Molecular Mechanism of the Spindle Checkpoint

The inheritance of normal assortment of chromosomes during each cell division relies on a cell‐cycle surveillance system called the mitotic spindle checkpoint. The existence of sister chromatids that do not achieve proper bipolar attachment to the mitotic spindle in a cell activate this checkpoint, which inhibits the ubiquitin ligase activity of the anaphase‐promoting complex or cyclosome (APC/C) and delays the onset of anaphase. Multiple mechanisms are utilized by the spindle checkpoint to inhibit APC/C, including binding of Mad2 and BubR1 to Cdc20 (a mitotic‐specific activator of APC/C) and phosphorylation of Cdc20 by the Bub1 kinase. I will present our recent biochemical and structural studies on Mad2 and Bub1, which has provided key insight into the molecular mechanism of this important cell cycle checkpoint.