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 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 PP2A-B56 opposes Mps1 phosphorylation of Knl1 and thereby promotes spindle assembly checkpoint silencing

2014 ◽  
Vol 206 (7) ◽  
pp. 833-842 ◽  
Author(s):  
Antonio Espert ◽  
Pelin Uluocak ◽  
Ricardo Nunes Bastos ◽  
Davinderpreet Mangat ◽  
Philipp Graab ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Mammalian Cells ◽  
Feedback Loop ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Eukaryotic Cells ◽  
Aurora B ◽  
Safeguard Mechanism

The spindle assembly checkpoint (SAC) monitors correct attachment of chromosomes to microtubules, an important safeguard mechanism ensuring faithful chromosome segregation in eukaryotic cells. How the SAC signal is turned off once all the chromosomes have successfully attached to the spindle remains an unresolved question. Mps1 phosphorylation of Knl1 results in recruitment of the SAC proteins Bub1, Bub3, and BubR1 to the kinetochore and production of the wait-anaphase signal. SAC silencing is therefore expected to involve a phosphatase opposing Mps1. Here we demonstrate in vivo and in vitro that BubR1-associated PP2A-B56 is a key phosphatase for the removal of the Mps1-mediated Knl1 phosphorylations necessary for Bub1/BubR1 recruitment in mammalian cells. SAC silencing is thus promoted by a negative feedback loop involving the Mps1-dependent recruitment of a phosphatase opposing Mps1. Our findings extend the previously reported role for BubR1-associated PP2A-B56 in opposing Aurora B and suggest that BubR1-bound PP2A-B56 integrates kinetochore surveillance and silencing of the SAC.

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 Enrichment of Aurora B kinase at the inner kinetochore controls outer kinetochore assembly

2019 ◽  
Vol 218 (10) ◽  
pp. 3237-3257 ◽  
Author(s):  
Mary Kate Bonner ◽  
Julian Haase ◽  
Jason Swinderman ◽  
Hyunmi Halas ◽  
Lisa M. Miller Jenkins ◽  
...  
Keyword(s):  
Xenopus Laevis ◽  
Central Region ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Kinetochore Assembly ◽  
Egg Extracts ◽  
Chromosome Attachment

Outer kinetochore assembly enables chromosome attachment to microtubules and spindle assembly checkpoint (SAC) signaling in mitosis. Aurora B kinase controls kinetochore assembly by phosphorylating the Mis12 complex (Mis12C) subunit Dsn1. Current models propose Dsn1 phosphorylation relieves autoinhibition, allowing Mis12C binding to inner kinetochore component CENP-C. Using Xenopus laevis egg extracts and biochemical reconstitution, we found that autoinhibition of the Mis12C by Dsn1 impedes its phosphorylation by Aurora B. Our data indicate that the INCENP central region increases Dsn1 phosphorylation by enriching Aurora B at inner kinetochores, close to CENP-C. Furthermore, centromere-bound CENP-C does not exchange in mitosis, and CENP-C binding to the Mis12C dramatically increases Dsn1 phosphorylation by Aurora B. We propose that the coincidence of Aurora B and CENP-C at inner kinetochores ensures the fidelity of kinetochore assembly. We also found that the central region is required for the SAC beyond its role in kinetochore assembly, suggesting that kinetochore enrichment of Aurora B promotes the phosphorylation of other kinetochore substrates.

scholarly journals Spindle assembly and cytokinesis in the absence of chromosomes during Drosophila male meiosis

2003 ◽  
Vol 160 (7) ◽  
pp. 993-999 ◽  
Author(s):  
Elisabetta Bucciarelli ◽  
Maria Grazia Giansanti ◽  
Silvia Bonaccorsi ◽  
Maurizio Gatti
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly ◽  
Male Meiosis ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Spindle Formation ◽  
Central Spindle ◽  
Morphological Transformations ◽  
Bipolar Spindles ◽  
Drosophila Mutants

Alarge body of work indicates that chromosomes play a key role in the assembly of both acentrosomal and centrosome-containing spindles. In animal systems, the absence of chromosomes either prevents spindle formation or allows the assembly of a metaphase-like spindle that fails to evolve into an ana-telophase spindle. Here, we show that Drosophila secondary spermatocytes can assemble morphologically normal spindles in the absence of chromosomes. The Drosophila mutants fusolo and solofuso are severely defective in chromosome segregation and produce secondary spermatocytes that are devoid of chromosomes. The centrosomes of these anucleated cells form robust asters that give rise to bipolar spindles that undergo the same ana-telophase morphological transformations that characterize normal spindles. The cells containing chromosome-free spindles are also able to assemble regular cytokinetic structures and cleave normally. In addition, chromosome-free spindles normally accumulate the Aurora B kinase at their midzones. This suggests that the association of Aurora B with chromosomes is not a prerequisite for its accumulation at the central spindle, or for its function during cytokinesis.

scholarly journals Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase

2008 ◽  
Vol 105 (51) ◽  
pp. 20215-20220 ◽  
Author(s):  
H. B. Mistry ◽  
D. E. MacCallum ◽  
R. C. Jackson ◽  
M. A. J. Chaplain ◽  
F. A. Davidson
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Temporal Evolution ◽  
Spindle Assembly ◽  
Aurora B ◽  
Aurora B Kinase

scholarly journals Kinetochores respond to subtle changes in the stability of microtubule attachments

2021 ◽  
Author(s):  
Jessica D. Warren ◽  
Sarah Y. Valles ◽  
Duane A. Compton
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Protein Localization ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Regulatory Enzymes ◽  
Summary Statement ◽  
Spindle Microtubules ◽  
The Stability ◽  
Induced Changes

AbstractProper attachment of spindle microtubules to kinetochores is necessary to satisfy the spindle assembly checkpoint and ensure faithful chromosome segregation. Microtubules detach from kinetochores to correct improperly oriented attachments, and overall kinetochore-microtubule (k-MT) attachment stability is determined in response to regulatory enzymes and the activities of kinetochore-associated microtubule stabilizing and destabilizing proteins. However, it is unknown whether regulatory enzyme activity or kinetochore-associated protein localization respond to subtle changes in k-MT attachment stability. To test for this feedback response, we monitored Aurora B kinase activity and the localization of select kinetochore proteins in metaphase cells following treatments that subtly stabilize or destabilize k-MT attachments using low dose Taxol or UMK57 (an MCAK agonist), respectively. Increasing k-MT stability induced changes in the abundance of some kinetochore proteins. In contrast, reducing k-MT stability induced both increases in Aurora B kinase signaling and changes in the abundance of some kinetochore proteins. Thus, kinetochores dynamically respond to changes in the stability of their attached microtubules. This feedback control contributes to tuning k-MT attachment stability required for efficient error correction to facilitate faithful chromosome segregation.Summary StatementLive cell imaging demonstrates that kinetochore signaling responds to feedback from attached microtubules to tune their stability to ensure faithful chromosome segregation during cell division.

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 Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

2021 ◽  
Author(s):  
Babhrubahan Roy ◽  
Simon J. Y. Han ◽  
Adrienne N. Fontan ◽  
Ajit P. Joglekar
Keyword(s):  
Error Correction ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Checkpoint ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Checkpoint Signaling ◽  
Binding Interface ◽  
Anaphase Onset ◽  
Error Correction Mechanism

SummaryAccurate chromosome segregation during cell division requires amphitelic attachment of each chromosome to the spindle apparatus. This is ensured by the Spindle Assembly Checkpoint (SAC) [1], which delays anaphase onset in response to unattached chromosomes, and an error correction mechanism, which eliminates syntelic chromosome attachments [2]. The SAC is activated by the Mps1 kinase. Mps1 sequentially phosphorylates the kinetochore protein Spc105/KNL1 to license the recruitment of several signaling proteins including Bub1. These proteins produce the Mitotic Checkpoint Complex (MCC), which delays anaphase onset [3-8]. The error correction mechanism is regulated by the Aurora B kinase, which phosphorylates the microtubule-binding interface of the kinetochore. Aurora B is also known to promote SAC signaling indirectly [9-12]. Here we present evidence that Aurora B kinase activity directly promotes MCC production in budding yeast and human cells. Using the ectopic SAC activation (eSAC) system, we find that the conditional dimerization of Aurora B (or an Aurora B recruitment domain) with either Bub1 or Mad1, but not the ‘MELT’ motifs in Spc105/KNL1, leads to a SAC-mediated mitotic arrest [13-16]. Importantly, ectopic MCC production driven by Aurora B requires the ability of Bub1 to bind both Mad1 and Cdc20. These and other data show that Aurora B cooperates with Bub1 to promote MCC production only after Mps1 licenses Bub1 recruitment to the kinetochore. This direct involvement of Aurora B in SAC signaling is likely important for syntelically attached sister kinetochores that must delay anaphase onset in spite of reduced Mps1 activity due to their end-on microtubule attachment.

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