A kinase‐dependent role for Haspin in antagonizing Wapl and protecting mitotic centromere cohesion. (14th November 2017) - Liang, Cai
Abstract: Sister‐chromatid cohesion mediated by the cohesin complex is fundamental for precise chromosome segregation in mitosis. Through binding the cohesin subunit Pds5, Wapl releases the bulk of cohesin from chromosome arms in prophase, whereas centromeric cohesin is protected from Wapl until anaphase onset. Strong centromere cohesion requires centromeric localization of the mitotic histone kinase Haspin, which is dependent on the interaction of its non‐catalytic N‐terminus with Pds5B. It remains unclear how Haspin fully blocks the Wapl–Pds5B interaction at centromeres. Here, we show that the C‐terminal kinase domain of Haspin (Haspin‐KD) binds and phosphorylates the YSR motif of Wapl (Wapl‐YSR), thereby directly inhibiting the YSR motif‐dependent interaction of Wapl with Pds5B. Cells expressing a Wapl‐binding‐deficient mutant of Haspin or treated with Haspin inhibitors show centromeric cohesion defects. Phospho‐mimetic mutation in Wapl‐YSR prevents Wapl from binding Pds5B and releasing cohesin. Forced targeting Haspin‐KD to centromeres partly bypasses the need for Haspin–Pds5B interaction in cohesion protection. Taken together, these results indicate a kinase‐dependent role for Haspin in antagonizing Wapl and protecting centromeric cohesion in mitosis. Synopsis: Wapl releases the bulk of cohesin from chromosome arms in prophase, whereas centromeric cohesin is protected until anaphase onset. The kinase Haspin phosphorylates Wapl, thereby inhibiting the interaction with Pds5B, and protecting centromeric cohesion. The mitotic histone kinase Haspin binds and phosphorylates the cohesin‐releasing factor Wapl at its YSR motif. Phosphorylated Wapl does not interact with the cohesin subunit Pds5B. Haspin has a kinase‐dependent role in protecting centromeric cohesion during mitosis. Abstract : Wapl releases the bulk of cohesin from chromosome arms in prophase, whereas centromeric cohesin is protected until anaphase onset. The kinase Haspin phosphorylates Wapl, thereby inhibiting the interaction with Pds5B, and protecting centromeric cohesion.