Scc1 sumoylation by Mms21 promotes sister chromatid recombination through counteracting Wapl

Abstract

DNA double‐strand break (DSB) is the most deleterious form of DNA damage and can cause chromosome translocations that drive cancer formation. Homologous recombination (HR) is a key DSB repair pathway. To maintain heterozygosity of the genome, sister‐chromatid homologous recombination (SCR) is preferred to HR between two homologous chromosomes. In human cells, two related structural maintenance of chromosomes (Smc) complexes, cohesin and Smc5/6, facilitate SCR. We have previously shown that the Smc5/6 subunit Mms21 functions as a SUMO ligase. In this study, we demonstrate that Mms21 sumoylates the cohesin subunit Scc1 at multiple sites. SUMO2/3 is accumulated on laser‐induced DNA damages, and this accumulation is dependent on Smc5/6 and cohesin during the S/G2 phase when DSBs are primarily repaired through SCR. Human cells expressing a non‐sumoylatable Scc1 mutant (15KR) maintain proper sister‐chromatid cohesion during mitosis, but are defective in SCR. These results show that Scc1 sumoylation by Mms21 is essential for SCR. On the other hand, Scc1 15KR is still recruited to laser‐induced DNA damage sites. Depletion of Wapl, the negative cohesin regulator, rescues SCR defects and IR sensitivity of Mms21‐deficient or Scc1 15KR‐expressing cells. Therefore, our results suggest that Scc1 sumoylation by Mms21 promotes SCR by antagonizing Wapl at a step after the initial cohesin loading at DSBs in human cells.