BUBR1 recruits PP2A via the B56 family of targeting subunits to promote chromosome congression

Xu, Peng; Raetz, Elizabeth A.; Kitagawa, Mayumi; Virshup, David M.; Lee, Sang Hyun

doi:10.1242/bio.20134051

Cited by 106 publications

(182 citation statements)

References 21 publications

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“…1B, panel b). Consistent with previous reports demonstrating that all B56 genes promote chromosome alignment in a redundant manner (Foley et al, 2011;Xu et al, 2013), depletion of B56 subunits also caused chromosome misalignment (Fig. 1B, panel c).…”

Section: Resultssupporting

confidence: 93%

“…Notably, the B56 subunits (B56-PP2A) recruit PP2A to form a complex with the essential mitotic checkpoint protein BUBR1 at the kinetochore and function redundantly for chromosome alignment (Foley et al, 2011;Kruse et al, 2013;Suijkerbuijk et al, 2012;Xu et al, 2013). The siRNA-mediated knockdown of B56 subunits leads to massive chromosome misalignment accompanied by increased Aurora-B-dependent phosphorylation of the KMN network components, whereas inhibiting Aurora B partly rescues this chromosome misalignment (Foley et al, 2011;Xu et al, 2013). Therefore, it has been proposed that B56-PP2A is directly responsible for K-fiber formation by reversing Aurora-B-mediated phosphorylation of the KMN network components.…”

Section: Introductionmentioning

confidence: 99%

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B56-PP2A regulates motor dynamics for mitotic chromosome alignment

Virshup

Lee

2014

Journal of Cell Science

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Proper alignment of duplicated chromosomes at the metaphase plate involves both motor-driven chromosome movement and the functional and physical end-on connection (K-fiber formation) between the kinetochore and the plus-end of microtubules. The B56 family of protein phosphatase 2A (PP2A) regulatory subunits (B56-PP2A), through their interaction with the mitotic checkpoint protein BUBR1, are required for proper chromosome alignment, but the underlying mechanism(s) has remained elusive. Here, we show that B56-PP2A promotes chromosome alignment primarily by balancing chromosome movement towards the metaphase plate, rather than by directly establishing stable K-fibers. Notably, the poleward movement of chromosomes in cells depleted of the B56 family can be rescued by depletion of HSET (also known as kinesin-14 or KIFC1), a major minus-end-directed motor protein. Strikingly, K-fiber formation can be restored if chromosome movement to the metaphase plate is rescued in B56-depleted cells. Furthermore, the B56-BUBR1 interaction is required for promoting motor-driven chromosome movement towards the metaphase plate. Thus, we propose that B56-PP2A functions in mitotic chromosome alignment by balancing chromosome movement towards the metaphase plate, which is essential for the subsequent establishment of stable and functional kinetochore-microtubule attachments, and mitotic exit.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

B56-PP2A regulates motor dynamics for mitotic chromosome alignment

Virshup

Lee

2014

Journal of Cell Science

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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: 88%

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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BUBR1 recruits PP2A via the B56 family of targeting subunits to promote chromosome congression

Cited by 106 publications

References 21 publications

B56-PP2A regulates motor dynamics for mitotic chromosome alignment

B56-PP2A regulates motor dynamics for mitotic chromosome alignment

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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