Antimicrotubule drugs are effective chemotherapeutic agents because they can disrupt normal mitotic spindle and activate the spindle-assembly checkpoint (SAC) to arrest cells in mitosis, thereby triggering cell death. However, cancer cells can escape these fates by undergoing mitotic slippage, allowing them to exit mitosis without division. Mitotic slippage can also be responsible for the chromosomal instability found in many cancer cells. The detailed molecular mechanism regulating the initiation of mitotic slippage is still unknown. In this study, I found that mitotic slippage was a SAC adaptation process during which APC/C-CDC20 became active to degrade cyclin B in a proteasome-dependent manner, thereby inactivating CDK1 to promote mitotic exit. This process required p31...[ Read more ]

Antimicrotubule drugs are effective chemotherapeutic agents because they can disrupt normal mitotic spindle and activate the spindle-assembly checkpoint (SAC) to arrest cells in mitosis, thereby triggering cell death. However, cancer cells can escape these fates by undergoing mitotic slippage, allowing them to exit mitosis without division. Mitotic slippage can also be responsible for the chromosomal instability found in many cancer cells. The detailed molecular mechanism regulating the initiation of mitotic slippage is still unknown. In this study, I found that mitotic slippage was a SAC adaptation process during which APC/C-CDC20 became active to degrade cyclin B in a proteasome-dependent manner, thereby inactivating CDK1 to promote mitotic exit. This process required p31^comet to promote the dissemble of the mitotic checkpoint complex. Deletion of the binding partner of p31^comet, TRIP13, enhanced the sensitivity to antimicrotubule drugs and promoted mitotic slippage. In addition, the greatwall kinase MASTL played a minor role in inhibiting APC/C-CDH1 activity to maintain the mitotic status and thus prevented the slippage process. Taken together, the SAC is a key mechanism in regulating mitotic slippage. These results may have implications in both the regulation of genome stability and anticancer therapies.