Sororin actively maintains sister chromatid cohesion

Abstract

Cohesion between sister chromatids is established during DNA replication but needs to be maintained to enable proper chromosome-spindle attachments in mitosis or meiosis. Cohesion is mediated by cohesin, but also depends on cohesin acetylation and sororin. Sororin contributes to cohesion by stabilizing cohesin on DNA. Sororin achieves this by inhibiting WAPL, which otherwise releases cohesin from DNA and destroys cohesion. Here we describe mouse models which enable the controlled depletion of sororin by gene deletion or auxin-induced degradation. We show that sororin is essential for embryonic development, cohesion maintenance, and proper chromosome segregation. We further show that the acetyltransferases ESCO1 and ESCO2 are essential for stabilizing cohesin on chromatin, that their only function in this process is to acetylate cohesin's SMC3 subunit, and that DNA replication is also required for stable cohesin-chromatin interactions. Unexpectedly, we find that sororin interacts dynamically with the cohesin complexes it stabilizes. This implies that sororin recruitment to cohesin does not depend on the DNA replication machinery or process itself, but on a property that cohesin acquires during cohesion establishment.

ESCO1/2's roles in chromosome structure and interphase chromatin organization

“…As SMC3 is the most studied and discussed target of ESCO1/2 (Minamino et al 2015;Ladurner et al 2016), we next sought to address the effects of defective or The results were confirmed with lysates from an independent biological experiment. (C) Growth curves.…”

“…Acetyl-mimicking mutations of K105 and K106 sites of SMC3 reduce cohesin mobility (Ladurner et al 2016), but whether SMC3 acetylation underlies the essential function of ESCO1 and ESCO2 in proliferation (see Fig. 2C) and whether that essential function is linked to SCC are not known.…”

“…Cohesin release and sister chromatid separation in esco1 esco2 cells are suppressed by depletion of WAPL Cohesin acetylation by ESCO1/2 is thought to promote SCC and proliferation by preventing WAPL-mediated removal of cohesin (Rowland et al 2009;Sutani et al 2009;Ladurner et al 2016). With the newly established tools and cell lines, we sought to address the relationship between ESCO1/2-mediated events in cellular proliferation and WAPL function.…”

“…Different pools of cohesin binding have been described, with cohesin bound in G1 being more loosely associated with chromatin, whereas the acetylated cohesin was bound longer to chromatin and was resistant to removal by WAPL (Ladurner et al 2016;Rhodes et al 2017). We performed chromatin fractionation experiments using synchronously growing cells treated with Auxin for 6 h and enriched in interphase (see Fig.…”

“…It was shown recently that the acetylation of the SMC3 subunit of cohesin at conserved lysine residues K105 and K106 by ESCO1/ESCO2 reduces cohesin mobility and promotes stable binding of Sororin to cohesin, presumably to enhance SCC (Ladurner et al 2016). Both ESCO1 and ESCO2 can acetylate SMC3 at K105 and K106, although ESCO1 can acetylate cohesin independently of DNA replication (Minamino et al 2015).…”