Joined at the hip: kinetochores, microtubules, and spindle assembly checkpoint signaling

Sacristán, Carlos; Kops, Geert J. P. L.

doi:10.1016/j.tcb.2014.08.006

Cited by 170 publications

(161 citation statements)

References 109 publications

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“…BubR1 is a component of SAC, a cell‐cycle surveillance system that prevents metaphase‐to‐anaphase transition by recruiting SAC proteins to this kinetochore and thus inhibiting the activation of APC/C (Jia, Kim, & Yu, 2013; Musacchio & Salmon, 2007; Sacristan & Kops, 2015). BubR1, as an integral part of the mitotic checkpoint complex (MCC), plays an essential role in this process.…”

Section: Discussionmentioning

confidence: 99%

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

et al. 2017

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SummaryThe level of Sirt2 protein is reduced in oocytes from aged mice, while exogenous expression of Sirt2 could ameliorate the maternal age‐associated meiotic defects. To date, the underlying mechanism remains unclear. Here, we confirmed that specific depletion of Sirt2 disrupts maturational progression and spindle/chromosome organization in mouse oocytes, with compromised kinetochore–microtubule attachments. Candidate screening revealed that acetylation state of lysine 243 on BubR1 (BubR1‐K243, an integral part of the spindle assembly checkpoint complex) functions during oocyte meiosis, and acetylation‐mimetic mutant BubR1‐K243Q results in the very similar phenotypes as Sirt2‐knockdown oocytes. Furthermore, we found that nonacetylatable‐mimetic mutant BubR1‐K243R partly prevents the meiotic deficits in oocytes depleted of Sirt2. Importantly, BubR1‐K243R overexpression in oocytes derived from aged mice markedly suppresses spindle/chromosome anomalies and thereupon lowers the incidence of aneuploid eggs. In sum, our data suggest that Sirt2‐dependent BubR1 deacetylation involves in the regulation of meiotic apparatus in normal oocytes and mediates the effects of advanced maternal age on oocyte quality.

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Section: Discussionmentioning

confidence: 99%

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

et al. 2017

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“…The spindle checkpoint senses the existence of kinetochores not attached or improperly attached to spindle microtubules and inhibits APC/C Cdc20 through promoting the formation of the APC/C-inhibitory mitotic checkpoint complex (MCC) consisting of BubR1, Bub3, mitotic arrest deficient 2 (Mad2), and Cdc20 (8)(9)(10)(11)(12). APC/C inhibition delays separase activation, cohesin cleavage, and the onset of chromosome segregation and provides time for unattached kinetochores to reach proper attachment before separation.…”

mentioning

confidence: 99%

Structure of an intermediate conformer of the spindle checkpoint protein Mad2

Hara

Özkan

Sun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The spindle checkpoint senses unattached kinetochores during prometaphase and inhibits the anaphase-promoting complex or cyclosome (APC/C), thus ensuring accurate chromosome segregation. The checkpoint protein mitotic arrest deficient 2 (Mad2) is an unusual protein with multiple folded states. Mad2 adopts the closed conformation (C-Mad2) in a Mad1–Mad2 core complex. In mitosis, kinetochore-bound Mad1–C-Mad2 recruits latent, open Mad2 (O-Mad2) from the cytosol and converts it to an intermediate conformer (I-Mad2), which can then bind and inhibit the APC/C activator cell division cycle 20 (Cdc20) as C-Mad2. Here, we report the crystal structure and NMR analysis of I-Mad2 bound to C-Mad2. Although I-Mad2 retains the O-Mad2 fold in crystal and in solution, its core structural elements undergo discernible rigid-body movements and more closely resemble C-Mad2. Residues exhibiting methyl chemical shift changes in I-Mad2 form a contiguous, interior network that connects its C-Mad2–binding site to the conformationally malleable C-terminal region. Mutations of residues at the I-Mad2–C-Mad2 interface hinder I-Mad2 formation and impede the structural transition of Mad2. Our study provides insight into the conformational activation of Mad2 and establishes the basis of allosteric communication between two distal sites in Mad2.

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“…16 Loss of MAD2 or other mitotic checkpoint components promotes catastrophic events such as early mitotic exit with chromosome mis-segregation and accumulation of aneuploidy. Activation of checkpoint signaling arrests the cells at metaphase until all the attachment errors are rectified and the chromosomes are properly bi-oriented at the metaphase plate.…”

Section: Discussionmentioning

confidence: 99%

Regulation of AURORA B function by mitotic checkpoint protein MAD2

2016

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Cell cycle checkpoint signaling stringently regulates chromosome segregation during cell division. MAD2 is one of the key components of the spindle and mitotic checkpoint complex that regulates the fidelity of cell division along with MAD1, CDC20, BUBR1, BUB3 and MAD3. MAD2 ablation leads to erroneous attachment of kinetochore-spindle fibers and defective chromosome separation. A potential role for MAD2 in the regulation of events beyond the spindle and mitotic checkpoints is not clear. Together with active spindle assembly checkpoint signaling, AURORA B kinase activity is essential for chromosome condensation as cells enter mitosis. AURORA B phosphorylates histone H3 at serine 10 and serine 28 to facilitate the formation of condensed metaphase chromosomes. In the absence of functional AURORA B cells escape mitosis despite the presence of misaligned chromosomes. In this study we report that silencing of MAD2 results in a drastic reduction of metaphase-specific histone H3 phosphorylation at serine 10 and serine 28. We demonstrate that this is due to mislocalization of AURORA B in the absence of MAD2. Conversely, overexpression of MAD2 concentrated the localization of AURORA B at the metaphase plate and caused hyper-phosphorylation of histone H3. We find that MAD1 plays a minor role in influencing the MAD2-dependent regulation of AURORA B suggesting that the effects of MAD2 on AURORA B are independent of the spindle checkpoint complex. Our findings reveal that, in addition to its role in checkpoint signaling, MAD2 ensures chromosome stability through the regulation of AURORA B.

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Joined at the hip: kinetochores, microtubules, and spindle assembly checkpoint signaling

Cited by 170 publications

References 109 publications

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

Structure of an intermediate conformer of the spindle checkpoint protein Mad2

Regulation of AURORA B function by mitotic checkpoint protein MAD2

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