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

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... 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