PARP inhibitors (PARPi) represent a game-changing treatment for patients with ovarian cancer with tumors deficient for the homologous recombination (HR) pathway treated with platinum (Pt)–based therapy. PARPi exert their cytotoxic effect by both trapping PARP1 on the damaged DNA and by restraining its enzymatic activity (PARylation). How PARP1 is recruited and trapped at the DNA damage sites and how resistance to PARPi could be overcome are still matters of investigation. Here, we described PARP1 as a substrate of the deubiquitinase USP1. At molecular level, USP1 binds PARP1 to remove its K63-linked polyubiquitination and controls PARP1 chromatin trapping and PARylation activity, regulating sensitivity to PARPi. In both Pt/PARPi-sensitive and -resistant cells, USP1/PARP1 combined blockade enhances replicative stress, DNA damage, and cell death. Our work dissected the biological interaction between USP1 and PARP1 and recommended this axis as a promising and powerful therapeutic choice for not only sensitive but also chemoresistant patients with ovarian cancer irrespective of their HR status.

中文翻译：

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USP1 使 PARP1 去泛素化以调节其捕获和 PARylation 活性


PARP 抑制剂 （PARPi） 代表了一种改变游戏规则的治疗方法，适用于肿瘤缺乏同源重组 （HR） 通路的卵巢癌患者，并接受铂类 （Pt） 治疗。PARPi 通过将 PARP1 捕获在受损的 DNA 上并抑制其酶活性 （PARylation） 来发挥其细胞毒作用。PARP1 如何被募集并捕获在 DNA 损伤位点，以及如何克服对 PARPi 的耐药性仍然是研究的问题。在这里，我们将 PARP1 描述为去泛素酶 USP1 的底物。在分子水平上，USP1 结合 PARP1 以去除其 K63 连接的多泛素化，并控制 PARP1 染色质捕获和 PARylation 活性，调节对 PARPi 的敏感性。在 Pt/PARPi 敏感和耐药细胞中，USP1/PARP1 联合阻断可增强复制应激、DNA 损伤和细胞死亡。我们的工作剖析了 USP1 和 PARP1 之间的生物相互作用，并推荐该轴作为一种有前途且强大的治疗选择，不仅适用于敏感且化疗耐药的卵巢癌患者，无论其 HR 状态如何。