Sororin is a master regulator of sister chromatid cohesion and separation

Abstract

The maintenance of sister chromatid cohesion from S phase to the onset of anaphase relies on a small but evolutionarily conserved protein called Sororin. Sororin is a phosphoprotein and its dynamic localization and function are regulated by protein kinases, such as Cdk1/cyclin B and Erk2. The association of Sororin with chromatin requires cohesin to be preloaded to chromatin and modification of Smc3 during DNA replication. Sororin antagonizes the function of Wapl in cohesin releasing from S to G 2 phase and promotes cohesin release from sister chromatid arms in prophase via interaction with Plk1. This review focuses on progress of the identification and regulation of Sororin during cell cycle; role of post-translational modification on Sororin function; role of Sororin in the maintenance and resolution of sister chromatid cohesion; and finally discusses Sororin's emerging role in cancer and the potential issues that need be addressed in the future.

Figure 1. Clustal format alignment of Sororin and Eco1 by MAFFT L-INS-i (v6.843b) with manual adjustment. The top line indicates the conserved amino acids of vertebrate Sororin, whereas the bottom line shows the conserved amino acids of S. cerevisiae (SC) Eco1 with respect to vertebrate Sororin. The conserved regions among Sororin molecules from different species are shown in blue, whereas the region in SC Eco1 conserved relative to Sororin are shown in orange. Invariant, conserved and semi-conserved residues are indicated by an asterisk (*), colon (:) and period (.), respectively.

Figure 2. Role of Sororin in cohesin cycle. A model showing Sororin’s function in the maintenance and resolution of sister chromatid cohesion. (A) Cohesin is loaded to and associates with chromatin via Smc1-Smc3 hinge domain. (B) During DNA replication at S phase, cohesin passes thorough the replication fork, possibly by opening the linkage of N-terminus of Rad21 and Smc3 head domain. Once cohesin passes the replication fork, Smc3 is acetylated by Esco1/2. Sister chromatid cohesion is generated after two of the acetylated cohesin rings are dimerized by SA1/2 and other cohesin-associated proteins. (C) Cohesin-releasing activity of the releasin complex (Wapl-Pds5) is blocked after Wapl is displaced from the central binding site of Pds5 by Sororin. Now the sister chromatid cohesion is stable and can be maintained until the initiation of mitosis. (D) At prophase, Sororin is phosphorylated by Cdk1/cyclin B, which facilitates Plk1 to bind to Sororin and phosphorylates SA2. Phosphorylation of SA2 destabilizes cohesin complexes. Sororin dissociates from chromatin after it is further phosphorylated, which provides opportunity for Wapl to bind back to Pds5 and restores their cohesin-releasing activity. After cohesins are removed by Wapl-Pds5, the arms of the sister chromatid are resolved. (E) The released cohesins are regenerated by deacetylation of Smc3 and dephosphorylation of SA2, which can be reused in telophase.