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.

DNA 双链断裂 (DSB) 通过同源定向修复 (HDR) 或非同源末端连接 (NHEJ) 进行修复。BRCA1/2缺陷的癌细胞无法进行 HDR，从而对聚（ADP-核糖）聚合酶抑制剂 (PARPi) 敏感。然而，在BRCA1缺陷细胞中同时丢失 pro-NHEJ 因子 53BP1、RIF1、REV7–Shieldin (SHLD1–3) 或 CST–DNA 聚合酶 α (Pol-α)可恢复 HDR 和 PARPi 抵抗。在这里，我们将 TRIP13 ATPase 确定为 REV7 的负调节因子。我们表明，REV7 以活性“闭合”构象和非活性“开放”构象存在，TRIP13 催化失活构象变化，从而解离 REV7-Shieldin 以促进 HDR。TRIP13 类似地分解 REV7-REV3 跨损伤合成 (TLS) 复合体（范可尼贫血途径的一个组成部分），抑制容易出错的复制损伤旁路和链间交联修复。重要的是，TRIP13 过度表达在BRCA1缺陷型癌症中很常见，导致 PARPi 耐药并与不良预后相关。因此，TRIP13 成为 DNA 修复途径选择的重要调节因子——促进 HDR，同时抑制 NHEJ 和 TLS。