Activation of the SUMO modification system is required for the accumulation of RAD51 at sites containing DNA damage

Abstract

SummaryGenetic information encoded in chromosomal DNA is challenged by intrinsic and exogenous sources of DNA damage. DNA doublestrand breaks (DSBs) are extremely dangerous DNA lesions. RAD51 plays a central role in homologous DSB repair, by facilitating the recombination of damaged DNA with intact DNA in eukaryotes. RAD51 accumulates at sites containing DNA damage to form nuclear foci. However, the mechanism of RAD51 accumulation at sites of DNA damage is still unclear. Post-translational modifications of proteins, such as phosphorylation, acetylation and ubiquitylation play a role in the regulation of protein localization and dynamics. Recently, the covalent binding of small ubiquitin-like modifier (SUMO) proteins to target proteins, termed SUMOylation, at sites containing DNA damage has been shown to play a role in the regulation of the DNA-damage response. Here, we show that the SUMOylation E2 ligase UBC9, and E3 ligases PIAS1 and PIAS4, are required for RAD51 accretion at sites containing DNA damage in human cells. Moreover, we identified a SUMO-interacting motif (SIM) in RAD51, which is necessary for accumulation of RAD51 at sites of DNA damage. These findings suggest that the SUMO-SIM system plays an important role in DNA repair, through the regulation of RAD51 dynamics.

SUMOylation controls stem cell proliferation and regional cell death through Hedgehog signaling in planarians

“…Mechanistically, our results demonstrate that the increase in DSBs after Ubc9(RNAi) are due to a disruption in DNA repair through HR. Ubc9(RNAi) restricts nuclear translocation of RAD51, which is consistent with previous studies showing UBC9 is involved in trafficking of nuclear proteins [21,[50][51][52][53][54]. These data together reveal Ubc9 is an essential component to maintain genomic integrity during renewal of adult tissues.…”

RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response

“…Additionally, cells expressing the K449R/ K577R RPA70 mutant had increased sensitivity to CPT, demonstrating the importance of RPA complex SUMOylation for the maintenance of genomic stability. Interestingly, recruitment of RAD51 to sites of damage was recently shown to require a SIM domain [127]. Additionally, the RPA complex may also have SUMO-recognition capacity.…”

Cell Biology of Mitotic Recombination

“…RAD51 focus formation is additionally regulated by small ubiquitin-like modifier (SUMO) in both yeast and mammalian cells (Bergink et al 2013;Shima et al 2013). It remains to be fully understood how BRCA2 is recruited to foci.…”