BRCA1 is critical for DNA double-strand break (DSB) repair by homologous recombination (HR). BRCA1 deficient mice are embryonic lethal. Previous studies have shown that 53BP1 knockout (KO) rescues embryonic lethality of BRCA1 hypomorphic mutant mice by restoring HR. Here, we show that 53BP1 KO can partially rescue embryonic lethality of BRCA1 total KO mice, but HR is not restored in BRCA1-53BP1 double knockout (DKO) mice. As a result, BRCA1-53BP1 DKO cells are extremely sensitive to PARP inhibitors (PARPi). In addition to HR deficiency, BRCA1-53BP1 DKO cells have elevated microhomology-mediated end joining (MMEJ) activity and G2/M cell cycle checkpoint defects, causing severe genomic instability in these cells. Interestingly, BRCA1-53BP1 DKO mice rapidly develop thymic lymphoma that is 100% penetrant, which is not observed in any BRCA1 mutant mice rescued by 53BP1 KO. Taken together, our study reveals that 53BP1 KO can partially rescue embryonic lethality caused by complete BRCA1 loss without rescuing HR-related defects. This finding suggests that loss of 53BP1 can support the development of cancers with silenced BRCA1 expression without causing PARPi resistance.

BRCA1 对于通过同源重组 (HR) 进行的 DNA 双链断裂 (DSB) 修复至关重要。BRCA1 缺陷小鼠胚胎致死。先前的研究表明，53BP1 敲除 (KO) 通过恢复 HR 来挽救 BRCA1 亚形突变小鼠的胚胎致死率。在这里，我们表明 53BP1 KO 可以部分挽救 BRCA1 总 KO 小鼠的胚胎致死率，但 BRCA1-53BP1 双敲除 (DKO) 小鼠的 HR 没有恢复。因此，BRCA1-53BP1 DKO 细胞对 PARP 抑制剂 (PARPi) 极为敏感。除了 HR 缺陷外，BRCA1-53BP1 DKO 细胞还具有微同源介导的末端连接 (MMEJ) 活性和 G2/M 细胞周期检查点缺陷，导致这些细胞的基因组严重不稳定。有趣的是，BRCA1-53BP1 DKO 小鼠迅速发展为 100% 渗透性的胸腺淋巴瘤，这在任何被 53BP1 KO 拯救的 BRCA1 突变小鼠中都没有观察到。总之，我们的研究表明，53BP1 KO 可以部分挽救由完全 BRCA1 丢失引起的胚胎致死率，而不会挽救 HR 相关的缺陷。这一发现表明，53BP1 的缺失可以支持 BRCA1 表达沉默的癌症的发展，而不会引起 PARPi 抗性。