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

Abstract

Sister chromatid cohesion depends on Sororin, a protein that stabilizes acetylated cohesin complexes on DNA by antagonizing the cohesin release factor Wings-apart like protein (Wapl). Cohesion is essential for chromosome biorientation but has to be dissolved to enable sister chromatid separation. To achieve this, the majority of cohesin is removed from chromosome arms in prophase and prometaphase in a manner that depends on Wapl and phosphorylation of cohesin's subunit stromal antigen 2 (SA2), whereas centromeric cohesin is cleaved in metaphase by the protease separase. Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. At centromeres, the cohesin protector shugoshin (Sgo1)-protein phosphatase 2A (PP2A) antagonizes Aurora B and Cdk1 partly by dephosphorylating Sororin and thus maintains cohesion until metaphase. We propose that the stepwise loss of cohesion between chromosome arms and centromeres is caused by local regulation of Wapl activity, which is controlled by the phosphorylation state of Sororin.cell cycle | chromosome segregation | prophase pathway R eplicated DNA molecules (sister chromatids) remain physically connected with each other from S phase until metaphase to enable biorientation of chromosomes on the mitotic spindle. This association, called sister chromatid cohesion, is mediated by cohesin, whose core subunits Structural maintenance of chromosomes 1 (Smc1), Smc3, Sister chromatid cohesion 1 (Scc1), and Scc3/stromal antigen (SA/STAG) form a molecular ring. This structure is crucial for cohesion, presumably because cohesin topologically embraces the two sister chromatids (reviewed in ref.

C-terminus of Sororin interacts with SA2 and regulates sister chromatid cohesion

“…After the cell cycle progresses to prophase/prometaphase, protein kinases, such as Ckd1/ cyclin B and Aurora B, phosphorylate Sororin, causing Sororin to dissociate from cohesin. 13 Wapl1 regains the binding to Pds5 via its FGF motif, and cohesin is removed from chromatid arms.…”

“…[6][7][8][9] The cohesin-associated Sororin maintains the sister chromatid cohesion established at S phase until Sororin is phosphorylated and dissociated from chromatids, when Wapl forms a complex with Pds5 to remove cohesin in prophase/prometaphase. 7,[10][11][12][13][14][15] In addition, Sororin plays a regulatory role in the resolution of sister chromatid cohesion during M-phase. 3,15 Sororin can co-immunoprecipitate (co-IP) cohesin core subunits Rad21, Smc1, Smc3, and SA1/2, as well as cohesin-associated protein Pds5A/B and Wapl.…”

Multiple Determinants and Consequences of Cohesion Fatigue in Mammalian Cells

“…In early mitosis, Cohesin is removed from chromosome arms by the prophase pathway through mitotic kinases and the protein, Wapl (Gandhi et al, 2006;Kueng et al;Nishiyama et al, 2010;Nishiyama et al, 2013;Shintomi and Hirano, 2009). In cells arrested .…”

“…Cohesin complexes containing SA1 appear important for arm and telomere cohesion, while Cohesin complexes containing SA2 have more critical roles for centromeric cohesion (Canudas and Smith, 2009). SA2 at centromeres recruits proteins that promote cohesion, including Sororin, Shugoshin (SGO1), and Protein Phosphatase 2A (PP2A), that shield centromeric Cohesin from phosphorylation and removal due to the prophase pathway (Hauf et al, 2005;McGuinness et al, 2005;Nishiyama et al, 2013).…”

Opposing Functions of the N-terminal Acetyltransferases Naa50 and NatA in Sister-chromatid Cohesion

“…Sororin antagonizes the cohesin-releasing activity of WaplPds5 and stabilizes cohesin on chromosomes, thus promoting sister-chromatid cohesion. In prophase, cohesin and sororin on chromosome arms are phosphorylated by Plk1 (polo-like kinase 1), Cdk1 (cyclin-dependent kinase 1), and other mitotic kinases and removed by Wapl-Pds5 (22)(23)(24)(25)(26)(27). The centromeric cohesin is bound and protected by the Sgo1-PP2A complex (28 -33).…”