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Molecular basis for DarT ADP-ribosylation of a DNA base
- Source :
- Nature. August 26, 2021, Vol. 596 Issue 7873, p597, 6 p.
- Publication Year :
- 2021
-
Abstract
- ADP-ribosyltransferases use NAD.sup.+ to catalyse substrate ADP-ribosylation.sup.1, and thereby regulate cellular pathways or contribute to toxin-mediated pathogenicity of bacteria.sup.2-4. Reversible ADP-ribosylation has traditionally been considered a protein-specific modification.sup.5, but recent in vitro studies have suggested nucleic acids as targets.sup.6-9. 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).sup.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. Structural and mechanistic data of the ADP-ribosyltransferase DarT demonstrate the role of ADP-ribosylation of DNA by this enzyme in generating toxicity and regulating cellular signalling processes in bacteria.<br />Author(s): Marion Schuller [sup.1] , Rachel E. Butler [sup.2] , Antonio Ariza [sup.1] , Callum Tromans-Coia [sup.1] , Gytis Jankevicius [sup.1] [sup.3] , Tim D. W. Claridge [sup.4] , Sharon [...]
Details
- Language :
- English
- ISSN :
- 00280836
- Volume :
- 596
- Issue :
- 7873
- Database :
- Gale General OneFile
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.673290464
- Full Text :
- https://doi.org/10.1038/s41586-021-03825-4