The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signalling

Aravamudhan, Pavithra; Goldfarb, Alan A.; Joglekar, Ajit P.

doi:10.1038/ncb3179

Cited by 117 publications

(183 citation statements)

References 69 publications

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“…One model is that kinetochore-microtubule attachment removes the SAC kinase Mps1 from kinetochores to silence the SAC, which is supported by recent observations in mammalian cells (Hiruma et al 2015;Ji et al 2015). Research work in budding yeast supports the model that the interaction of microtubuleassociated Dam1 complex with the Ndc80 kinetochore complex separates Ndc80-associated Mps1 from its substrates to trigger SAC silencing (Aravamudhan et al 2015). On the other hand, protein phosphatase PP1 has been shown to be essential for SAC silencing likely through its dephosphorylation of Mps1 kinase substrates at the kinetochore (London et al 2012).…”

supporting

confidence: 50%

Premature Silencing of the Spindle Assembly Checkpoint Is Prevented by the Bub1-H2A-Sgo1-PP2A Axis in Saccharomyces cerevisiae

Jin¹,

Bokros²,

Wang

2017

Genetics

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The spindle assembly checkpoint (SAC) monitors mistakes in kinetochore-microtubule interaction and its activation prevents anaphase entry. The SAC remains active until all chromosomes have achieved bipolar attachment which applies tension on kinetochores. Our previous data in budding yeast Saccharomyces cerevisiae show that Ipl1/Aurora B kinase and a centromereassociated protein, Sgo1, are required to prevent SAC silencing prior to tension generation, but we believe that this regulatory network is incomplete. Bub1 kinase is one of the SAC components, and Bub1-dependent H2A phosphorylation triggers centromere recruitment of Sgo1 by H2A in yeast and human cells. Although yeast cells lacking the kinase domain of Bub1 show competent SAC activation, we found that the mutant cells fail to maintain a prolonged checkpoint arrest in the presence of tensionless attachment. Mutation of the Bub1 phosphorylation site in H2A also results in premature SAC silencing in yeast cells. Previous data indicate that Sgo1 protein binds to PP2A Rts1 , and we found that rts1D mutants exhibited premature SAC silencing as well. We further revealed that sgo1 mutants with abolished binding to H2A or PP2A Rts1 displayed premature SAC silencing. Together, our results suggest that, in budding yeast S. cerevisiae, the Bub1-H2A-Sgo1-PP2A Rts1 axis prevents SAC silencing and helps prolonged checkpoint arrest prior to tension establishment at kinetochores.

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supporting

confidence: 50%

Premature Silencing of the Spindle Assembly Checkpoint Is Prevented by the Bub1-H2A-Sgo1-PP2A Axis in Saccharomyces cerevisiae

Jin¹,

Bokros²,

Wang

2017

Genetics

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“…Together with the localized feedback loop between PP1 and PP2A-B56 (62), this event leads further to the liberation of Mps1 from kinetochores (checkpoint satisfaction) and stable MT attachment concurrently with the dephosphorylated Knl1-Mis12-Ndc80 network. Alternatively, end-on MT attachment separates Mps1 from KNL1/Spc105 and enables SAC silencing (63). The dynamic association of Mps1 with Ndc80C provides exquisite temporal regulation to prevent premature stable association between Hec1/Nuf2 and MT at early prometaphase, and prompt activation of Mps1 promotes its release for an accurate kinetochore-MT attachment (Fig.…”

Section: Mis12cmentioning

confidence: 99%

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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“…44,45 In accordance with these observations, a recent study demonstrates that microtubule attachment factually induces physical separation between Mps1 kinase (docked on CH domain of Ndc80) and phosphodomain of Spc105 (Knl1 ortholog in yeast) to abrogate MELT phosphorylation and SAC silencing. 46 …”

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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The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signalling

Cited by 117 publications

References 69 publications

Premature Silencing of the Spindle Assembly Checkpoint Is Prevented by the Bub1-H2A-Sgo1-PP2A Axis in Saccharomyces cerevisiae

Premature Silencing of the Spindle Assembly Checkpoint Is Prevented by the Bub1-H2A-Sgo1-PP2A Axis in Saccharomyces cerevisiae

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

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

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