TRIP13 regulates DNA repair pathway choice through REV7 conformational change

Abstract

DNA double-strand breaks (DSBs) are repaired through homology-directed repair (HDR) or non-homologous end joining (NHEJ). BRCA1/2-deficient cancer cells cannot perform HDR, conferring sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). However, concomitant loss of the pro-NHEJ factors 53BP1, RIF1, REV7–Shieldin (SHLD1–3) or CST–DNA polymerase alpha (Pol-α) in BRCA1-deficient cells restores HDR and PARPi resistance. Here, we identify the TRIP13 ATPase as a negative regulator of REV7. We show that REV7 exists in active ‘closed’ and inactive ‘open’ conformations, and TRIP13 catalyses the inactivating conformational change, thereby dissociating REV7–Shieldin to promote HDR. TRIP13 similarly disassembles the REV7–REV3 translesion synthesis (TLS) complex, a component of the Fanconi anaemia pathway, inhibiting error-prone replicative lesion bypass and interstrand crosslink repair. Importantly, TRIP13 overexpression is common in BRCA1-deficient cancers, confers PARPi resistance and correlates with poor prognosis. Thus, TRIP13 emerges as an important regulator of DNA repair pathway choice—promoting HDR, while suppressing NHEJ and TLS.

Clairmont et al. find that the TRIP13 ATPase regulates REV7–Shieldin dissociation to promote homology-directed repair and suppress non-homologous end joining, and show the importance of PARPi resistance in BRCA1-deficient cancers.