Direct binding between BubR1 and B56–PP2A phosphatase complexes regulate mitotic progression

Kruse, Thomas; Zhang, Gang; Larsen, Marie Sofie Yoo; Lischetti, Tiziana; Streicher, Werner; Nielsen, T.K.; Bjørn, Sara Petersen; Nilsson, Jakob

doi:10.1242/jcs.122481

Cited by 192 publications

(318 citation statements)

References 21 publications

(29 reference statements)

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“…BubR1, as an integral part of the mitotic checkpoint complex (MCC), plays an essential role in this process. It has been demonstrated that BubR1 participates in the stabilization of K‐MT attachment by counteracting Aurora B phosphorylation through the recruitment of the B56 family of protein phosphatase 2A (PP2A) (Ditchfield et al., 2003; Kruse et al., 2013; Lampson & Kapoor, 2005; Varadkar, Abbasi, Takeda, Dyson, & McCright, 2017). Touati et al.…”

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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“…BubR1 is recruited to improperly attached kinetochores and thus its function in recruiting Cdc20 to the kinetochore to facilitate interaction with Mad2 and at the same time recruiting PP2A [39][40][41] to stabilize kinetochore-microtubule interactions shows the remarkable ability of BubR1 to integrate important kinetochore activities through short interaction motifs. Once proper kinetochore-microtubule interactions are established, BubR1 leaves the kinetochore and the IC20BD then acts to destabilize the MCC for efficient mitotic exit.…”

Section: Discussionmentioning

confidence: 99%

The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing

et al. 2014

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Improperly attached kinetochores activate the spindle assembly checkpoint (SAC) and by an unknown mechanism catalyse the binding of two checkpoint proteins, Mad2 and BubR1, to Cdc20 forming the mitotic checkpoint complex (MCC). Here, to address the functional role of Cdc20 kinetochore localization in the SAC, we delineate the molecular details of its interaction with kinetochores. We find that BubR1 recruits the bulk of Cdc20 to kinetochores through its internal Cdc20 binding domain (IC20BD). We show that preventing Cdc20 kinetochore localization by removal of the IC20BD has a limited effect on the SAC because the IC20BD is also required for efficient SAC silencing. Indeed, the IC20BD can disrupt the MCC providing a mechanism for its role in SAC silencing. We thus uncover an unexpected dual function of the second Cdc20 binding site in BubR1 in promoting both efficient SAC signalling and SAC silencing.

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“…1F). Taken together, these observations suggest that a primary role of kinetochore BUBR1 lies not in SAC activation but most likely in other processes, such as chromosome bi-orientation through recruitment of the phosphatase PP2-B56 (Kruse et al, 2013;Suijkerbuijk et al, 2012;Xu et al, 2013).…”

Section: Introductionmentioning

confidence: 87%

Dissecting the roles of human BUB1 in the spindle assembly checkpoint

Vleugel

Hoek

Tromer

et al. 2015

Journal of Cell Science

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Mitotic chromosome segregation is initiated by the anaphase promoting complex/cyclosome (APC/C) and its co-activator CDC20 (forming APC/C CDC20 ). APC/C CDC20 is inhibited by the spindle assembly checkpoint (SAC) when chromosomes have not attached to spindle microtubules. Unattached kinetochores catalyze the formation of a diffusible APC/C CDC20 inhibitor that comprises BUBR1 (also known as BUB1B), BUB3, MAD2 (also known as MAD2L1) and a second molecule of CDC20. Recruitment of these proteins to the kinetochore, as well as SAC activation, rely on the mitotic kinase BUB1, but the molecular mechanism by which BUB1 accomplishes this in human cells is unknown. We show that kinetochore recruitment of BUBR1 and BUB3 by BUB1 is dispensable for SAC activation. Unlike its yeast and nematode orthologs, human BUB1 does not associate stably with the MAD2 activator MAD1 (also known as MAD1L1) and, although required for accelerating the loading of MAD1 onto kinetochores, BUB1 is dispensable for the maintenance of steady-state levels of MAD1 there. Instead, we identify a 50-amino-acid segment that harbors the recently reported ABBA motif close to a KEN box as being crucial for the role of BUB1 in SAC signaling. The presence of this segment correlates with SAC activity and efficient binding of CDC20 but not of MAD1 to kinetochores.

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Direct binding between BubR1 and B56–PP2A phosphatase complexes regulate mitotic progression

Cited by 192 publications

References 21 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

The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing

Dissecting the roles of human BUB1 in the spindle assembly checkpoint

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