Spindle checkpoint

The spindle checkpoint blocks the entry of a cell undergoing mitosis into anaphase until all chromosomes are properly attached to the meiotic or mitotic spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome.

Overview

The spindle checkpoint is an active signal produced by improperly attached kinetochores. Unattached kinetochores trigger the spindle checkpoint. When sister kinetochores are properly attached to opposite spindle poles, forces in the mitotic spindle generate tension at the kinetochores. Kinetochores that are attached to the mitotic spindle but that are not under tension also trigger the spindle checkpoint. The mechanism by which kinetochores detect attachment and tension is unclear.

The spindle checkpoint blocks anaphase entry by inhibiting the anaphase-promoting complex. The inhibiting of the APC is achieved through direct interaction between Mad2 and the APC activator Cdc20. During normal anaphase of the cell cycle, APC containing Cdc20 becomes activated. When this happens the Cdc20 directs the enzyme complex to ubiquitinate the anaphase inhibitor securin. The ubiquitination and destruction of securin at the end of metaphase releases the active protease called separase. Separase cleaves the cohesion molecules that hold the sister chromatids together to activate anaphase. When the kinetochores don't receive spindle fibers from both poles of the cell, Mad2 binds to Cdc20 and doesn't allow the APC to bind to the Cdc20 and consequently allow the ubiquitination of securin. As a result, the centromeres receive the signal and extend more chromosomal spindle fibers until the kinetochores are attached. When this happens the Mad2 protein complex releases Cdc20 and allows APC to bind to it and initiate the ubiquitination of securin to continue into anaphase.