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), http://dx.doi.org/10.1016/j.chembiol.2016.08.01

Small-molecule chemical probe rescues cells from mono-ADP-ribosyltransferase ARTD10/PARP10-induced apoptosis and sensitizes cancer cells to DNA damage

Saved in:
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: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe201701181176
Language: English
Published: 2016
Publish Date: 2017-10-20
Description:

Highlights

- OUL35 is a potent inhibitor of ARTD10 and can be used to study its biological functions

- OUL35 rescues HeLa cells from ARTD10-induced cell death

- OUL35 sensitizes cells to DNA damage

Summary

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.
see all

Volume: 23
Issue: 10
DOI: 10.1016/j.chembiol.2016.08.012
OADOI: https://oadoi.org/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
Subjects: