A kinase‐dependent role for Haspin in antagonizing Wapl and protecting mitotic centromere cohesion

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.

Centromere-localized Aurora B kinase is required for the fidelity of chromosome segregation

“…Therefore, these two residues (K62 and H80) are crucial for the phospho-specific binding of Survivin to H3. When endogenous Survivin was stably depleted by CRISPR/Cas9-mediated genome editing, the stably expressed Survivin mutants with Myc-tag (Survivin-K62A-Myc and Survivin-H80A-Myc) are largely impaired in supporting Aurora B localization at centromeres (Liang et al, 2018).…”

Haspin inhibition delays cell cycle progression through interphase in cancer cells

“…In terms of functions, H3T3ph acts as a docking site for the chromosome passenger complex (CPC) at the centromere and ensures the proper kinetochore‐microtubule attachment mediated by the Aurora B kinase (Wang et al, ). Haspin and H3T3ph are also critical for the maintenance of sister chromatid cohesion via interactions with heterochromatin HP1 and a number of other centromeric proteins (Liang et al, ; Yi et al, ). These findings substantiate haspin as a member of the select group of mitotic kinases that include cyclin‐dependent kinases (CDKs), Aurora kinases, and Polo‐like kinases (Plks; Ma & Poon, ).…”

Histone H2A phosphorylation recruits topoisomerase II α to centromeres to safeguard genomic stability

“…The first step occurs during prophase, which requires the cohesin release protein Wapl as well as the phosphorylation of cohesin subunits and regulators by mitotic kinases (Losada et al, 2002;Sumara et al, 2002;Gimenez-Abian et al, 2004;Hauf et al, 2005;Gandhi et al, 2006;Kueng et al, 2006;Nishiyama et al, 2013;Tedeschi et al, 2013). Centromeric cohesin is resistant to the prophase pathway due to the actions of the shugoshin protein Sgo1 in complex with protein phosphatase 2A (PP2A) (Kitajima et al, 2004(Kitajima et al, , 2006Salic et al, 2004;McGuinness et al, 2005;Riedel et al, 2006;Tang et al, 2006), Sororin (Rankin et al, 2005;Nishiyama et al, 2010Nishiyama et al, , 2013Liu et al, 2013b;Ladurner et al, 2016), and the mitotic kinase Haspin (Dai et al, 2006;Goto et al, 2017;Zhou et al, 2017;Liang et al, 2018a;Yi et al, 2018). Centromeric cohesin is resistant to the prophase pathway due to the actions of the shugoshin protein Sgo1 in complex with protein phosphatase 2A (PP2A) (Kitajima et al, 2004(Kitajima et al, , 2006Salic et al, 2004;McGuinness et al, 2005;Riedel et al, 2006;Tang et al, 2006), Sororin (Rankin et al, 2005;Nishiyama et al, 2010Nishiyama et al, , 2013Liu et al, 2013b;Ladurner et al, 2016), and the mitotic kinase Haspin (Dai et al, 2006;…”

“…This process, referred to as the prophase pathway, removes the bulk of cohesin from chromosome arms in a proteolysis-independent manner, resulting in sister chromatid resolution and the classical X-shaped mitotic chromosomes. Centromeric cohesin is resistant to the prophase pathway due to the actions of the shugoshin protein Sgo1 in complex with protein phosphatase 2A (PP2A) (Kitajima et al, 2004(Kitajima et al, , 2006Salic et al, 2004;McGuinness et al, 2005;Riedel et al, 2006;Tang et al, 2006), Sororin (Rankin et al, 2005;Nishiyama et al, 2010Nishiyama et al, , 2013Liu et al, 2013b;Ladurner et al, 2016), and the mitotic kinase Haspin (Dai et al, 2006;Goto et al, 2017;Zhou et al, 2017;Liang et al, 2018a;Yi et al, 2018). At anaphase onset, cohesin at centromeres is removed through proteolytic cleavage by the protease separase, leading to the segregation of sister chromatids toward opposite poles (Uhlmann et al, 2000;Hauf et al, 2001).…”