Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage.
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| Abstract |
Members of the human diphtheria toxin-like ADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation (MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available. Here we describe a small-molecule ARTD10 inhibitor, OUL35, a selective and potent inhibitor for this enzyme. We characterize its selectivity profile, model its binding, and demonstrate activity in HeLa cells where OUL35 rescued cells from ARTD10 induced cell death. Using OUL35 as a cell biology tool we show that ARTD10 inhibition sensitizes the cells to the hydroxyurea-induced genotoxic stress. Our study supports the proposed role of ARTD10 in DNA-damage repair and provides a tool compound for selective inhibition of ARTD10-mediated MARylation.
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| Authors | Harikanth Venkannagari, Patricia Verheugd, Jarkko Koivunen, Teemu Haikarainen, Ezeogo Obaji, Yashwanth Ashok, Mohit Narwal, Taina Pihlajaniemi, Bernhard Lüscher, Lari Lehtiö |
| Journal | Cell chemical biology (Cell Chem Biol) Vol. 23 Issue 10 Pg. 1251-1260 (Oct 20 2016) ISSN: 2451-9448 [Electronic] United States |
| PMID | 27667561 (Publication Type: Journal Article) |
| Copyright | Copyright © 2016 Elsevier Ltd. All rights reserved. |
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