Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target.

聚（ADP-核糖）（PAR）聚合酶（PARPi）抑制剂已进入临床，用于治疗同源重组（HR）缺陷型癌症。尽管这种方法取得了成功，但 PARPi 的临床前和临床研究揭示了多种耐药机制，突出了识别新型功能性生物标志物和联合治疗策略的必要性。在通过丢失 53BP1 获得对 PARPi 抗性的细胞和类器官中进行的功能性遗传筛选确定 LIG3 的丢失是 BRCA1 缺陷细胞中 PARPi 毒性的增强剂。LIG3 耗尽对 PARPi 毒性的增强依赖于 BRCA1 缺乏，但与 53BP1 通路的丧失无关。机械地，我们表明，LIG3 缺失促进了暴露于 PARPi 的 BRCA1 缺陷和 BRCA1/53BP1 双缺陷细胞中 MRE11 介导的复制后 ssDNA 间隙的形成，导致染色体异常的积累。LIG3 耗竭还增强了 PARPi 对小鼠 BRCA1 缺陷型乳腺肿瘤的疗效，表明 LIG3 是一种潜在的治疗靶点。