A Bub1–Mad1 interaction targets the Mad1–Mad2 complex to unattached kinetochores to initiate the spindle checkpoint

Moyle, Mark W.; Kim, Tae‐Kyung; Hattersley, Neil; Espeut, Julien; Cheerambathur, Dhanya K.; Oegema, Karen; Desai, Arshad

doi:10.1083/jcb.201311015

Cited by 121 publications

(142 citation statements)

References 49 publications

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“…37 Further, Mps1 has also been shown to phosphorylate BUB1 to promote Mad1 recruitment to kinetochores in budding yeast. 37,38 Previously, a direct interaction between BUB1 and Mad1 in both budding yeast and nematodes was also shown. 37,39 Therefore, Zhang et al conjectures that the yeast BUB1-Mad1/2 interaction evolved to BUB1-RZZ-Mad1/2 in higher and complex eukaryotes.…”

Section: How the Sac Gets The Axe: Integrating Kinetochore Microtubulmentioning

confidence: 99%

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

Agarwal

Varma

2015

BioArchitecture

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ABSTRACT. Mitosis entails the bona fide segregation of duplicated chromosomes. This process is accomplished by the attachment of kinetochores on chromosomes to microtubules (MTs) of the mitotic spindle. Once the appropriate attachment is achieved, the spindle assembly checkpoint (SAC) that delays the premature onset of anaphase needs to be silenced for the cell to proceed to anaphase and cytokinesis. Therefore, while it is imperative to preserve the SAC when kinetochores are unattached, it is of paramount importance that SAC components are removed post kinetochore microtubule (kMT) attachment. Precise knowledge of how kMT attachments trigger the removal of SAC components from kinetochores or how the checkpoint proteins feedback in to the attachment machinery remains elusive. This review aims to describe the recent advances that provide an insight into the interplay of molecular events that coordinate and regulate the SAC activity in response to kMT attachment during cell division.

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Section: How the Sac Gets The Axe: Integrating Kinetochore Microtubulmentioning

confidence: 99%

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

Agarwal

Varma

2015

BioArchitecture

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“…Human cell studies have proven equally inconsistentone study proposes that BUB1 directly phosphorylates and inhibits CDC20 (Kang et al, 2008), whereas another shows that a truncated BUB1 protein lacking the kinase domain significantly restored SAC activity to BUB1-depleted cells (Klebig et al, 2009). Recent studies show that in budding yeast and Caenorhabditis elegans, BUB1 directly binds to MAD1 through a region preceding the kinase domain (S. cerevisiae), or through the kinase domain itself (C. elegans) (London and Biggins, 2014;Moyle et al, 2014). Whether this function of BUB1 is conserved in human cells is unknown.…”

Section: Introductionmentioning

confidence: 99%

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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“…Recently, Bub3 has been shown to bind the phospho MELT motif on KNL-1 for kinetochore localization of Bub1 (budding uninhibited by benzimidazole 1), disruption of which caused a defective checkpoint (24)(25)(26)(27) with Bub1 binding to kinetochores apparently required for binding of other checkpoint proteins (28)(29)(30)(31)(32). A role for Bub3 in mitotic checkpoint silencing has also been proposed in fission yeast (33).…”

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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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A Bub1–Mad1 interaction targets the Mad1–Mad2 complex to unattached kinetochores to initiate the spindle checkpoint

Abstract: A Bub1–Mad1 interaction targets the Mad1–Mad2 complex to unattached kinetochores to initiate the spindle checkpoint.

Cited by 121 publications

References 49 publications

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling

Dissecting the roles of human BUB1 in the spindle assembly checkpoint

Bimodal activation of BubR1 by Bub3 sustains mitotic checkpoint signaling

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