RAD52 Adjusts Repair of Single-Strand Breaks via Reducing DNA-Damage-Promoted XRCC1/LIG3α Co-localization

Radiation sensitive 52 (RAD52) is an important factor for double-strand break repair (DSBR). However, deficiency in vertebrate/mammalian Rad52 has no apparent phenotype. The underlying mechanism remains elusive. Here, we report that RAD52 deficiency increased cell survival after camptothecin (CPT) treatment. CPT generates single-strand breaks (SSBs) that further convert to double-strand breaks (DSBs) if they are not repaired. RAD52 inhibits SSB repair (SSBR) through strong single-strand DNA (ssDNA) and/or poly(ADP-ribose) (PAR) binding affinity to reduce DNA-damage-promoted X-Ray Repair Cross Complementing 1 (XRCC1)/ligase III alpha (LIG3 alpha) co-localization. The inhibitory effects of RAD52 on SSBR neutralize the role of RAD52 in DSBR, suggesting that RAD52 may maintain a balance between cell survival and genomic integrity. Furthermore, we demonstrate that blocking RAD52 oligomerization that disrupts RAD52's DSBR, while retainingits ssDNA binding capacity that is required for RAD52's inhibitory effects on SSBR, sensitizes cells to different DNA-damaging agents. This discovery provides guidance for developing efficient RAD52 inhibitors in cancer therapy.

Automated summary

RAD52 deficiency increases cell survival after CPT treatment by inhibiting SSBR through its strong binding affinity to ssDNA and/or PAR. This neutralizes RAD52's role in DSBR, suggesting a balance between cell survival and genomic integrity. Blocking RAD52 oligomerization disrupts DSBR while retaining its ssDNA binding capacity, sensitizing cells to DNA-damaging agents and providing guidance for developing RAD52 inhibitors in cancer therapy.