AI26 inhibits the ADP-ribosylhydrolase ARH3 and suppresses DNA damage repair
AI26 inhibits the ADP-ribosylhydrolase ARH3 and suppresses DNA damage repair
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AI26 抑制 ADP-核糖基水解酶 ARH3 并抑制 DNA 损伤修复
DOI：
10.1074/jbc.ra120.012801
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发表时间：
2020-10-02
影响因子：
4.8
通讯作者：
Yu, Xiaochun
中科院分区：
文献类型：
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作者：
Liu, Xiuhua;Xie, Rong;Yu, Xiaochun
ADP-核糖水解酶ARH 3在DNA损伤修复、消化多聚ADP-核糖和从底物的丝氨酸残基去除ADP-核糖中起关键作用。选择性靶向ARH 3的特异性抑制剂将是检测DNA损伤修复的有用工具，也是抑制肿瘤的可能策略。然而，迄今为止的努力尚未鉴定出任何合适的化合物。在这里，我们使用计算机和生物化学筛选来寻找ARH 3抑制剂。我们发现了一种名为ARH 3抑制剂26（AI 26）的小分子化合物，据我们所知，这是第一种ARH 3抑制剂。AI 26与ARH 3的催化口袋结合并抑制ARH 3的酶活性，估计IC（50）与体外2.41 μ min相似。此外，DNA损伤诱导的ADP-核糖基化的水解被明显抑制，当细胞用AI 26预处理时，导致DNA损伤修复缺陷。此外，具有DNA损伤修复缺陷的肿瘤细胞对AI 26治疗以及AI 26和其他DNA损伤剂如喜树碱和多柔比星的组合过敏。总的来说，这些结果不仅揭示了研究ARH 3介导的DNA损伤修复的化学探针，而且还揭示了肿瘤抑制的化疗策略。
The ADP-ribosylhydrolase ARH3 plays a key role in DNA damage repair, digesting poly(ADP-ribose) and removing ADP-ribose from serine residues of the substrates. Specific inhibitors that selectively target ARH3 would be a useful tool to examine DNA damage repair, as well as a possible strategy for tumor suppression. However, efforts to date have not identified any suitable compounds. Here, we usedin silicoand biochemistry screening to search for ARH3 inhibitors. We discovered a small molecule compound named ARH3 inhibitor 26 (AI26) as, to our knowledge, the first ARH3 inhibitor. AI26 binds to the catalytic pocket of ARH3 and inhibits the enzymatic activity of ARH3 with an estimated IC(50)of similar to 2.41 mu min vitro. Moreover, hydrolysis of DNA damage-induced ADP-ribosylation was clearly inhibited when cells were pretreated with AI26, leading to defects in DNA damage repair. In addition, tumor cells with DNA damage repair defects were hypersensitive to AI26 treatment, as well as combinations of AI26 and other DNA-damaging agents such as camptothecin and doxorubicin. Collectively, these results reveal not only a chemical probe to study ARH3-mediated DNA damage repair but also a chemotherapeutic strategy for tumor suppression.