POLθ-mediated end joining is restricted by RAD52 and BRCA2 until the onset of mitosis

BRCA2-mutant cells are defective in homologous recombination, making them vulnerable to the inactivation of other pathways for the repair of DNA double-strand breaks (DSBs). This concept can be clinically exploited but is currently limited due to insufficient knowledge about how DSBs are repaired in the absence of BRCA2. We show that DNA polymerase theta (POL theta)-mediated end joining (TMEJ) repairs DSBs arising during the S phase in BRCA2-deficient cells only after the onset of the ensuing mitosis. This process is regulated by RAD52, whose loss causes the premature usage of TMEJ and the formation of chromosomal fusions. Purified RAD52 and BRCA2 proteins both block the DNA polymerase function of POL theta, suggesting a mechanism explaining their synthetic lethal relationships. We propose that the delay of TMEJ until mitosis ensures the conversion of originally one-ended DSBs into two-ended DSBs. Mitotic chromatin condensation might further serve to juxtapose correct break ends and limit chromosomal fusions. Lobrich and colleagues report that RAD52 and BRCA2 limit polymerase theta activity until the onset of mitosis to ensure double-strand breaks arising in the S phase are repaired by polymerase theta-mediated end joining in mitosis, not in S phase.

Automated summary

BRCA2-deficient cells are vulnerable to inactivation of DNA repair pathways for DSBs, which can be exploited clinically. RAD52 and BRCA2 regulate the TMEJ process by blocking the POL theta function, ensuring proper repair of DSBs in mitosis.