TRIP12's role in the governance of DNA polymerase β involvement in DNA damage response and repair.

Abstract

The multitude of DNA lesion types, and the nuclear dynamic context in which they occur, presents a challenge for genome integrity maintenance as this requires the engagement of different DNA repair pathways. Specific "repair controllers" that facilitate DNA repair pathway crosstalk between double-strand break (DSB) repair and base excision repair (BER) and that regulate BER protein engagement at lesion sites have yet to be identified. Here, we find that DNA polymerase β (Polβ), crucial for BER, is ubiquitylated in a BER complex-dependent manner by TRIP12, an E3 ligase that partners with UBR5 to restrain DSB repair signaling. Furthermore, we find that TRIP12, but not UBR5, controls cellular levels and chromatin loading of Polβ. Required for Polβ foci formation, TRIP12 influences Polβ involvement after radiation-induced DNA damage, a process regulated by TRIP12-mediated ubiquitylation of Polβ. Notably, excessive TRIP12-mediated engagement of Polβ affects DSB formation and radiation sensitivity, underscoring its role in promoting precedence for BER over DSB repair. The herein discovered function of TRIP12, in the governance of Polβ-directed BER, supports a role for TRIP12 in assuring BER lesion removal at complex DSB sites to optimize DSB repair at the nexus of DNA repair pathways.