targets remains largely unrealized. Here, we optimized the potency and solubility of metabolically stable, druglike colchicinoid microtubule inhibitors based on the styrylbenzothiazole (SBT) scaffold that are nonresponsive to typical fluorescent protein imaging wavelengths and so enable multichannel imaging studies. We applied these reagents both to 3D organoids and tissue explants and to classic model organisms (zebrafish, clawed frog) in one- and two-protein imaging experiments, in which spatiotemporally localized illuminations allowed them to photocontrol microtubule dynamics, network architecture, and microtubule-dependent processes in vivo with cellular precision and second-level resolution. These nanomolar, in vivo capable photoswitchable reagents should open up new dimensions for high-precision cytoskeleton research in cargo transport, cell motility, cell division, and development. More broadly, their design can also inspire similarly capable optical reagents for a range of cytosolic protein targets, thus bringing in vivo photopharmacology one step closer to general realization.
    DOI:  https://doi.org/10.1021/jacs.2c01020
  11. Oxid Med Cell Longev. 2022 ;2022 1623181
    Microtubule Organization Is Essential for Maintaining Cellular Morphology and Function.
    Lijiang Huang, Yan Peng, Xuetao Tao, Xiaoxiao Ding, Rui Li, Yongsheng Jiang, Wei Zuo.
      Microtubules (MTs) are highly dynamic polymers essential for a wide range of cellular physiologies, such as acting as directional railways for intracellular transport and position, guiding chromosome segregation during cell division, and controlling cell polarity and morphogenesis. Evidence has established that maintaining microtubule (MT) stability in neurons is vital for fundamental cellular and developmental processes, such as neurodevelopment, degeneration, and regeneration. To fulfill these diverse functions, the nervous system employs an arsenal of microtubule-associated proteins (MAPs) to control MT organization and function. Subsequent studies have identified that the disruption of MT function in neurons is one of the most prevalent and important pathological features of traumatic nerve damage and neurodegenerative diseases and that this disruption manifests as a reduction in MT polymerization and concomitant deregulation of the MT cytoskeleton, as well as downregulation of microtubule-associated protein (MAP) expression. A variety of MT-targeting agents that reverse this pathological condition, which is regarded as a therapeutic opportunity to intervene the onset and development of these nervous system abnormalities, is currently under development. Here, we provide an overview of the MT-intrinsic organization process and how MAPs interact with the MT cytoskeleton to promote MT polymerization, stabilization, and bundling. We also highlight recent advances in MT-targeting therapeutic agents applied to various neurological disorders. Together, these findings increase our current understanding of the function and regulation of MT organization in nerve growth and regeneration.
    DOI:  https://doi.org/10.1155/2022/1623181
  12. Cell Signal. 2022 Mar 15. pii: S0898-6568(22)00071-7. [Epub ahead of print] 110310
    The expanding role of WEE1.
    Siang-Boon Koh.
      Upon DNA damage, complex transduction cascades are unleashed to locate, recognise and repair affected lesions. The process triggers a pause in the cell cycle until the damage is resolved. Even under physiologic conditions, this deliberate interruption of cell division is essential to ensure orderly DNA replication and chromosomal segregation. WEE1 is an established regulatory protein in this vast fidelity-monitoring machinery. Its involvement in the DNA damage response and cell cycle has been a subject of study for decades. Emerging studies have also implicated WEE1 directly and indirectly in other cellular functions, including chromatin remodelling and immune response. The expanding role of WEE1 in pathophysiology is matched by the keen surge of interest in developing WEE1-targeted therapeutic agents. This review summarises WEE1 involvement in the cell cycle checkpoints, epigenetic modification and immune signalling, as well as the current state of WEE1 inhibitors in cancer therapeutics.
    Keywords:  DNA damage response; WEE1; cell cycle checkpoint; epigenetics; molecularly targeted agents; tumour immunity
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110310
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