scholarly journals Synchronizing chromosome segregation by flux-dependent force equalization at kinetochores

2009 ◽  
Vol 186 (1) ◽  
pp. 11-26 ◽  
Author(s):  
Irina Matos ◽  
António J. Pereira ◽  
Mariana Lince-Faria ◽  
Lisa A. Cameron ◽  
Edward D. Salmon ◽  
...  
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Mechanical Model ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
S2 Cells ◽  
Spindle Microtubule ◽  
Anaphase Onset ◽  
Drosophila S2 Cells ◽  
Segregation Of Chromosomes

The synchronous movement of chromosomes during anaphase ensures their correct inheritance in every cell division. This reflects the uniformity of spindle forces acting on chromosomes and their simultaneous entry into anaphase. Although anaphase onset is controlled by the spindle assembly checkpoint, it remains unknown how spindle forces are uniformly distributed among different chromosomes. In this paper, we show that tension uniformity at metaphase kinetochores and subsequent anaphase synchrony in Drosophila S2 cells are promoted by spindle microtubule flux. These results can be explained by a mechanical model of the spindle where microtubule poleward translocation events associated with flux reflect relaxation of the kinetochore–microtubule interface, which accounts for the redistribution and convergence of kinetochore tensions in a timescale comparable to typical metaphase duration. As predicted by the model, experimental acceleration of mitosis precludes tension equalization and anaphase synchrony. We propose that flux-dependent equalization of kinetochore tensions ensures a timely and uniform maturation of kinetochore–microtubule interfaces necessary for error-free and coordinated segregation of chromosomes in anaphase.

scholarly journals Centromere-localized Aurora B kinase is required for the fidelity of chromosome segregation

2019 ◽  
Vol 219 (2) ◽  
Author(s):  
Cai Liang ◽  
Zhenlei Zhang ◽  
Qinfu Chen ◽  
Haiyan Yan ◽  
Miao Zhang ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Essential Role ◽  
Spindle Assembly Checkpoint ◽  
Histone H3 ◽  
Spindle Assembly ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Chromosome Missegregation ◽  
Proper Timing ◽  
Segregation Of Chromosomes

Aurora B kinase plays an essential role in chromosome bi-orientation, which is a prerequisite for equal segregation of chromosomes during mitosis. However, it remains largely unclear whether centromere-localized Aurora B is required for faithful chromosome segregation. Here we show that histone H3 Thr-3 phosphorylation (H3pT3) and H2A Thr-120 phosphorylation (H2ApT120) can independently recruit Aurora B. Disrupting H3pT3-mediated localization of Aurora B at the inner centromere impedes the decline in H2ApT120 during metaphase and causes H2ApT120-dependent accumulation of Aurora B at the kinetochore-proximal centromere. Consequently, silencing of the spindle assembly checkpoint (SAC) is delayed, whereas the fidelity of chromosome segregation is negligibly affected. Further eliminating an H2ApT120-dependent pool of Aurora B restores proper timing for SAC silencing but increases chromosome missegregation. Our data indicate that H2ApT120-mediated localization of Aurora B compensates for the loss of an H3pT3-dependent pool of Aurora B to correct improper kinetochore–microtubule attachments. This study provides important insights into how centromeric Aurora B regulates SAC and kinetochore attachment to microtubules to ensure error-free chromosome segregation.

scholarly journals ISWI is a RanGTP-dependent MAP required for chromosome segregation

2009 ◽  
Vol 187 (6) ◽  
pp. 813-829 ◽  
Author(s):  
Hideki Yokoyama ◽  
Sofia Rybina ◽  
Rachel Santarella-Mellwig ◽  
Iain W. Mattaj ◽  
Eric Karsenti
Keyword(s):  
Chromatin Remodeling ◽  
Chromosome Segregation ◽  
Spindle Assembly ◽  
S2 Cells ◽  
Culture Cells ◽  
Egg Extract ◽  
Drosophila S2 Cells ◽  
Egg Extracts ◽  
Localization Signal

Production of RanGTP around chromosomes induces spindle assembly by activating nuclear localization signal (NLS)–containing factors. Here, we show that the NLS protein ISWI, a known chromatin-remodeling ATPase, is a RanGTP-dependent microtubule (MT)-associated protein. Recombinant ISWI induces MT nucleation, stabilization, and bundling in vitro. In Xenopus culture cells and egg extract, ISWI localizes within the nucleus in interphase and on spindles during mitosis. Depletion of ISWI in egg extracts does not affect spindle assembly, but in anaphase spindle MTs disappear and chromosomes do not segregate. We show directly that ISWI is required for the RanGTP-dependent stabilization of MTs during anaphase independently of its effect on chromosomes. ISWI depletion in Drosophila S2 cells induces defects in spindle MTs and chromosome segregation in anaphase, and the cells eventually stop growing. Our results demonstrate that distinctly from its role in spindle assembly, RanGTP maintains spindle MTs in anaphase through the local activation of ISWI and that this is essential for proper chromosome segregation.

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 The copy-number and varied strengths of MELT motifs in Spc105 balance the strength and responsiveness the Spindle Assembly Checkpoint

2020 ◽  
Author(s):  
Babhrubahan Roy ◽  
Simon JY Han ◽  
Adrienne N. Fontan ◽  
Ajit P. Joglekar
Keyword(s):  
Chromosome Segregation ◽  
Copy Number ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Evolutionary Trend ◽  
Binding Affinities ◽  
Chromosome Missegregation ◽  
Anaphase Onset ◽  
Maintain Genome Stability

SummaryThe Spindle Assembly Checkpoint (SAC) maintains genome stability while enabling timely anaphase onset. To maintain genome stability, the SAC must be strong so that it delays cell division even if one chromosome is unattached, but for timely anaphase onset, it must be responsive to silencing mechanisms. How it meets these potentially antagonistic requirements is unclear. Here we show that the balance between SAC strength and responsiveness is determined by the number of ‘MELT’ motifs in the kinetochore protein Spc105/KNL1 and their Bub3-Bub1 binding affinities. Spc105/KNL1 must contain many strong MELT motifs to prevent chromosome missegregation, but not too many, because this delays SAC silencing and anaphase onset. We demonstrate this by constructing a Spc105 variant that trades SAC responsiveness for significantly improved chromosome segregation accuracy. We propose that the necessity of balancing SAC strength with responsiveness drives the evolutionary trend of MELT motif number amplification and degeneration of their functionally optimal amino acid sequence.

scholarly journals Delineating the contribution of Spc105-bound PP1 to spindle checkpoint silencing and kinetochore microtubule attachment regulation

2019 ◽  
Vol 218 (12) ◽  
pp. 3926-3942 ◽  
Author(s):  
Babhrubahan Roy ◽  
Vikash Verma ◽  
Janice Sim ◽  
Adrienne Fontan ◽  
Ajit P. Joglekar
Keyword(s):  
Cell Division ◽  
Error Correction ◽  
Chromosome Segregation ◽  
Protein Phosphatase ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Spindle Assembly ◽  
Protein Phosphatase 1 ◽  
Microtubule Attachment ◽  
Error Correction Mechanism

Accurate chromosome segregation during cell division requires the spindle assembly checkpoint (SAC), which detects unattached kinetochores, and an error correction mechanism that destabilizes incorrect kinetochore–microtubule attachments. While the SAC and error correction are both regulated by protein phosphatase 1 (PP1), which silences the SAC and stabilizes kinetochore–microtubule attachments, how these distinct PP1 functions are coordinated remains unclear. Here, we investigate the contribution of PP1, docked on its conserved kinetochore receptor Spc105/Knl1, to SAC silencing and attachment regulation. We find that Spc105-bound PP1 is critical for SAC silencing but dispensable for error correction; in fact, reduced PP1 docking on Spc105 improved chromosome segregation and viability of mutant/stressed states. We additionally show that artificially recruiting PP1 to Spc105/Knl1 before, but not after, chromosome biorientation interfered with error correction. These observations lead us to propose that recruitment of PP1 to Spc105/Knl1 is carefully regulated to ensure that chromosome biorientation precedes SAC silencing, thereby ensuring accurate chromosome segregation.

scholarly journals Aurora B Tension Sensing Mechanisms in the Kinetochore Ensure Accurate Chromosome Segregation

2021 ◽  
Vol 22 (16) ◽  
pp. 8818
Author(s):  
Shelby L. McVey ◽  
Jenna K. Cosby ◽  
Natalie J. Nannas
Keyword(s):  
Chromosome Segregation ◽  
Birth Defects ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Aurora B ◽  
Sister Chromatids ◽  
Congenital Birth Defects ◽  
Biochemical Signals ◽  
Segregation Of Chromosomes

The accurate segregation of chromosomes is essential for the survival of organisms and cells. Mistakes can lead to aneuploidy, tumorigenesis and congenital birth defects. The spindle assembly checkpoint ensures that chromosomes properly align on the spindle, with sister chromatids attached to microtubules from opposite poles. Here, we review how tension is used to identify and selectively destabilize incorrect attachments, and thus serves as a trigger of the spindle assembly checkpoint to ensure fidelity in chromosome segregation. Tension is generated on properly attached chromosomes as sister chromatids are pulled in opposing directions but resisted by centromeric cohesin. We discuss the role of the Aurora B kinase in tension-sensing and explore the current models for translating mechanical force into Aurora B-mediated biochemical signals that regulate correction of chromosome attachments to the spindle.

scholarly journals Chromosome biorientation and APC activity remain uncoupled in oocytes with reduced volume

2017 ◽  
Vol 216 (12) ◽  
pp. 3949-3957 ◽  
Author(s):  
Simon I.R. Lane ◽  
Keith T. Jones
Keyword(s):  
Cell Volume ◽  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Anaphase Promoting Complex ◽  
Chromosome Missegregation ◽  
Anaphase Onset ◽  
Reduced Volume ◽  
Chromosome Attachment ◽  
Meiosis I

The spindle assembly checkpoint (SAC) prevents chromosome missegregation by coupling anaphase onset with correct chromosome attachment and tension to microtubules. It does this by generating a diffusible signal from free kinetochores into the cytoplasm, inhibiting the anaphase-promoting complex (APC). The volume in which this signal remains effective is unknown. This raises the possibility that cell volume may be the reason the SAC is weak, and chromosome segregation error-prone, in mammalian oocytes. Here, by a process of serial bisection, we analyzed the influence of oocyte volume on the ability of the SAC to inhibit bivalent segregation in meiosis I. We were able to generate oocytes with cytoplasmic volumes reduced by 86% and observed changes in APC activity consistent with increased SAC control. However, bivalent biorientation remained uncoupled from APC activity, leading to error-prone chromosome segregation. We conclude that volume is one factor contributing to SAC weakness in oocytes. However, additional factors likely uncouple chromosome biorientation with APC activity.

scholarly journals The copy-number and varied strengths of MELT motifs in Spc105 balance the strength and responsiveness of the spindle assembly checkpoint

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Babhrubahan Roy ◽  
Simon JY Han ◽  
Adrienne Nicole Fontan ◽  
Ajit P Joglekar
Keyword(s):  
Chromosome Segregation ◽  
Copy Number ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Evolutionary Trend ◽  
Binding Affinities ◽  
Chromosome Missegregation ◽  
Anaphase Onset ◽  
Maintain Genome Stability

During mitosis, the Spindle Assembly Checkpoint (SAC) maintains genome stability while also ensuring timely anaphase onset. To maintain genome stability, the SAC must be strong to delay anaphase even if just one chromosome is unattached, but for timely anaphase onset, it must promptly respond to silencing mechanisms. How the SAC meets these potentially antagonistic requirements is unclear. Here we show that the balance between SAC strength and responsiveness is determined by the number of ‘MELT’ motifs in the kinetochore protein Spc105/KNL1 and their Bub3-Bub1 binding affinities. Many strong MELT motifs per Spc105/KNL1 minimize chromosome missegregation, but too many delay anaphase onset. We demonstrate this by constructing a Spc105 variant that trades SAC responsiveness for much more accurate chromosome segregation. We propose that the necessity of balancing SAC strength and responsiveness drives the dual evolutionary trend of the amplification of MELT motif number, but degeneration of their functionally optimal amino acid sequence.

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 Deregulation of Chromosome Segregation and Cancer

2020 ◽  
Vol 4 (1) ◽  
pp. 257-278 ◽  
Author(s):  
Natalie L. Curtis ◽  
Gian Filippo Ruda ◽  
Paul Brennan ◽  
Victor M. Bolanos-Garcia
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Drug Targets ◽  
Spindle Assembly Checkpoint ◽  
Genetic Material ◽  
Cancer Therapies ◽  
Mitotic Spindle Assembly ◽  
Protein Components ◽  
Stable Genome ◽  
Segregation Of Chromosomes

The mitotic spindle assembly checkpoint (SAC) is an intricate cell signaling system that ensures the high fidelity and timely segregation of chromosomes during cell division. Mistakes in this process can lead to the loss, gain, or rearrangement of the genetic material. Gross chromosomal aberrations are usually lethal but can cause birth and development defects as well as cancer. Despite advances in the identification of SAC protein components, important details of the interactions underpinning chromosome segregation regulation remain to be established. This review discusses the current understanding of the function, structure, mode of regulation, and dynamics of the assembly and disassembly of SAC subcomplexes, which ultimately safeguard the accurate transmission of a stable genome to descendants. We also discuss how diverse oncoviruses take control of human cell division by exploiting the SAC and the potential of this signaling circuitry as a pool of drug targets to develop effective cancer therapies.

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