dc.contributor.author | Schuller, Marion | |
dc.contributor.author | Butler, Rachel | |
dc.contributor.author | Ariza, Antonio | |
dc.contributor.author | Tromans-Coia, Callum | |
dc.contributor.author | Jankevicius, Gytis | |
dc.contributor.author | Claridge, Tim | |
dc.contributor.author | Kendall, Sharon | |
dc.contributor.author | Goh, Shan | |
dc.contributor.author | Stewart, Graham | |
dc.contributor.author | Ahel, Ivan | |
dc.date.accessioned | 2021-08-24T13:45:00Z | |
dc.date.available | 2021-08-24T13:45:00Z | |
dc.date.issued | 2021-08-26 | |
dc.identifier.citation | Schuller , 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 , vol. 596 , no. 7873 , pp. 597-602 . https://doi.org/10.1038/s41586-021-03825-4 | |
dc.identifier.issn | 0028-0836 | |
dc.identifier.other | ORCID: /0000-0002-9028-0303/work/99079143 | |
dc.identifier.uri | http://hdl.handle.net/2299/25013 | |
dc.description | © 2021, The Author(s), under exclusive licence to Springer Nature Limited. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1038/s41586-021-03825-4 | |
dc.description.abstract | ADP-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.format.extent | 6 | |
dc.format.extent | 14305855 | |
dc.language.iso | eng | |
dc.relation.ispartof | Nature | |
dc.title | Molecular basis for DarT ADP-ribosylation of a DNA base | en |
dc.contributor.institution | Biosciences Research Group | |
dc.contributor.institution | Extracellular Vesicle Research Unit | |
dc.contributor.institution | School of Life and Medical Sciences | |
dc.contributor.institution | Department of Clinical, Pharmaceutical and Biological Science | |
dc.contributor.institution | Centre for Agriculture, Food and Environmental Management Research | |
dc.contributor.institution | Centre for Research in Mechanisms of Disease and Drug Discovery | |
dc.description.status | Peer reviewed | |
dc.date.embargoedUntil | 2022-02-18 | |
dc.identifier.url | http://www.scopus.com/inward/record.url?scp=85113217760&partnerID=8YFLogxK | |
rioxxterms.versionofrecord | 10.1038/s41586-021-03825-4 | |
rioxxterms.type | Journal Article/Review | |
herts.preservation.rarelyaccessed | true | |