Redox Regulation of RAD51 and Homologous Recombination by Peroxiredoxin 1 and Electrophilic Nitro-Fatty Acids

Peroxiredoxin 1 (PRDX1) senses and reduces peroxides and coordinates the signaling actions of its binding partners. We show that PRDX1 protects RAD51 from oxidation-induced repression of homologous recombination (HR) repair following ɣ-irradiation. PRDX1-deficient human breast cancer cells and mouse embryonic fibroblasts display disrupted RAD51 foci formation and decreased HR, resulting in increased DNA damage and sensitization of cells to irradiation. The oxidation of RAD51 Cys319, a thiol located in the SH3 domain targeted by ABL, is prevented by PRDX1. Alkylation of RAD51 Cys319 by the electrophilic fatty acid nitroalkene 10- nitro-octadec-9-enoic acid (OA-NO2) inhibited RAD51-ABL protein complex formation and downstream Y315 phosphorylation. In breast cancer cells, this reactivity of OA-NO2 was manifested by diminished RAD51 foci formation and sensitization of cells to irradiation. These data establish RAD51 Cys319 as a functionally-significant site for the redox regulation of HR and cellular responses to IR by PRDX1 and soft electrophiles such as OA-NO2.