Caspases-Dependent Cleavage of Mitotic Checkpoint Proteins in Response to Microtubule Inhibitor

Abstract

The mitotic checkpoint ensures the fidelity of chromosomal segregation by delaying the onset of anaphase until all chromosomes are aligned on the metaphase plate. After sustained mitotic arrest, however, cells eventually exit mitosis without the mitotic checkpoint being silenced. These cells then undergo apoptosis, an event that is important for prevention of the chromosomal instability observed in human cancers. An interesting question is to establish the biochemical link between the mitotic checkpoint and the subsequent apoptotic cell death. Here, we found that following prolonged spindle damage, the mitotic checkpoint kinases such as Bub1 and BubR1 were cleaved through a mechanism sensitive to caspases inhibitor. Interestingly, the expression of these mutants resistant to caspases-dependent cleavage led to increased apoptosis after sustained mitotic arrest, and a correspondingly more efficient elimination of the polyploid population than that seen in cells expressing wild-type proteins. These findings provide the novel biochemical properties of mitotic checkpoint proteins through its cleavage by caspases-dependent manner.