Finding degradation at the checkpoint

When the mitotic apparatus is disturbed by agents such as nocodazole, mitotic checkpoints delay mitosis to avert disaster. Defects in the anaphase-onset checkpoint are rarely seen in cancers, but defects in the G2/M (prophase) checkpoint are present in multiple tumor cell lines. Now, on page 249, Kang et al. report that the recently identified G2/M checkpoint protein Chfr is a ubiquitin ligase that promotes the degradation of a regulatory protein. In addition to describing a novel cell cycle checkpoint mechanism, the authors have developed an experimental system that should be useful in future studies on Chfr.

Kang et al. found that Chfr can ubiquitinate itself and other proteins in vitro and in vivo. In a Xenopus egg extract system, recombinant Chfr delays the activation of the kinase Cdc2 during the G2/M transition. Using this system,the authors determined that Chfr ubiquitinates polo-like kinase 1 (Plk1), leading to its degradation. Plk1 ordinarily triggers a cascade that leads to Cdc2 dephosphorylation and mitosis, so its degradation leaves Cdc2 phosphorylated and halts progression into mitosis. Future work on the cell-free system should help uncover the mechanisms that link Chfr activity to mitotic stresses, such as microtubule defects. ▪