TARG1 protects against toxic DNA ADP-ribosylation. Issue 18 (11th September 2021)

• Record Type: Journal Article
• Authors: Tromans-Coia, Callum; Sanchi, Andrea; Moeller, Giuliana K; Timinszky, Gyula; Lopes, Massimo; Ahel, Ivan
• Is Part Of: Nucleic acids research. Volume 49:Issue 18(2021)
• Page Start: 10477
• Page End: 10492
• Publication Date: 2021-09-11
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkab771
• Languages: English
• ISSNs: 0305-1048

Abstract

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.