TARG1 protects against toxic DNA ADP-ribosylation |
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| Authors: | Callum Tromans-Coia Andrea Sanchi Giuliana K Moeller Gyula Timinszky Massimo Lopes Ivan Ahel |
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| Affiliation: | Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK;Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland;Department of Physiological Chemistry, Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152, Planegg-Martinsried, Germany;Lendület Laboratory of DNA Damage and Nuclear Dynamics, Institute of Genetics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), 6276 Szeged, Hungary |
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| Abstract: | ADP-ribosylation is a modification that targets a variety of macromolecules and regulates a diverse array of important cellular processes. ADP-ribosylation is catalysed by ADP-ribosyltransferases and reversed by ADP-ribosylhydrolases. Recently, an ADP-ribosyltransferase toxin termed ‘DarT’ from bacteria, which is distantly related to human PARPs, was shown to modify thymidine in single-stranded DNA in a sequence specific manner. The antitoxin of DarT is the macrodomain containing ADP-ribosylhydrolase DarG, which shares striking structural homology with the human ADP-ribosylhydrolase TARG1. Here, we show that TARG1, like DarG, can reverse thymidine-linked DNA ADP-ribosylation. We find that TARG1-deficient human cells are extremely sensitive to DNA ADP-ribosylation. Furthermore, we also demonstrate the first detection of reversible ADP-ribosylation on genomic DNA in vivo from human cells. Collectively, our results elucidate the impact of DNA ADP-ribosylation in human cells and provides a molecular toolkit for future studies into this largely unknown facet of ADP-ribosylation. |
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