Stalling in mitosis and releasing the apoptotic brake.

Microtubule poisons induce mitotic arrest that leads to apoptotic cell death if not resolved in a timely manner, but the mechanisms that directly link this cell cycle arrest to apoptosis have been elusive. In this issue of The EMBO Journal, Clarke and colleagues show that Mcl-1, an anti-apoptotic Bcl-2 family protein, is phosphorylated by the mitotic kinase CDK1/cyclin B1. This targets the protein for degradation by anaphase-promoting complex/cyclosome (APC/C)-mediated ubiquitination, in a manner such that only prolonged arrest allows sufficient Mcl-1 phosphorylation and degradation to trigger apoptosis. Thus, the APC/C, a major effector of the spindle assembly checkpoint (SAC), not only ensures cell cycle arrest upon spindle disruption, but promotes cell death when the duration of mitotic arrest is too long. Apoptotic cell death proceeds through a series of signalling events that bring about the dismantling of cellular components by a family of cysteine proteases, the caspases. In particular, genotoxic and/or cytotoxic stress promotes the release of