This research identifies shugoshin 2 (SGO2) as a critical, direct inhibitor of separase in human cells, functioning through a previously unknown pathway controlled by the spindle assembly checkpoint (SAC). While the protein securin was long considered the primary regulator of chromosome segregation, these findings reveal that SGO2 can functionally replace it by binding to MAD2 to block the active site of separase. The study demonstrates that SGO2 acts as a competitive pseudosubstrate inhibitor, effectively mimicking securin's mechanism to prevent premature sister chromatid separation. Scientists found that the TRIP13–p31comet molecular machine is responsible for dismantling this complex, thereby triggering the onset of anaphase. These results establish a redundant regulatory system that ensures genomic stability even when canonical inhibitors are absent. This discovery provides a more complete understanding of how cells strictly time the cleavage of cohesin during the mitotic cycle.

References:

• Hellmuth, S., Gómez-H, L., Pendás, A.M. et al. Securin-independent regulation of separase by checkpoint-induced shugoshin–MAD2. Nature 580, 536–541 (2020). doi.org