Phosphorylation-enabled binding of SGO1–PP2A to cohesin protects sororin and centromeric cohesion during mitosis

Abstract

Timely dissolution of sister-chromatid cohesion in mitosis ensures accurate chromosome segregation to guard against aneuploidy and tumorigenesis. The complex of shugoshin and protein phosphatase 2A (Sgo1–PP2A) protects cohesin at centromeres from premature removal by mitotic kinases and Wapl in prophase. Here we address the regulation and mechanism of human Sgo1 in centromeric cohesion protection, and show that cyclin-dependent kinase (Cdk)-mediated, mitosis-specific phosphorylation of Sgo1 activates its cohesion-protection function and enables its direct binding to cohesin. The phospho-Sgo1-bound cohesin complex contains PP2A, Pds5, and hypophosphorylated sororin, but lacks Wapl. Expression of non-phosphorylatable sororin bypasses the requirement for Sgo1–PP2A in centromeric cohesion. Thus, mitotic phosphorylation of Sgo1 targets Sgo1–PP2A to cohesin, promotes dephosphorylation of Pds5-bound sororin, and protects centromeric cohesin from Wapl. PP2A-orchestrated, selective removal of a specific subset of phosphorylation from cohesin and its regulators underlies centromeric cohesion protection.

Aurora B and Cdk1 mediate Wapl activation and release of acetylated cohesin from chromosomes by phosphorylating Sororin

“…S6C). During preparation of this manuscript, similar observations were reported by Liu et al (27). Expression of nonphosphorylatable SA2 mutants also restores cohesion and mitotic progression in Sgo1-depleted cells (25), indicating that both phosphorylation of Sororin and SA2 are essential for the removal of cohesin from mitotic chromosomes (Fig.…”

“…S1A). Only 5 of the 15 sites identified in our experiments were among the 9 putative Cdk1 sites that had been mutated in previous studies (26,27).…”

“…The dissociation of Sororin from chromosomes in mitosis has been shown to depend on Cdk1 (26,27), but our results indicated that not only Cdk1 but also Aurora B reduces Sororin's ability to bind to Pds5A. If Sororin's dissociation from mitotic chromosomes is mediated by releasing Sororin from Pds5, our results predict that both Cdk1 and Aurora B contribute to the dissociation of Sororin from mitotic chromosomes.…”

“…Previous work had shown that Sororin is phosphorylated in mitosis (10), that this phosphorylation prevents binding of Sororin to Pds5A in vitro (2), that the phosphorylation of Sororin on putative Cdk1 sites is required for its dissociation from chromatin and partial loss of cohesion (26), and that alanine mutation of these sites bypasses the requirement for Sgo1 in cohesion (27). It has also been proposed that Sororin phosphorylation by Cdk1 enables Plk1 binding to Sororin, leading to SA2 phosphorylation by Plk1 (28).…”

Insights into centromeric transcription in mitosis

“…1), to protect the centromeric cohesion in mitosis, thus preventing chromosome missegregation and chromosome instability. [16][17][18][19][20] Our recent immunofluorescence microscopy demonstrated that Sgo1 is sequentially recruited to kinetochores and inner centromeres. 10 The kinetochore and centromeric receptors for Sgo1 are histone H2A phosphor Thr120 (H2A pT120) and cohesin, respectively.…”