At anaphase onset, Sgo1 function of cohesion protection must be disabled to allow timely chromosome segregation, but how this is achieved is not fully understood. Here, we show that SET, a known PP2A inhibitor, directly binds to a domain in Sgo1 in close proximity to the cohesin-binding motif. The Sgo1–cohesin binding can be disrupted by SET in a dose-dependent manner in vitro as well as by SET overexpression in cells, suggesting that SET is also an inhibitor to the Sgo1–cohesin binding. Furthermore, the SET binding–deficient Sgo1 mutant fully supports centromeric cohesion protection but delays chromosome segregation, suggesting that the SET–Sgo1 binding is required for timely chromosome segregation. Moreover, overexpression of SET WT, not the Sgo1 binding–deficient mutant, exacerbates the occurrence of cohesion fatigue in MG132-arrested cells. Conversely, SET depletion delays it. Thus, we propose that a major function of SET during mitosis is to disrupt the Sgo1–cohesin interaction, thereby promoting centromeric cohesion de-protection and timely chromosome segregation at anaphase onset.

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