期刊
NUCLEIC ACIDS RESEARCH
卷 49, 期 18, 页码 10477-10492出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab771
关键词
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资金
- Wellcome Trust [101794, 210634]
- Biotechnology and Biological Sciences Research Council [BB/R007195/1]
- Ovarian Cancer Research Alliance (Collaborative Research Development) [813369]
- Cancer Research United Kingdom [C35050/A22284]
- Swiss National Science Foundation (SNF) [310030 189206]
- Hungarian Academy of Sciences [LP201711/2017]
- National Research Development and Innovation Office [K128239]
- Swiss National Science Foundation (SNF) [310030_189206] Funding Source: Swiss National Science Foundation (SNF)
- BBSRC [BB/R007195/1] Funding Source: UKRI
ADP-ribosylation is a crucial cellular process catalyzed by ADP-ribosyltransferases and reversed by ADP-ribosylhydrolases. The study demonstrates TARG1 can reverse thymidine-linked DNA ADP-ribosylation and TARG1-deficient human cells are extremely sensitive to this modification. Additionally, it represents the first detection of reversible ADP-ribosylation on genomic DNA in vivo from human cells, providing insight into the largely unknown facet of ADP-ribosylation.
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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