The mitotic checkpoint—controlled by Mad1, Mad2, Bub1, BubR1, and Bub3— delays anaphase by inhibiting APC until all kinetochores are properly attached to the spindle. Because inhibition of Mad2 leads to an accelerated mitosis and a precocious anaphase, it has been assumed that the checkpoint itself also regulates mitotic timing.
But Mad2 does not represent all of its kinetochore partners. “The assumption was that all were required for the checkpoint, so all would be needed here too,” says Meraldi. But the authors found that only Mad2 and BubR1 delay anaphase even in cells with properly aligned chromosomes. The others monitor only gross problems with kinetochore attachments.
Mad2 and BubR1 could be prevented from binding to kinetochores and yet still regulate mitotic timing. In cells where mitosis requires nuclear breakdown, checkpoint proteins need to find their way to kinetochores after breakdown, leaving a window of time when the spindle checkpoint is not active. “APC could be held in check with this cytoplasmic function [of Mad2/BubR1],” says Meraldi. Now, the group needs to determine how this function is inactivated. ▪