Journal
MOLECULAR CELL
Volume 64, Issue 6, Pages 1109-1116Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.11.014
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Funding
- Benjamin Thomas and Svenja Hester at Sir William Dunn School of Pathology Proteomics Facility
- Wellcome Trust [101794]
- European Research Council [281739]
- Cancer Research UK [C35050/A22284]
- European Research Council (ERC) [281739] Funding Source: European Research Council (ERC)
- Cancer Research UK [22284] Funding Source: researchfish
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The discovery and study of toxin-antitoxin (TA) systems helps us advance our understanding of the strategies prokaryotes employ to regulate cellular processes related to the general stress response, such as defense against phages, growth control, biofilm formation, persistence, and programmed cell death. Here we identify and characterize a TA system found in various bacteria, including the global pathogen Mycobacterium tuberculosis. The toxin of the system (DarT) is a domain of unknown function (DUF) 4433, and the antitoxin (DarG) a macrodomain protein. We demonstrate that DarT is an enzyme that specifically modifies thymidines on single-stranded DNA in a sequence-specific manner by a nucleotide-type modification called ADP-ribosylation. We also show that this modification can be removed by DarG. Our results provide an example of reversible DNA ADP-ribosylation, and we anticipate potential therapeutic benefits by targeting this enzyme-enzyme TA system in bacterial pathogens such as M. tuberculosis.
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