期刊
CELL CHEMICAL BIOLOGY
卷 23, 期 10, 页码 1251-1260出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2016.08.012
关键词
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资金
- Biocenter Oulu
- Academy of Finland [287063, 294085, 266922, 294617, 284605]
- Sigrid Juselius Foundation
- Jane and Aatos Erkko Foundation
- German Science Foundation (DFG) [LU466/16-1]
- IZKF Aachen of the Medical School of the RWTH Aachen University [SP01-2011, O2-1-2014]
- EMBO short-term fellowship
- Academy of Finland (AKA) [284605, 294617, 284605, 294617] Funding Source: Academy of Finland (AKA)
Members of the human diphtheria toxin-likeADP-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 hydroxyureainduced 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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