Molecular basis for DarT ADP-ribosylation of a DNA base

Marion Schuller, Rachel E. Butler, Antonio Ariza, Callum Tromans-Coia, Gytis Jankevicius, Tim D. W. Claridge, Sharon L. Kendall, Shan Goh, Graham R. Stewart () and Ivan Ahel ()
Additional contact information
Marion Schuller: University of Oxford
Rachel E. Butler: University of Surrey
Antonio Ariza: University of Oxford
Callum Tromans-Coia: University of Oxford
Gytis Jankevicius: University of Oxford
Tim D. W. Claridge: University of Oxford
Sharon L. Kendall: Pathology and Population Sciences, The Royal Veterinary College
Shan Goh: Pathology and Population Sciences, The Royal Veterinary College
Graham R. Stewart: University of Surrey
Ivan Ahel: University of Oxford

Nature, 2021, vol. 596, issue 7873, 597-602

Abstract: 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 thymine-linked 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-03825-4 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:596:y:2021:i:7873:d:10.1038_s41586-021-03825-4

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-03825-4

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().