18.12: The Spindle Assembly Checkpoint

The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.

Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the segregation of chromosomes regardless of the completion of all the prerequisite steps. Consequently, the daughter cells formed may receive fewer or greater than the normal number of chromosomes. This condition with an abnormal chromosome number in a cell is called aneuploidy, which can lead to many developmental defects.

The spindle assembly checkpoint is activated by the presence of unattached or improperly attached kinetochores. Two models explain the release of the checkpoint mechanism — the attachment model and the tension model. The attachment model emphasizes that the saturation or full occupation of the kinetochores by kinetochore-microtubules causes the checkpoint mechanism to switch off. Alternatively, the tension model states that the tension generated from the attachment of the correct spindle-microtubule to the kinetochore is responsible for switching off the checkpoint mechanism. However, studies suggest that the attachment and tension mechanisms are both required to ensure the fidelity of spindle assembly checkpoint surveillance.

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.