Cohesin, the SMC5/6 Complex and Sumo in DNA Repair

Abstract

DNA double-strand breaks (DSBs) fuel cancer-driving chromosome translocations. Two related structural maintenance of chromosomes (Smc) complexes, cohesin and Smc5/6, promote DSB repair through sister-chromatid homologous recombination (SCR). Our results show that the Smc5/6 subunit Mms21 sumoylates multiple lysines of the cohesin subunit Scc1. Mms21 promotes cohesin-dependent SUMO accumulation at laser-induced DNA damage sites in S/G2 human cells. Cells expressing the non-sumoylatable Scc1 mutant (15KR) maintain sister-chromatid cohesion during mitosis, but are defective in SCR and sensitive to ionizing radiation (IR). Scc1 15KR is recruited to DNA damage sites. Depletion of Wapl, a negative cohesin regulator, rescues SCR defects of Mms21-deficient or Scc1 15KR-expressing cells. Expression of the acetylation-mimicking Smc3 mutant does not bypass the requirement for Mms21 in SCR. We propose that Scc1 sumoylation by Mms21 promotes SCR by antagonizing Wapl at a step after cohesin loading at DSBs and in a way not solely dependent on Smc3 acetylation. Our results establish a new posttranslational regulatory mechanism of cohesin during DNA repair, and reveal both conserved principles and organism-specific features in cohesin regulation during sister-chromatid recombination