scholarly journals Physiological relevance of post-translational regulation of the spindle assembly checkpoint protein BubR1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Celia R. Bloom ◽  
Brian J. North
Keyword(s):  
Translational Regulation ◽  
Molecular Mechanisms ◽  
Spindle Assembly Checkpoint ◽  
Critical Role ◽  
Spindle Assembly ◽  
Post Translational Modifications ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Physiological Relevance ◽  
Mosaic Variegated Aneuploidy

AbstractBubR1 is an essential component of the spindle assembly checkpoint (SAC) during mitosis where it functions to prevent anaphase onset to ensure proper chromosome alignment and kinetochore-microtubule attachment. Loss or mutation of BubR1 results in aneuploidy that precedes various potential pathologies, including cancer and mosaic variegated aneuploidy (MVA). BubR1 is also progressively downregulated with age and has been shown to be directly involved in the aging process through suppression of cellular senescence. Post-translational modifications, including but not limited to phosphorylation, acetylation, and ubiquitination, play a critical role in the temporal and spatial regulation of BubR1 function. In this review, we discuss the currently characterized post-translational modifications to BubR1, the enzymes involved, and the biological consequences to BubR1 functionality and implications in diseases associated with BubR1. Understanding the molecular mechanisms promoting these modifications and their roles in regulating BubR1 is important for our current understanding and future studies of BubR1 in maintaining genomic integrity as well as in aging and cancer.

scholarly journals Alternative Cdc20 translational isoforms bypass the spindle assembly checkpoint to control mitotic arrest duration

2021 ◽  
Author(s):  
Mary Jane Tsang ◽  
Iain M Cheeseman
Keyword(s):  
Translational Regulation ◽  
Spindle Assembly Checkpoint ◽  
Critical Role ◽  
Spindle Assembly ◽  
Mitotic Arrest ◽  
Mitotic Exit ◽  
Regulatory Control ◽  
Cycle Arrest ◽  
Anaphase Onset ◽  
Mitotic Slippage

Mitotic chromosome segregation defects activate the Spindle Assembly Checkpoint (SAC), which inhibits the APC/C co-activator Cdc20 to induce a prolonged cell cycle arrest. Once errors are corrected, the SAC is silenced thereby allowing anaphase onset and mitotic exit to proceed. However, in the presence of persistent, unresolvable errors, cells can undergo "mitotic slippage", exiting mitosis into a tetraploid G1 state and escaping the cell death that results from a prolonged arrest. The molecular logic that allows cells to balance these dueling mitotic arrest and slippage behaviors remains unclear. Here we demonstrate that human cells modulate their mitotic arrest duration through the presence of conserved, alternative Cdc20 translational isoforms. Translation initiation at downstream start sites results in truncated Cdc20 isoforms that are resistant to SAC-mediated inhibition and promote mitotic exit even in the presence of mitotic perturbations. Targeted molecular changes or naturally-occurring mutations in cancer cells that alter the relative Cdc20 isoform levels or its translational regulatory control modulate both mitotic arrest duration and anti-mitotic drug sensitivity. Our work reveals a critical role for the differential translational regulation of Cdc20 in mitotic arrest timing, with important implications for the diagnosis and treatment of human cancers.

scholarly journals Interactions between N-Terminal Modules in MPS1 Enable Spindle Checkpoint Silencing

2018 ◽  
Author(s):  
Spyridon T. Pachis ◽  
Yoshitaka Hiruma ◽  
Anastassis Perrakis ◽  
Geert J.P.L. Kops
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Spindle ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Intramolecular Interactions ◽  
Mitotic Progression ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Regulatory Input ◽  
Tpr Domain

ABSTRACTFaithful chromosome segregation relies on the ability of the spindle assembly checkpoint (SAC) to delay anaphase onset until all chromosomes are attached to the mitotic spindle via their kinetochores. MPS1 kinase is recruited to unattached kinetochores to initiate SAC signaling, and is removed from kinetochores once stable microtubule attachments have been formed to allow normal mitotic progression. Here we show that a helical fragment within the kinetochore-targeting NTE module of MPS1 is required for interactions with kinetochores, and also forms intramolecular interactions with its adjacent TPR domain. Bypassing this NTE-TPR interaction results in high MPS1 levels at kinetochores due to loss of regulatory input into MPS1 localization, ineffecient MPS1 delocalization from kinetochores upon microtubule attachment, and SAC silencing defects. These results show that SAC responsiveness to attachments relies on regulated intramolecular interactions in MPS1 and highlight the sensitivity of mitosis to perturbations in the dynamics of the MSP1-NDC80-C interactions.

scholarly journals Spindly, a novel protein essential for silencing the spindle assembly checkpoint, recruits dynein to the kinetochore

2007 ◽  
Vol 177 (6) ◽  
pp. 1005-1015 ◽  
Author(s):  
Eric R. Griffis ◽  
Nico Stuurman ◽  
Ronald D. Vale
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Metaphase Plate ◽  
Spindle Assembly ◽  
Cytoplasmic Dynein ◽  
Checkpoint Proteins ◽  
Drosophila Melanogaster S2 Cells ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Cell Biol ◽  
Novel Protein

The eukaryotic spindle assembly checkpoint (SAC) monitors microtubule attachment to kinetochores and prevents anaphase onset until all kinetochores are aligned on the metaphase plate. In higher eukaryotes, cytoplasmic dynein is involved in silencing the SAC by removing the checkpoint proteins Mad2 and the Rod–Zw10–Zwilch complex (RZZ) from aligned kinetochores (Howell, B.J., B.F. McEwen, J.C. Canman, D.B. Hoffman, E.M. Farrar, C.L. Rieder, and E.D. Salmon. 2001. J. Cell Biol. 155:1159–1172; Wojcik, E., R. Basto, M. Serr, F. Scaerou, R. Karess, and T. Hays. 2001. Nat. Cell Biol. 3:1001–1007). Using a high throughput RNA interference screen in Drosophila melanogaster S2 cells, we have identified a new protein (Spindly) that accumulates on unattached kinetochores and is required for silencing the SAC. After the depletion of Spindly, dynein cannot target to kinetochores, and, as a result, cells arrest in metaphase with high levels of kinetochore-bound Mad2 and RZZ. We also identified a human homologue of Spindly that serves a similar function. However, dynein's nonkinetochore functions are unaffected by Spindly depletion. Our findings indicate that Spindly is a novel regulator of mitotic dynein, functioning specifically to target dynein to kinetochores.

scholarly journals Deubiquitylase UCHL3 drives error correction at kinetochores and chromosome segregation independent of spindle assembly checkpoint

2020 ◽  
Author(s):  
Katerina Jerabkova ◽  
Yongrong Liao ◽  
Charlotte Kleiss ◽  
Sadek Fournane ◽  
Matej Durik ◽  
...  
Keyword(s):  
Error Correction ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Cellular Transformation ◽  
Aurora B ◽  
Mitotic Kinase ◽  
Daughter Cells ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Segregation Of Chromosomes

AbstractEqual segregation of chromosomes during mitosis ensures euploidy of daughter cells. Defects in this process may result in imbalance in chromosomal composition and cellular transformation. Two surveillance pathways, the spindle assembly checkpoint (SAC) and the error-correction (EC), exist at kinetochores that monitor microtubule attachment and faithful segregation of chromosomes at the metaphase to anaphase transition. However, the molecular understanding of the interplay between EC and SAC signaling remains limited. Here we describe a role of deubiquitylase UCHL3 in the regulation of EC pathway during mitosis. Downregulation or inhibition of UCHL3 leads to improper attachments of chromosomes to spindle microtubules and to chromosome alignment defects during metaphase. Frequent segregation errors during anaphase and consequently aneuploidy is also observed upon inactivation of UCHL3. Surprisingly, UCHL3 is not involved in SAC signaling as both recruitment of SAC proteins to kinetochores and timely anaphase onset are not perturbed in UCHL3-deficient cells. Mechanistically, UCHL3 interacts with and deubiquitylates the mitotic kinase Aurora B known to drive both SAC and EC signaling. UCHL3 promotes interaction of Aurora B with MCAK, important EC factor but does not regulate Aurora B binding to other interacting partners or subcellular localization of Aurora B. Our results thus suggest that UCHL3-mediated deubiquitylation functionally separates EC from SAC signaling during mitosis and is critical for maintenance of euploidy in human cells.

scholarly journals Spindle assembly checkpoint strength is linked to cell fate in the Caenorhabditis elegans embryo

2018 ◽  
Vol 29 (12) ◽  
pp. 1435-1448 ◽  
Author(s):  
Abigail R. Gerhold ◽  
Vincent Poupart ◽  
Jean-Claude Labbé ◽  
Paul S. Maddox
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Size ◽  
Cell Fate ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
Asymmetric Cell Division ◽  
Spindle Assembly ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
The Difference

The spindle assembly checkpoint (SAC) is a conserved mitotic regulator that preserves genome stability by monitoring kinetochore–microtubule attachments and blocking anaphase onset until chromosome biorientation is achieved. Despite its central role in maintaining mitotic fidelity, the ability of the SAC to delay mitotic exit in the presence of kinetochore–microtubule attachment defects (SAC “strength”) appears to vary widely. How different cellular aspects drive this variation remains largely unknown. Here we show that SAC strength is correlated with cell fate during development of Caenorhabditis elegans embryos, with germline-fated cells experiencing longer mitotic delays upon spindle perturbation than somatic cells. These differences are entirely dependent on an intact checkpoint and only partially attributable to differences in cell size. In two-cell embryos, cell size accounts for half of the difference in SAC strength between the larger somatic AB and the smaller germline P1 blastomeres. The remaining difference requires asymmetric cytoplasmic partitioning downstream of PAR polarity proteins, suggesting that checkpoint-regulating factors are distributed asymmetrically during early germ cell divisions. Our results indicate that SAC activity is linked to cell fate and reveal a hitherto unknown interaction between asymmetric cell division and the SAC.

scholarly journals Releasing the spindle assembly checkpoint without tension

2009 ◽  
Vol 184 (3) ◽  
pp. 355-356 ◽  
Author(s):  
Bruce F. McEwen ◽  
Yimin Dong
Keyword(s):  
Molecular Mechanism ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Eukaryotic Cells ◽  
Important Advance ◽  
Molecular Rearrangements ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Cell Biol

Eukaryotic cells have evolved a spindle assembly checkpoint (SAC) that facilitates accurate genomic segregation during mitosis by delaying anaphase onset in response to errors in kinetochore microtubule attachment. In contrast to the well-studied molecular mechanism by which the SAC blocks anaphase onset, the events triggering SAC release are poorly understood. Papers in this issue by Uchida et al. (Uchida, K.S.K., K. Takagaki, K. Kumada, Y. Hirayama, T. Noda, and T. Hirota. 2009. J. Cell Biol. 184:383–390) and Maresca and Salmon (Maresca, T.J., and E.D. Salmon. 2009. J. Cell Biol. 184:373–381) make an important advance by demonstrating that SAC release depends on molecular rearrangements within the kinetochore rather than tension-produced stretch between sister kinetochores.

scholarly journals An Overview of the Spindle Assembly Checkpoint Status in Oral Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
José Henrique Teixeira ◽  
Patrícia Manuela Silva ◽  
Rita Margarida Reis ◽  
Inês Moranguinho Moura ◽  
Sandra Marques ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Molecular Mechanisms ◽  
Spindle Assembly Checkpoint ◽  
Metaphase Plate ◽  
Spindle Assembly ◽  
Altered Expression ◽  
Anaphase Onset ◽  
The Status ◽  
Human Solid Tumors ◽  
Core Components

Abnormal chromosome number, or aneuploidy, is a common feature of human solid tumors, including oral cancer. Deregulated spindle assembly checkpoint (SAC) is thought as one of the mechanisms that drive aneuploidy. In normal cells, SAC prevents anaphase onset until all chromosomes are correctly aligned at the metaphase plate thereby ensuring genomic stability. Significantly, the activity of this checkpoint is compromised in many cancers. While mutations are rather rare, many tumors show altered expression levels of SAC components. Genomic alterations such as aneuploidy indicate a high risk of oral cancer and cancer-related mortality, and the molecular basis of these alterations is largely unknown. Yet, our knowledge on the status of SAC components in oral cancer remains sparse. In this review, we address the state of our knowledge regarding the SAC defects and the underlying molecular mechanisms in oral cancer, and discuss their therapeutic relevance, focusing our analysis on the core components of SAC and its target Cdc20.

scholarly journals Cyclin B3 controls anaphase onset independent of spindle assembly checkpoint in meiotic oocytes

Cell Cycle ◽  
2015 ◽  
Vol 14 (16) ◽  
pp. 2648-2654 ◽  
Author(s):  
Teng Zhang ◽  
Shu-Tao Qi ◽  
Lin Huang ◽  
Xue-Shan Ma ◽  
Ying-Chun Ouyang ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Anaphase Onset ◽  
Cyclin B3

scholarly journals The HECT E3 ligase Smurf2 is required for Mad2-dependent spindle assembly checkpoint

2008 ◽  
Vol 183 (2) ◽  
pp. 267-277 ◽  
Author(s):  
Evan C. Osmundson ◽  
Dipankar Ray ◽  
Finola E. Moore ◽  
Qingshen Gao ◽  
Gerald H. Thomsen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
E3 Ligase ◽  
Spindle Assembly ◽  
Cyclin B ◽  
Carboxyl Terminus ◽  
Anaphase Promoting Complex ◽  
Mitotic Spindles ◽  
Anaphase Onset

Activation of the anaphase-promoting complex/cyclosome (APC/C) by Cdc20 is critical for the metaphase–anaphase transition. APC/C-Cdc20 is required for polyubiquitination and degradation of securin and cyclin B at anaphase onset. The spindle assembly checkpoint delays APC/C-Cdc20 activation until all kinetochores attach to mitotic spindles. In this study, we demonstrate that a HECT (homologous to the E6-AP carboxyl terminus) ubiquitin ligase, Smurf2, is required for the spindle checkpoint. Smurf2 localizes to the centrosome, mitotic midbody, and centromeres. Smurf2 depletion or the expression of a catalytically inactive Smurf2 results in misaligned and lagging chromosomes, premature anaphase onset, and defective cytokinesis. Smurf2 inactivation prevents nocodazole-treated cells from accumulating cyclin B and securin and prometaphase arrest. The silencing of Cdc20 in Smurf2-depleted cells restores mitotic accumulation of cyclin B and securin. Smurf2 depletion results in enhanced polyubiquitination and degradation of Mad2, a critical checkpoint effector. Mad2 is mislocalized in Smurf2-depleted cells, suggesting that Smurf2 regulates the localization and stability of Mad2. These data indicate that Smurf2 is a novel mitotic regulator.

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