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

作者：Toda Kazuhiro; Naito Kayoko; Mase Satoru; Ueno Masaru; Uritani Masahiro; Yamamoto Ayumu; Ushimaru Takashi^*

来源：Cell Division, 2012, 7: 4.

DOI：10.1186/1747-1028-7-4

• Anaphase promoting complex/cyclosome (APC/C)
• Bub2
• Cdh1
• mitotic exit network ( MEN)
• mitotic slippage
• Saccharomyces cerevisiae
• securin

Background: The spindle assembly checkpoint (SAC) inhibits anaphase progression in the presence of insufficient kinetochore-microtubule attachments, but cells can eventually override mitotic arrest by a process known as mitotic slippage or adaptation. This is a problem for cancer chemotherapy using microtubule poisons. %26lt;br%26gt;Results: Here we describe mitotic slippage in yeast bub2 Delta 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. %26lt;br%26gt;Conclusions: 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.

• 出版日期2012-2-9