Switching a Checkpoint On and Off Again

The spindle checkpoint is a key mechanism that ensures accurate distribution of the chromosomes during cell division by delaying completion of mitosis until kinetochores of the chromosomes are attached to spindle microtubules and until tension is being applied to pull the sister kinetochores toward opposite spindle poles. Why, then, once anaphase begins and the sister chromatids begin to separate, is the checkpoint not reactivated? Palframan et al. describe a feedback loop of mutual inhibition between the APC (anaphase-promoting complex, a ubiquitin E3 ligase complex that targets proteins for degradation) and Mps1 (a protein kinase that is part of the checkpoint signaling pathway). Once the checkpoint conditions are satisfied and anaphase begins, the inhibition of APC by Mps appears to dip below a critical threshold. At this point, the APC apparently switches to an "on" state in which anaphase is promoted and Mps1 (which is itself a target of the APC) is degraded and can thus no longer activate the checkpoint. W. J. Palframan, J. B. Meehl, S. L. Jaspersen, M. Winey, A. W. Murray, Anaphase inactivation of the spindle checkpoint. Science 313 , 680-684 (2006). [Abstract] [Full Text] M. A. Hoyt, Extinguishing a cell cycle checkpoint. Science 313 , 624-625 (2006). [Summary] [Full Text]