18.12 : The Spindle Assembly Checkpoint

The spindle assembly checkpoint is a surveillance mechanism that monitors the transition from metaphase to anaphase.

This checkpoint ensures that all chromosomes are correctly attached to opposite spindle poles on the mitotic spindle. The checkpoint delays the onset of anaphase until all chromosomes are bioriented, sensing the tension generated within the kinetochore, thereby  preventing premature and improper chromosomal segregation.

The absence of kinetochore-spindle attachments generates minimal tension between the outer-kinetochore layer and the inner-kinetochore layer. This insufficient tension level generates a negative signal sensed by the spindle assembly checkpoint pathway.

This negative signal promotes the recruitment of Mad2, a component of the checkpoint pathway, to the unattached kinetochores. The unattached kinetochore catalyzes a conformational change in Mad2, activating the protein. Activated Mad2 associates with other components from the checkpoint pathway, forming the mitotic checkpoint complex, or MCC.

The MCC binds to and inhibits the Cdc20-APC/C complex. The inactive APC/C complex is unable to ubiquitinate and degrade the protein securin bound to the protease called separase. The securin-bound separase is inactive and is unable to cleave the cohesin rings binding the sister chromatids together, thereby preventing the separation of sister chromatids.

Proper bi-orientation of all sister chromatids within the cell silences the spindle assembly checkpoint pathway. The Cdc20-APC/C complexes are now activated and ubiquitinates securin to release an active separase. Separase cleaves the cohesin rings, permitting the separation of sister chromatids.

Hence, the spindle assembly checkpoint mechanism ensures the fidelity of chromosomal segregation.