Uncoupling of the spindle-checkpoint and chromosome-congression functions of BubR1

Elowe, Sabine; Dulla, Kalyan; Uldschmid, Andreas; Li, Xiuling; Dou, Zhen; Nigg, Erich A.

doi:10.1242/jcs.056507

Cited by 105 publications

(143 citation statements)

References 26 publications

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“…1 A and B). Consistent with published results, knocking down BubR1 disrupted normal chromosome alignment (38)(39)(40). However, when Mps1 was knocked down by shRNAs (designated "shMps1-1" and "shMps1-2"), most chromosomes aligned correctly.…”

Section: Resultssupporting

confidence: 89%

Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment

Dou

Liu

Wang

et al. 2015

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

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The spindle assembly checkpoint (SAC) is a conserved signaling pathway that monitors faithful chromosome segregation during mitosis. As a core component of SAC, the evolutionarily conserved kinase monopolar spindle 1 (Mps1) has been implicated in regulating chromosome alignment, but the underlying molecular mechanism remains unclear. Our molecular delineation of Mps1 activity in SAC led to discovery of a previously unidentified structural determinant underlying Mps1 function at the kinetochores. Here, we show that Mps1 contains an internal region for kinetochore localization (IRK) adjacent to the tetratricopeptide repeat domain. Importantly, the IRK region determines the kinetochore localization of inactive Mps1, and an accumulation of inactive Mps1 perturbs accurate chromosome alignment and mitotic progression. Mechanistically, the IRK region binds to the nuclear division cycle 80 complex (Ndc80C), and accumulation of inactive Mps1 at the kinetochores prevents a dynamic interaction between Ndc80C and spindle microtubules (MTs), resulting in an aberrant kinetochore attachment. Thus, our results present a previously undefined mechanism by which Mps1 functions in chromosome alignment by orchestrating Ndc80C-MT interactions and highlight the importance of the precise spatiotemporal regulation of Mps1 kinase activity and kinetochore localization in accurate mitotic progression.Mps1 kinase | spindle assembly checkpoint | chromosome alignment | kinetochore-microtubule attachment | reversine

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Section: Resultssupporting

confidence: 89%

Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment

Dou

Liu

Wang

et al. 2015

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

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“…Failure of Bub3 binding to BubR1 has been shown to weaken the mitotic checkpoint (39)(40)(41). However, it has remained unclear how Bub3 stimulates mitotic checkpoint signaling through binding to BubR1.…”

Section: Significancementioning

confidence: 99%

Bimodal activation of BubR1 by Bub3 sustains mitotic checkpoint signaling

Han¹,

Vitre²,

Fachinetti³

et al. 2014

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

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Significance The mitotic checkpoint (or the spindle assembly checkpoint) ensures genome integrity by preventing premature chromosome segregation. The pathway is triggered locally by kinetochores, multiprotein complexes assembled onto centromeres. Unattached kinetochores produce Mad2 bound to Cdc20, the mitotic activator of the E3 ubiquitin ligase APC/C. The initial Mad2–Cdc20 complex is then converted into the final mitotic checkpoint inhibitor Bub3–BubR1–Cdc20 that blocks APC/C (anaphase promoting complex or cyclosome)-dependent ubiquitination of cyclin B and securin, thereby stabilizing them and preventing an advance to anaphase. In this study, we identify dual mechanisms by which Bub3 promotes mitotic checkpoint signaling. Bub3 binding to BubR1 promotes two distinct BubR1–Cdc20 interactions, one acting at unattached kinetochores and the other cytoplasmically to facilitate production of the mitotic checkpoint inhibitor.

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“…The central region of BubR1 does not contain any obvious structural motifs but is required for the role of the protein in stabilizing kinetochore-microtubule interactions (Suijkerbuijk et al, 2010). This region of BubR1 is heavily phosphorylated by Cdk1 and Plk1 and the respective phosphorylation of S670 and S676 by these kinases is important for the role of BubR1 in stabilizing kinetochore-microtubule interactions (Elowe et al, 2010;Elowe et al, 2007;Huang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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

Kruse

Zhang

Larsen

et al. 2013

Journal of Cell Science

197

284

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SummaryBubR1 is a central component of the spindle assembly checkpoint that inhibits progression into anaphase in response to improper kinetochore-microtubule interactions. In addition, BubR1 also helps stabilize kinetochore-microtubule interactions by counteracting the Aurora B kinase but the mechanism behind this is not clear. Here we show that BubR1 directly binds to the B56 family of protein phosphatase 2A (PP2A) regulatory subunits through a conserved motif that is phosphorylated by cyclin-dependent kinase 1 (Cdk1) and polo-like kinase 1 (Plk1). Two highly conserved hydrophobic residues surrounding the serine 670 Cdk1 phosphorylation site are required for B56 binding. Mutation of these residues prevents the establishment of a proper metaphase plate and delays cells in mitosis. Furthermore, we show that phosphorylation of serines 670 and 676 stimulates the binding of B56 to BubR1 and that BubR1 targets a pool of B56 to kinetochores. Our data suggest that BubR1 counteracts Aurora B kinase activity at improperly attached kinetochores by recruiting B56-PP2A phosphatase complexes.

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Uncoupling of the spindle-checkpoint and chromosome-congression functions of BubR1

Cited by 105 publications

References 26 publications

Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment

Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment

Bimodal activation of BubR1 by Bub3 sustains mitotic checkpoint signaling

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

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