Escaping the firing squad: Acetylation of BubR1 protects it from degradation in checkpoint cells

The Gurdon Institute, Cambridge, UK.
The EMBO Journal (Impact Factor: 10.43). 08/2009; 28(14):1991-3. DOI: 10.1038/emboj.2009.149
Source: PubMed


The spindle assembly checkpoint (SAC) is responsible for blocking cells in mitosis in the presence of unattached kinetochores. A substantial body of work has identified many of the players in this checkpoint and shown that they target the Cdc20 protein to prevent the ubiquitylation of cyclin B and securin by the anaphase promoting complex/cyclosome (APC/C). The exact mechanism by which the SAC restrains Cdc20, however, remains elusive but some evidence indicates that it may target Cdc20 for destruction by the APC/C. An interesting study in this issue of The EMBO Journal offers a new insight into this by showing that BubR1, a crucial effector, of the SAC, is acetylated in checkpoint-arrested cells and this modification is crucial for preventing BubR1 itself from destruction and the inactivation of the SAC.

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    • "Previously, we reported that BubR1 is acetylated by PCAF acetyltransferase at prometaphase and that the acetylated BubR1 inhibits APC/C. When checkpoint is satisfied, BubR1 is deacetylated and becomes a substrate of APC/C-Cdc20 (Choi et al., 2009; Yekezare and Pines, 2009). "
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    ABSTRACT: Germline mutations that inactivate BRCA2 promote early-onset cancer with chromosome instability. Here, we report that BRCA2 regulates the spindle assembly checkpoint (SAC). Previously, we reported that BubR1 acetylation is essential for SAC activity. In this study we show that BRCA2 recruits the PCAF acetyltransferase and aids in BubR1 acetylation during mitosis. In the absence of BRCA2, BubR1 acetylation is abolished, and the level of BubR1 decreases during mitosis. Similarly, Brca2-deficient mouse embryonic fibroblasts exhibited weak SAC activity. Transgenic mice that were engineered to have interruptions in the BRCA2-BubR1 association exhibited marked decrease of BubR1 acetylation, weakened SAC activity, and aneuploidy. These transgenic mice developed spontaneous tumors at 40% penetrance. Moreover, immunohistochemical analyses of human breast cancer specimens suggested that BRCA2 mutation and BubR1 status is closely linked. Our results provide an explanation for how mutation of BRCA2 can lead to chromosome instability without apparent mutations in SAC components.
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    • "Conversely, mimicking BubR1 acetylation prevents mitotic exit. Together, these data suggest that BubR1 degradation by the APC/C is important for checkpoint inactivation (Choi et al. 2009; Yekezare and Pines 2009). However, apart from the CENP-E/BubR1 interaction , it remains unclear how these mechanisms are regulated by chromosome biorientation. "
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    ABSTRACT: The multidomain protein kinase BubR1 is a central component of the mitotic spindle assembly checkpoint (SAC), an essential self-monitoring system of the eukaryotic cell cycle that ensures the high fidelity of chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bi-oriented on the mitotic spindle. We discuss the roles of BubR1 in the SAC and the implications of BubR1-mediated interactions that protect against aneuploidy. We also describe the emerging roles of BubR1 in cellular processes that extend beyond the SAC, discuss how mice models have revealed unanticipated functions for BubR1 in the regulation of normal aging, and the potential role of BubR1 as therapeutic target for the development of innovative anticancer therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.
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