Working model depicting how SET promotes chromosome segregation at the metaphase-to-anaphase transition. At metaphase-to-anaphase transition, by inhibiting the Sgo1–cohesin interaction and/or evicting Sgo1 from chromatin, SET removes Sgo1 from inner centromeres to disable its function of cohesion protection, thereby promoting chromosome segregation. SET may also de-protect centromeric cohesion by directly inhibiting PP2A activity.