Targeting dePARylation selectively suppresses DNA repair-defective and PARP inhibitor-resistant malignancies
Targeting dePARylation selectively suppresses DNA repair-defective and PARP inhibitor-resistant malignancies
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DOI：
10.1126/sciadv.aav4340
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发表时间：
2019-04-01
期刊：
影响因子：
13.6
通讯作者：
Yu, Xiaochun
中科院分区：
文献类型：
--
作者：
Chen, Shih-Hsun;Yu, Xiaochun
虽然聚（ADP-核糖基）化（PAR化）在DNA修复中起重要作用，但去PAR化在DNA修复中的作用仍然是难以捉摸的。在这里，我们报告说，一种新的小分子从NCI数据库，COH 34，特异性抑制聚（ADP-核糖）糖水解酶（PARG），主要的去PAR化酶，在体外和体内的纳摩尔效力。COH 34与PARG的催化结构域结合，从而延长DNA损伤处的PAR化并捕获DNA修复因子。该化合物在具有DNA修复缺陷的癌细胞中诱导致死性，并在异种移植小鼠癌症模型中表现出抗肿瘤活性。此外，COH 34可以使具有DNA修复缺陷的肿瘤细胞对其他DNA损伤剂敏感，例如广泛用于癌症化疗的拓扑异构酶I抑制剂和DNA烷基化剂。值得注意的是，COH 34还有效地杀死PARP抑制剂耐药癌细胞。总之，我们的研究揭示了PARG在DNA修复中的分子机制，并为未来的癌症治疗提供了有效的策略。
While poly(ADP-ribosyl)ation (PARylation) plays an important role in DNA repair, the role of dePARylation in DNA repair remains elusive. Here, we report that a novel small molecule identified from the NCI database, COH34, specifically inhibits poly(ADP-ribose) glycohydrolase (PARG), the major dePARylation enzyme, with nanomolar potency in vitro and in vivo. COH34 binds to the catalytic domain of PARG, thereby prolonging PARylation at DNA lesions and trapping DNA repair factors. This compound induces lethality in cancer cells with DNA repair defects and exhibits antitumor activity in xenograft mouse cancer models. Moreover, COH34 can sensitize tumor cells with DNA repair defects to other DNA-damaging agents, such as topoisomerase I inhibitors and DNA-alkylating agents, which are widely used in cancer chemotherapy. Notably, COH34 also efficiently kills PARP inhibitor-resistant cancer cells. Together, our study reveals the molecular mechanism of PARG in DNA repair and provides an effective strategy for future cancer therapies.