University of Oulu

Venkannagari et al., Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10- Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage, Cell Chemical Biology (2016),

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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Author: Venkannagari, Harikanth1; Verheugd, Patricia2; Koivunen, Jarkko1;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu 90014, Finland
2Institute of Biochemistry and Molecular Biology, RWTH Aachen University, 52074 Aachen, Germany
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 2.2 MB)
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Language: English
Published: Elsevier, 2016
Publish Date: 2017-10-20


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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Series: Cell chemical biology
ISSN: 2451-9456
ISSN-E: 2451-9448
ISSN-L: 2451-9456
Volume: 23
Issue: 10
DOI: 10.1016/j.chembiol.2016.08.012
Type of Publication: A1 Journal article – refereed
Field of Science: 116 Chemical sciences
1182 Biochemistry, cell and molecular biology
3111 Biomedicine
3122 Cancers
317 Pharmacy
Funding: The research was funded by Biocenter Oulu, the Academy of Finland (287063 and 294085 to L.L., 266922 to T.H., and 294617 to J.K.), a Center of Excellence Grant 2012–2017 of the Academy of Finland (284605 to T.P.), the Sigrid Jusélius Foundation, the Jane and Aatos Erkko Foundation, the German Science Foundation (DFG LU466/16-1 to B.L.), and the IZKF Aachen (SP01-2011 and O2-1-2014 to B.L.) of the Medical School of the RWTH Aachen University. H.V. was supported by an EMBO short-term fellowship for his visit to the RWTH Aachen University to perform cell-based assays.
Academy of Finland Grant Number: 287063
Detailed Information: 287063 (Academy of Finland Funding decision)
294085 (Academy of Finland Funding decision)
266922 (Academy of Finland Funding decision)
294617 (Academy of Finland Funding decision)
284605 (Academy of Finland Funding decision)
Copyright information: © 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license