title: The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA.
abstract: 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.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE Oxford, UK.
authors.forename: Gytis
authors.initials: G
authors.lastname: Jankevicius
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE Oxford, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ariza
authors.affiliation: Division for Marine and Environmental Research, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia.
authors.forename: Marijan
authors.initials: M
authors.lastname: Ahel
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE Oxford, UK. Electronic address: ivan.ahel@path.ox.ac.uk.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ahel
mesh_terms: D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism; D020816:Amino Acid Motifs; D000992:Antitoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D013936:Thymidine / Q000378:metabolism
chemical_list: D000992:Antitoxins; D001427:Bacterial Toxins; D004277:DNA, Single-Stranded; D011994:Recombinant Proteins; D000244:Adenosine Diphosphate; D036002:ADP Ribose Transferases; D013936:Thymidine
keywords: ADP-ribosylation; DNA damage; DUF; DarTG; NAD; PARP; antitoxin; macrodomain; persistence; toxin