Activating and silencing the mitotic checkpoint through CENP-E-dependent activation/inactivation of BubR1

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Abstract

The mitotic checkpoint prevents advance to anaphase prior to successful attachment of every centromere/kinetochore to mitotic spindle microtubules. Using purified components and Xenopus egg extracts, the kinetochore-associated microtubule motor CENP-E is now shown to be the activator of the essential checkpoint kinase BubR1. Since kinase activity and the checkpoint are silenced following CENP-E-dependent microtubule attachment in extracts or binding of CENP-E antibodies that do not disrupt CENP-E association with BubR1, CENP-E mediates silencing of BubR1 signaling. Checkpoint signaling requires the normal level of BubR1 containing a functional Mad3 domain implicated in Cdc20 binding, but only a small fraction need be kinase competent. This supports bifunctional roles for BubR1 in the checkpoint: an enzymatic one requiring CENP-E-dependent activation of its kinase activity at kinetochores and a stoichiometric one as a direct inhibitor of Cdc20.

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Mao, Y., Abrieu, A., & Cleveland, D. W. (2003). Activating and silencing the mitotic checkpoint through CENP-E-dependent activation/inactivation of BubR1. Cell, 114(1), 87–98. https://doi.org/10.1016/S0092-8674(03)00475-6

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