Abstract
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 used in silico and 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 IC50 of ∼2.41 μm in 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.
Highlights
Genomic DNA can be damaged by numerous internal and external hazards
Based on the structure of the complex and small molecule compound library of the National Cancer Institute (NCI), we designed a strategy that combines both virtual screening and biochemical screening to search for specific small molecules targeting ARH3 (Fig. 1A)
Using an in silico approach, we first screened more than 260,000 compounds from NCI small molecule database and modeled the compounds that could be inserted into the catalytic pocket of ARH3 and suppress its activity (Fig. 1B)
Summary
Genomic DNA can be damaged by numerous internal and external hazards. during evolution, cells have developed sophisticated systems to sense and repair DNA lesions. It is likely that transient ADP-ribosylation mediates the recruitment of DNA damage repair factors Those ADPR-binding DNA repair factors may be trapped by any prolonged ADP-ribosylation [7, 23]. Similar to PARP inhibitor, emerging evidence suggests that targeting dePARylation has similar effects on the suppression of DNA damage repair, as well as tumor cell growth [23, 24].
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