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dc.contributor.authorSchuller, Marion
dc.contributor.authorButler, Rachel
dc.contributor.authorAriza, Antonio
dc.contributor.authorTromans-Coia, Callum
dc.contributor.authorJankevicius, Gytis
dc.contributor.authorClaridge, Tim
dc.contributor.authorKendall, Sharon
dc.contributor.authorGoh, Shan
dc.contributor.authorStewart, Graham
dc.contributor.authorAhel, Ivan
dc.date.accessioned2021-08-24T13:45:00Z
dc.date.available2021-08-24T13:45:00Z
dc.date.issued2021-08-18
dc.identifier.citationSchuller , M , Butler , R , Ariza , A , Tromans-Coia , C , Jankevicius , G , Claridge , T , Kendall , S , Goh , S , Stewart , G & Ahel , I 2021 , ' Molecular basis for DarT ADP-ribosylation of a DNA base ' , Nature . https://doi.org/10.1038/s41586-021-03825-4
dc.identifier.issn0028-0836
dc.identifier.otherPURE: 25810809
dc.identifier.otherPURE UUID: ecbcfa30-8df4-4c99-bcf6-b02d0b76341c
dc.identifier.otherORCID: /0000-0002-9028-0303/work/99079143
dc.identifier.otherScopus: 85113217760
dc.identifier.urihttp://hdl.handle.net/2299/25013
dc.description.abstractADP-ribosyltransferases use NAD+ to catalyse substrate ADP-ribosylation1, and thereby regulate cellular pathways or contribute to toxin-mediated pathogenicity of bacteria2–4. Reversible ADP-ribosylation has traditionally been considered a protein-specific modification5, but recent in vitro studies have suggested nucleic acids as targets6–9. Here we present evidence that specific, reversible ADP-ribosylation of DNA on thymidine bases occurs in cellulo through the DarT–DarG toxin–antitoxin system, which is found in a variety of bacteria (including global pathogens such as Mycobacterium tuberculosis, enteropathogenic Escherichia coli and Pseudomonas aeruginosa)10. We report the structure of DarT, which identifies this protein as a diverged member of the PARP family. We provide a set of high-resolution structures of this enzyme in ligand-free and pre- and post-reaction states, which reveals a specialized mechanism of catalysis that includes a key active-site arginine that extends the canonical ADP-ribosyltransferase toolkit. Comparison with PARP–HPF1, a well-established DNA repair protein ADP-ribosylation complex, offers insights into how the DarT class of ADP-ribosyltransferases evolved into specific DNA-modifying enzymes. Together, our structural and mechanistic data provide details of this PARP family member and contribute to a fundamental understanding of the ADP-ribosylation of nucleic acids. We also show that thyminelinked ADP-ribose DNA adducts reversed by DarG antitoxin (functioning as a noncanonical DNA repair factor) are used not only for targeted DNA damage to induce toxicity, but also as a signalling strategy for cellular processes. Using M. tuberculosis as an exemplar, we show that DarT–DarG regulates growth by ADP-ribosylation of DNA at the origin of chromosome replication.en
dc.language.isoeng
dc.relation.ispartofNature
dc.rightsEmbargoed
dc.titleMolecular basis for DarT ADP-ribosylation of a DNA baseen
dc.contributor.institutionBiosciences Research Group
dc.contributor.institutionExtracellular Vesicle Research Unit
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionDepartment of Clinical, Pharmaceutical and Biological Science
dc.contributor.institutionCentre for Agriculture, Food and Environmental Management Research
dc.description.statusPeer reviewed
dc.date.embargoedUntil2022-02-18
dc.relation.schoolSchool of Life and Medical Sciences
dc.description.versiontypeFinal Accepted Version
dcterms.dateAccepted2021-08-18
rioxxterms.versionAM
rioxxterms.versionofrecordhttps://doi.org/10.1038/s41586-021-03825-4
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue
herts.rights.accesstypeEmbargoed


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