The response to poly(ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identified the PAR-binding chromatin remodeller ALC1/CHD1L as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of breast cancer gene (BRCA)-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication-associated DNA damage, increased PARP trapping and a reliance on HR. These findings establish PAR-dependent chromatin remodelling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers.

对聚（ADP-核糖）聚合酶抑制剂 (PARPi) 的反应取决于同源重组 (HR) DNA 修复和捕获 PARP 酶的病变的丰度。然而，尚不清楚 PARP 在促进染色质可及性方面的既定作用是否会影响这些环境中的生存能力。使用基于 CRISPR 的筛选，我们将 PAR 结合染色质重塑因子 ALC1/CHD1L 鉴定为 HR 缺陷细胞中 PARPi 毒性的关键决定因素。ALC1 缺失降​​低了乳腺癌基因 (BRCA) 突变细胞的活力，并将对 PARPi 的敏感性提高了 250 倍，同时克服了几种耐药机制。ALC1 缺陷降低了染色质的可及性，同时减少了碱基损伤修复因子的相关性。这导致了与复制相关的 DNA 损伤的积累，增加 PARP 捕获和对 HR 的依赖。这些发现将 PAR 依赖性染色质重塑确立为 HR 缺陷癌症中 PARPi 反应和治疗靶点的一个机制上不同的方面。