APC/C-Cdh1-dependent anaphase and telophase progression during mitotic slippage

Here we describe mitotic slippage in yeast bub2Δ mutant cells that are defective in the repression of precocious telophase onset (mitotic exit). Precocious activation of anaphase promoting complex/cyclosome (APC/C)-Cdh1 caused mitotic slippage in the presence of nocodazole, while the SAC was still active. APC/C-Cdh1, but not APC/C-Cdc20, triggered anaphase progression (securin degradation, separase-mediated cohesin cleavage, sister-chromatid separation and chromosome missegregation), in addition to telophase onset (mitotic exit), during mitotic slippage. This demonstrates that an inhibitory system not only of APC/C-Cdc20 but also of APC/C-Cdh1 is critical for accurate chromosome segregation in the presence of insufficient kinetochore-microtubule attachments.The sequential activation of APC/C-Cdc20 to APC/C-Cdh1 during mitosis is central to accurate mitosis. Precocious activation of APC/C-Cdh1 in metaphase (pre-anaphase) causes mitotic slippage in SAC-activated cells. For the prevention of mitotic slippage, concomitant inhibition of APC/C-Cdh1 may be effective for tumor therapy with mitotic spindle poisons in humans.The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that plays a major role in cell cycle control by targeting substrates for proteasomal degradation. The complex is activated by two WD40 activator proteins, Cdc20/Fizzy/Fzy or Cdh1/Fizzy-related/Fzr. This destruction is strictly ordered to ensure that cell cycle events are executed in a timely fashion [1-5]. Whereas APC/C-Cdc20 is activated at metaphase-anaphase transition, APC/C-Cdh1 is activated after APC/C-Cdc20 activation. In the budding yeast Saccharomyces cerevisiae, APC/C-Cdh1 is activated from telophase to late G1 phase [6,7]. The switch from APC/C-Cdc20 to APC/C-Cdh1 is regulated by multiple mechanisms [5,8-10]: Cyclin B-Cdk1 (cyclin-dependent kinase) inhibits Cdh1 activation in metaphase, but cyclin B degradation mediated by APC/C in late M phase reduces cyclin B-Cdk1 acti