RAD52 underlies the synthetic-lethal relationship between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta loss.

Cells lacking several DNA repair proteins, including those promoting homologous recombination (HR), are sensitive to polymerase theta (Polθ) repression. Polθ drives theta-mediated end joining (TMEJ) and suppresses HR but what mediates its synthetic lethal relationships is unclear. Here we examine murine Brca1C61G/ C61G 53bp1-/-cells and find they are largely HR proficient by using RNF168 and RAD52. They exhibit no more TMEJ than 53bp1-/- cells yet are more sensitive to targeting of Polθ. We find that RAD52 recruitment to damaged chromatin is increased following Polθ depletion. RAD52 accumulation and cellular sensitivity to Polθ repression can be curbed by the RAD51-binding regions of BARD1 and BRCA2, and sensitivity of BRCA1/2 depleted cells to Polθ repression is suppressed by RAD52 inhibition. 53bp1-/- cells exhibit a smaller increase in RAD52 recruitment following Polθ repression and also become resistant to Polθ repression following RAD52 inhibition. Thus, RAD52 mediates sensitivity to targeting Polθ in these contexts ### Competing Interest Statement The authors have declared no competing interest.