Motoring through the checkpoint

The mitotic spindle checkpoint is a crucial cellular safety feature ensuring that both daughter cells will receive the correct number of chromosomes during cell division. Somehow the checkpoint is turned off only when the chromosomes are attached and aligned. Now on page 1159, Howell et al. show that a transport system using the cytoplasmic dynein/dynactin microtubule motor depletes several proteins from the outer domain of the kinetochore to inactivate the spindle checkpoint and allow mitosis to proceed.

Previously, Howell et al. found that the Mad2 checkpoint protein is transported from kinetochores to the spindle poles along spindle microtubules. The authors have now found that the microtubule motors CENP-E and cytoplasmic dynein, as well as the checkpoint-related proteins BubR1 and the 3F3/2 antigen, are also depleted from kinetochores and accumulate at the spindle poles. Inhibiting dynein/dynactin activity stops this transport process and simultaneously blocks mitosis at metaphase.

The data suggest that proteins in the outer kinetochore domain maintain a dynamic equilibrium that shifts as the kinetochore interacts with microtubules. Once the association pathways are blocked, constitutive dissociation pathways, including dynein/dynactin transport, deplete proteins from the metaphase kinetochores and inactivate the checkpoint. Recent results in Drosophila melanogaster, in which mutations in cytoplasmic dynein cause checkpoint-related proteins to accumulate at metaphase kinetochores, underscore the importance of dynein in kinetochore disassembly (Wojcik, E., et al. 2001. Nat. Cell Biol. 3:1001–1007).▪