Negative feedback at kinetochores underlies a responsive spindle checkpoint signal

Abstract

Saurin, Kops and colleagues suggest that rapid spindle assembly checkpoint (SAC) responsiveness is mediated by a mechanism in which active SAC recruits PP2A, leading to PP1 recruitment, which in turn displaces PP2A and shuts off the SAC. Kinetochores are specialized multi-protein complexes that play a crucial role in maintaining genome stability1. They bridge attachments between chromosomes and microtubules during mitosis and they activate the spindle assembly checkpoint (SAC) to arrest division until all chromosomes are attached2. Kinetochores are able to efficiently integrate these two processes because they can rapidly respond to changes in microtubule occupancy by switching localized SAC signalling ON or OFF2,3,4. We show that this responsiveness arises because the SAC primes kinetochore phosphatases to induce negative feedback and silence its own signal. Active SAC signalling recruits PP2A-B56 to kinetochores where it antagonizes Aurora B to promote PP1 recruitment. PP1 in turn silences the SAC and delocalizes PP2A-B56. Preventing or bypassing key regulatory steps demonstrates that this spatiotemporal control of phosphatase feedback underlies rapid signal switching at the kinetochore by: allowing the SAC to quickly transition to the ON state in the absence of antagonizing phosphatase activity; and ensuring phosphatases are then primed to rapidly switch the SAC signal OFF when kinetochore kinase activities are diminished by force-producing microtubule attachments.

Cite this article

Nijenhuis, W., Vallardi, G., Teixeira, A. et al. Negative feedback at kinetochores underlies a responsive spindle checkpoint signal. Nat Cell Biol 16, 1257–1264 (2014). https://doi.org/10.1038/ncb3065

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