The checkpoint is activated by Mad1 and Mad2 proteins, which bind to kinetochores that are not attached to the spindle microtubules. The prevailing theory has been that release of Mad1/Mad2 inactivates the checkpoint and allows mitosis to proceed.
Nigg and colleagues looked for human Mad1-interacting proteins and found Hec1, which recruited Mad1 and Mad2 to kinetochores. Given this function, the group was surprised to find that reducing Hec1 prevented cells from dividing, despite the fact that Mad1/Mad2 were not on the kinetochores. “This is different from all that has been shown so far,” says Stucke. “The components are depleted [from kinetochores], but you still get arrest and an active checkpoint.” Hec1-depleted cells that also lacked Mad2 continued through mitosis and ended in mitotic catastrophe. Thus, checkpoint components can signal from the cytoplasm.
According to one model of Mad function, the Mad proteins make a brief visit to kinetochores to sample the environment, but then propagate their inhibitory signal in the cytoplasm. Hec1 may regulate this process, but for now the details of Hec1 action remain obscure. ▪