|Title:||AI26 inhibits the ADP-ribosylhydrolase ARH3 and suppresses DNA damage repair||Authors:||Liu, X.
|Issue Date:||2020||Journal Volume:||295||Journal Issue:||40||Start page/Pages:||13838-13849||Source:||The Journal of biological chemistry||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 mM 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. ? 2020 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
|DOI:||10.1074/jbc.RA120.012801||metadata.dc.subject.other:||Amino acids; Defects; Diagnosis; DNA; Tumors; ADP-ribosylation; Camptothecin (CPT); DNA damaging agents; Enzymatic activities; Serine residues; Small molecules; Specific inhibitors; Tumor suppression; Repair; ADP ribosylhydrolase 3; ADP ribosylhydrolase 3 inhibitor 26; camptothecin; DNA; doxorubicin; hydrolase; hydrolase inhibitor; unclassified drug; ADPRS protein, human; enzyme inhibitor; glycosidase; adenosine diphosphate ribosylation; antineoplastic activity; Article; cancer inhibition; computer model; controlled study; DNA repair; drug effect; drug screening; drug structure; enzyme activity; enzyme inhibition; human; human cell; hydrolysis; IC50; in vitro study; priority journal; tumor cell; DNA damage; DNA repair; genetics; metabolism; tumor cell line; Cell Line, Tumor; DNA Damage; DNA Repair; Enzyme Inhibitors; Glycoside Hydrolases; Humans
|Appears in Collections:||生化科學研究所|
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