The N-Terminal Non-Kinase-Domain-Mediated Binding of Haspin to Pds5B Protects Centromeric Cohesion in Mitosis.

Sister-chromatid cohesion, mediated by the multi-subunit cohesin complex, must be precisely regulated to prevent chromosome mis-segregation. In prophase and prometaphase, whereas the bulk of cohesin on chromosome arms is removed by its antagonist Wapl, cohesin at centromeres is retained to ensure chromosome biorientation until anaphase onset. It remains incompletely understood how centromeric cohesin is protected against Wapl in mitosis. Here we show that the mitotic histone kinase Haspin binds to the cohesin regulatory subunit Pds5B through a conserved YGA/R motif in its non-catalytic N terminus, which is similar to the recently reported YSR-motif-dependent binding of Wapl to Pds5B. Knockout of Haspin or disruption of Haspin-Pds5B interaction causes weakened centromeric cohesion and premature chromatid separation, which can be reverted by centromeric targeting of a N-terminal short fragment of Haspin containing the Pds5B-binding motif or by prevention of Wapl-dependent cohesin removal. Conversely, excessive Haspin capable of binding Pds5B displaces Wapl from Pds5B and suppresses Wapl activity, and it largely bypasses the Wapl antagonist Sgo1 for cohesion protection. Taken together, these data indicate that the Haspin-Pds5B interaction is required to ensure proper sister-chromatid cohesion, most likely through antagonizing Wapl-mediated cohesin release from mitotic centromeres.