Anti-mitotic drugs block cells in mitosis and trigger mitotic cell death. Chemotherapeutic drugs can fail, however, if cells undergo mitotic slippage. Understanding of molecular mechanism of mitotic cell fate can improve strategies targeting mitosis for anti-cancer therapy. A threshold model has been used to explain why cells undergo mitotic cell death or mitotic slippage, which is, however, too simplistic a view. Here this study demonstrates that anti-apoptotic protein MCL1, which is degraded rapidly in mitosis, is involved in setting the threshold of mitotic cell death during early stages of mitotic arrest. Degradation of MCL1 is independent on the mitotic ubiquitin ligase APC/C^CDC20 or SCF complex, which have been reported to regulate MCL-1 degradation during interphase. Basal level...[ Read more ]

Anti-mitotic drugs block cells in mitosis and trigger mitotic cell death. Chemotherapeutic drugs can fail, however, if cells undergo mitotic slippage. Understanding of molecular mechanism of mitotic cell fate can improve strategies targeting mitosis for anti-cancer therapy. A threshold model has been used to explain why cells undergo mitotic cell death or mitotic slippage, which is, however, too simplistic a view. Here this study demonstrates that anti-apoptotic protein MCL1, which is degraded rapidly in mitosis, is involved in setting the threshold of mitotic cell death during early stages of mitotic arrest. Degradation of MCL1 is independent on the mitotic ubiquitin ligase APC/C^CDC20 or SCF complex, which have been reported to regulate MCL-1 degradation during interphase. Basal level of MCL1 in mitosis is regulated by ubiquitin ligase MARCH5, whose depletion induces mitotic cell death even with stabilized MCL1. MARCH5 depletion mediates mitotic cell death in MCL1-dependent or independent manner. MARCH5 regulates mitotic cell death through BAK. Degradation of cyclin B1 is believed to determine the threshold of mitotic slippage. This study shows that mitotic slippage involves reduction of MAD2 at the kinetochores, resulting in a progressive weakening of spindle-assembly checkpoint (SAC) during mitotic arrest. Inhibition of APC/C^CDC20 reduces the loss of kinetochore MAD2, which indicates a feedback control of APC/C^CDC20 to SAC. SAC weakening enables APC/C^CDC20 to ubiquitinate cyclin B1, leading to cyclin B1 degradation and mitotic slippage. These results highlight the multiple factors controlling the fate of mitotic arrested cells.