The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation during mitosis by delaying anaphase until all kinetochores are correctly attached. The mitotic checkpoint complex (MCC) – a protein complex that contains Mad2, Cdc20, BubR1 and BubR3 – is a key SAC component and inhibits APC/C activation. The Mad2-binding protein p31comet antagonises the SAC, but the mechanism behind its action remained poorly understood. A previous model proposed that p31comet creates an ‘inhibitory cap’ at kinetochores, that prevents the recruitment of additional Mad2 molecules and needs to be removed to allow MCC formation. On page , Stephen Taylor and colleagues now provide evidence that p31comet, instead, exerts its checkpoint inhibitory role downstream of kinetochores. Using a series of immunoprecipitation and RNAi approaches, they show that p31comet binds to Mad2 when it is associated with the MCC components Cdc20 and BubR1, and subsequently extracts Mad2 from this complex. Although the remaining protein complex can still inhibit APC/C, the authors propose that this extraction presents an early step in MCC disassembly that is required for efficient entry into anaphase once all kinetochores are attached. Further, they propose that the constitutive turnover of the MCC presents a mechanism by which the spindle checkpoint can be fine-tuned.
