Shugoshin collaborates with protein phosphatase 2A to protect cohesin

Abstract

Sister chromatid cohesion, mediated by a complex called cohesin, is crucial--particularly at centromeres--for proper chromosome segregation in mitosis and meiosis. In animal mitotic cells, phosphorylation of cohesin promotes its dissociation from chromosomes, but centromeric cohesin is protected by shugoshin until kinetochores are properly captured by the spindle microtubules. However, the mechanism of shugoshin-dependent protection of cohesin is unknown. Here we find a specific subtype of serine/threonine protein phosphatase 2A (PP2A) associating with human shugoshin. PP2A colocalizes with shugoshin at centromeres and is required for centromeric protection. Purified shugoshin complex has an ability to reverse the phosphorylation of cohesin in vitro, suggesting that dephosphorylation of cohesin is the mechanism of protection at centromeres. Meiotic shugoshin of fission yeast also associates with PP2A, with both proteins collaboratively protecting Rec8-containing cohesin at centromeres. Thus, we have revealed a conserved mechanism of centromeric protection of eukaryotic chromosomes in mitosis and meiosis.

Shugoshin regulates cohesion by driving relocalization of PP2A in Xenopus extracts

“…Anomalous PP2A distribution in the absence of Sgo impairs cohesin release Sgo associates with PP2A in yeast and human cells, and this association is important for cohesin protection (Kitajima et al 2006;Riedel et al 2006;Tang et al 2006). In HeLa cells depleted of Sgo1 by siRNA, cohesion is completely lost even though the centromeric localization of PP2A is preserved, a result that led Kitajima et al (2006) to suggest that Sgo could have an additional role and provide protection by itself, maybe through physical association with cohesin.…”

“…In HeLa cells depleted of Sgo1 by siRNA, cohesion is completely lost even though the centromeric localization of PP2A is preserved, a result that led Kitajima et al (2006) to suggest that Sgo could have an additional role and provide protection by itself, maybe through physical association with cohesin. We have found no evidence for a direct physical interaction of cohesin and Sgo in Xenopus extracts.…”

“…It has been proposed that one specific variant of the protein phosphatase PP2A associates with Sgo and protects centromeric cohesin in meiosis I by counteracting Rec8 phosphorylation by Polo (Riedel et al 2006). A second report showed that PP2A associates with Sgo proteins also in HeLa cells and most likely counteracts SA2 phosphorylation by Polo (Kitajima et al 2006). In Saccharomyces cerevisiae, an organism in which there is no prophase release of cohesin, Sgo1 is not required for cohesion but for sensing tension between sister chromatids (Indjeian et al 2005).…”

Cohesin and chromatin organisation

“…This coincides with the increased binding of another SMC complex, condensin, which promotes the packaging of chromatin into the highly condensed mitotic chromatids. A limited amount of cohesin persists at the centromeres under the protection of Shugoshin-PP2A [38][39][40][41].…”

“…This coincides with the increased binding of another SMC complex, condensin, which promotes the packaging of chromatin into the highly condensed mitotic chromatids. A limited amount of cohesin persists at the centromeres under the protection of Shugoshin-PP2A [38][39][40][41].These residual cohesin complexes are critical for holding sister chromatids together at their centromeres, giving mitotic chromosomes their iconic shape. At anaphase the ubiquitin-ligase anaphase-promoting complex (APC) induces the degradation of Securin, an inhibitor of the protease Separase, which in turn cleaves the Rad21 subunit of cohesin [42][43][44].…”