The Spindle Assembly Checkpoint

The spindle assembly checkpoint is a surveillance mechanism that monitors the transition from metaphase to anaphase, ensuring all chromosomes are correctly attached to opposite spindle poles. It delays anaphase onset until chromosomes are bioriented, preventing premature and improper chromosomal segregation. This checkpoint maintains the fidelity of chromosome segregation, protecting cells from aneuploidy and developmental defects.

Unattached kinetochores generate minimal tension between outer and inner kinetochore layers, producing a negative signal. This signal recruits Mad2 to unattached kinetochores, causing a conformational change that activates Mad2. Activated Mad2 associates with other checkpoint components to form the mitotic checkpoint complex, which inhibits the Cdc20-APC/C complex and prevents anaphase progression.

When the spindle assembly checkpoint is active, the mitotic checkpoint complex inhibits the Cdc20-APC/C complex, preventing ubiquitination of securin. Securin remains bound to separase, keeping separase inactive. Inactive separase cannot cleave cohesin rings, so sister chromatids remain attached and cannot separate until checkpoint silencing occurs.

Proper biorientation of all sister chromatids silences the spindle assembly checkpoint. When chromosomes attach correctly to opposite spindle poles, tension is generated at kinetochores, switching off the checkpoint pathway. The Cdc20-APC/C complex becomes activated, ubiquitinating securin to release active separase, which then cleaves cohesin rings and permits sister chromatid separation.

The attachment model proposes that full occupation of kinetochores by kinetochore-microtubules switches off the checkpoint. The tension model states that tension generated from correct spindle-microtubule attachment to the kinetochore is responsible for checkpoint silencing. Current evidence suggests both attachment and tension mechanisms are required together to ensure the fidelity of spindle assembly checkpoint surveillance.

Aneuploidy is an abnormal chromosome number in a cell. Mutations affecting spindle checkpoint proteins can allow cells to proceed into anaphase prematurely, regardless of whether all prerequisite steps are complete. This results in daughter cells receiving fewer or more than the normal number of chromosomes, leading to developmental defects and cellular dysfunction.

The mitotic checkpoint complex binds to and inhibits the Cdc20-APC/C complex, a ubiquitin ligase responsible for degrading cell cycle regulators. By blocking the anaphase promoting complex, the MCC prevents ubiquitination of securin and other substrates, halting the molecular cascade required for anaphase entry and maintaining metaphase arrest until checkpoint conditions are satisfied.