Integration of Kinase and Phosphatase Activities by BUBR1 Ensures Formation of Stable Kinetochore-Microtubule Attachments

Suijkerbuijk, Saskia J.E.; Vleugel, Mathijs; Teixeira, António P. S.; Kops, Geert J. P. L.

doi:10.1016/j.devcel.2012.09.005

Cited by 253 publications

(461 citation statements)

References 41 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: 79%

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: 79%

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 spindles often appear "hollow," which can reflect loss of kinetochore but not central spindle microtubules (Radford et al 2015). These results are consistent with a role for Polo in stabilizing microtubule-kinetochore attachments (Elowe et al 2007;Lénárt et al 2007;Liu et al 2012;Suijkerbuijk et al 2012) but with no function in the central spindle. These results also show that, while the meiotic metaphase central spindle contains many proteins found in the anaphase midzone, it also has important Significantly higher mono-orientation defects in mutants are indicated by asterisks, and P-values are indicated in Table 3. differences.…”

Section: Discussionsupporting

confidence: 77%

Spindle Assembly and Chromosome Segregation Requires Central Spindle Proteins inDrosophilaOocytes

et al. 2015

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Oocytes segregate chromosomes in the absence of centrosomes. In this situation, the chromosomes direct spindle assembly. It is still unclear in this system which factors are required for homologous chromosome bi-orientation and spindle assembly. The Drosophila kinesin-6 protein Subito, although nonessential for mitotic spindle assembly, is required to organize a bipolar meiotic spindle and chromosome bi-orientation in oocytes. Along with the chromosomal passenger complex (CPC), Subito is an important part of the metaphase I central spindle. In this study we have conducted genetic screens to identify genes that interact with subito or the CPC component Incenp. In addition, the meiotic mutant phenotype for some of the genes identified in these screens were characterized. We show, in part through the use of a heat-shock-inducible system, that the Centralspindlin component RacGAP50C and downstream regulators of cytokinesis Rho1, Sticky, and RhoGEF2 are required for homologous chromosome bi-orientation in metaphase I oocytes. This suggests a novel function for proteins normally involved in mitotic cell division in the regulation of microtubulechromosome interactions. We also show that the kinetochore protein, Polo kinase, is required for maintaining chromosome alignment and spindle organization in metaphase I oocytes. In combination our results support a model where the meiotic central spindle and associated proteins are essential for acentrosomal chromosome segregation. KEYWORDS meiosis; synthetic lethal mutation; homolog bi-orientation; spindle; chromosome segregation; Drosophila C HROMOSOMES are segregated during cell division by the spindle, a bipolar array of microtubules. In somatic cells, spindle assembly is guided by the presence of centrosomes at the poles. In this conventional spindle assembly model, the kinetochores attach to microtubules from opposing centrosomes and tension is established. This satisfies the spindle assembly checkpoint, which then allows the cell to proceed to anaphase (Musacchio and Salmon 2007). Cell division is completed by recruiting proteins to a midzone of antiparallel microtubules that forms between the segregated chromosomes, signaling furrow formation (Fededa and Gerlich 2012;D'Avino et al. 2015). However, spindle morphogenesis in oocytes of many animals occurs in the absence of centrosomes. This may contribute to the high rates of segregation errors that are maternal in origin and are a leading cause of miscarriages, birth defects, and infertility (Herbert et al. 2015). How a robust spindle assembles without guidance from the centrosomes is not well understood. While it is clear that the chromosomes can recruit microtubules and drive spindle assembly (Tseng et al. 2010;Dumont and Desai 2012), how a bipolar spindle is organized and chromosomes make the correct attachments to microtubules is not understood.The Drosophila oocyte provides a genetically tractable system for the identification of genes involved in acentrosomal spindle assembly. Substantial evidence in Drosop...

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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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Integration of Kinase and Phosphatase Activities by BUBR1 Ensures Formation of Stable Kinetochore-Microtubule Attachments

Cited by 253 publications

References 41 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

Spindle Assembly and Chromosome Segregation Requires Central Spindle Proteins inDrosophilaOocytes

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

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