Caspase-Independent Mitotic Death

Abstract

The spindle checkpoint ensures proper chromosomal segregation by monitoring kinetochore–microtubule attachment. A failure of this checkpoint causes aneuploidy, which leads to tumorigenesis. The cell death that prevents the aneuploidy caused by failure of the spindle checkpoint is yet unknown. We have identified a novel type of mitotic cell death, which we term caspase-independent mitotic death (CIMD). When BUB1 but not MAD2 is depleted, CIMD is induced by conditions that activate the spindle checkpoint [e.g., cold shock or treatment with microtubule inhibitors or 17-AAG (17-allylaminogeldanamycin)]. CIMD depends on the apoptosis-inducing factor (AIF) and endonuclease G (Endo G), which are effectors of caspase-independent cell death. CIMD also depends on p73, a homologue of p53, but not on p53. When BUB1 is completely depleted, aneuploidy occurs instead of CIMD. Therefore, CIMD may be the programmed cell death that protects cells from aneuploidy by inducing the death of cells prone to substantial chromosome missegregation.