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.
© 2019 Qu et al.