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AI26 inhibits the ADP-ribosylhydrolase ARH3 and suppresses DNA damage repair
- Source :
- J Biol Chem
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
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 IC(50) 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.
- Subjects :
- 0301 basic medicine
DNA Repair
Glycoside Hydrolases
DNA repair
In silico
DNA and Chromosomes
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Cell Line, Tumor
medicine
Humans
Doxorubicin
Enzyme Inhibitors
Molecular Biology
chemistry.chemical_classification
030102 biochemistry & molecular biology
Cell Biology
In vitro
Cell biology
030104 developmental biology
Enzyme
chemistry
ADP-ribosylation
Camptothecin
DNA
DNA Damage
medicine.drug
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 295
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....51ee0b336d178055684bbd524cb2926e
- Full Text :
- https://doi.org/10.1074/jbc.ra120.012801