The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA

Jankevicius, Gytis; Ariza, Antonio; Ahel, Marijan; Ahel, Ivan

doi:10.1016/j.molcel.2016.11.014

Cited by 161 publications

(288 citation statements)

References 26 publications

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“…Substrates modified by secreted antibacterial ARTs may encompass arginine or other residues on a variety of proteins, or they may potentially extend to nucleic acid or small molecule targets (Aravind et al, 2015). Precedence for the antibacterial activity of DNA-targeting ARTs was recently established through the characterization of a toxin/antitoxin (TA) module found in Mycobacterium tuberculosis (Jankevicius et al, 2016). Additional physiologically relevant targets of Tre1 may also exist.…”

Section: Discussionmentioning

confidence: 99%

“…We find that genes encoding ARH domain proteins with NTEs are more common in bacterial genomes than corresponding E–I pairs, suggesting that the fitness benefit of the ARH domain is significant even when cognate toxins are lost. Interestingly, the antitoxin responsible for conferring protection from the recently described DNA-targeting ART toxin of M. tuberculosis , DarG, also exhibits both ARH and cognate toxin-binding activities (Jankevicius et al, 2016). While the contribution of the interaction between DarT and DarG towards the antitoxin function of DarG remains to be determined, the similarities with the E–I pair interaction described here suggest the potential of parallel evolution.…”

Section: Discussionmentioning

confidence: 99%

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Bifunctional Immunity Proteins Protect Bacteria against FtsZ-Targeting ADP-Ribosylating Toxins

Ting

Bosch

Mangiameli

et al. 2018

Cell

115

110

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Summary ADP-ribosylation of proteins can profoundly impact their function and serves as an effective mechanism by which bacterial toxins impair eukaryotic cell processes. Here we report the discovery that bacteria also employ ADP-ribosylating toxins against each other during interspecies competition. We demonstrate that one such toxin from Serratia proteamaculans interrupts the division of competing cells by modifying the essential bacterial tubulin-like protein, FtsZ, adjacent to its protomer interface, blocking its capacity to polymerize. The structure of the toxin in complex with its immunity determinant revealed two distinct modes of inhibition: active site occlusion and enzymatic removal of ADP-ribose modifications. We show that each is sufficient to support toxin immunity; however, the latter additionally provides unprecedented broad protection against non-cognate ADP-ribosylating effectors. Our findings reveal how an interbacterial arms race has produced a unique solution for safeguarding the integrity of bacterial cell division machinery against inactivating post-translational modifications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bifunctional Immunity Proteins Protect Bacteria against FtsZ-Targeting ADP-Ribosylating Toxins

Ting

Bosch

Mangiameli

et al. 2018

Cell

115

110

View full text Add to dashboard Cite

show abstract

“…). Interestingly, ADP‐ribosylation can happen not only on proteins but also on other macromolecules such as DNA, or small chemical groups (Fig. ).…”

Section: Introductionmentioning

confidence: 99%

ADP‐ribosylation: new facets of an ancient modification

2017

Self Cite

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Rapid response to environmental changes is achieved by uni‐ and multicellular organisms through a series of molecular events, often involving modification of macromolecules, including proteins, nucleic acids and lipids. Amongst these, ADP‐ribosylation is of emerging interest because of its ability to modify different macromolecules in the cells, and its association with many key biological processes, such as DNA‐damage repair, DNA replication, transcription, cell division, signal transduction, stress and infection responses, microbial pathogenicity and aging. In this review, we provide an update on novel pathways and mechanisms regulated by ADP‐ribosylation in organisms coming from all kingdoms of life.

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“…Other types of DNA-targeting ARTs have also been identified recently. DarT is found as the ADP-ribosyltransferase of thymidines in single-stranded DNA (18). Eukaryotic enzyme poly-ADP-ribose polymerases (PARPs) can mono-ADP-ribosylate double-stranded DNA ends, which can be reversed by several known ADP-ribosylhydrolases (19)(20)(21).…”

Section: Adp-ribosylationmentioning

confidence: 99%

Substrate N2 atom recognition mechanism in pierisin family DNA-targeting, guanine-specific ADP-ribosyltransferase ScARP

Yoshida

Tsuge

2018

Journal of Biological Chemistry

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ScARP from the bacterium Streptomyces coelicolor belongs to the pierisin family of DNA-targeting ADP-ribosyltransferases (ARTs). These enzymes ADP-ribosylate the N 2 amino groups of guanine residues in DNA to yield N 2 -(ADP-ribos-1-yl)-2'-deoxyguanosine. Although the structures of pierisin-1 and Scabin were revealed recently, the substrate recognition mechanisms remain poorly understood because of the lack of a substrate-binding structure. Here, we report the apo structure of ScARP and of ScARP bound to NADH and its GDP substrate at 1.50 and 1.57 Å resolutions, respectively. The bound structure revealed that the guanine of GDP is trapped between N-ribose of NADH and Trp159. Interestingly, N 2 and N 3 of guanine formed hydrogen bonds with the OE1 and NE2 atoms of Gln162, respectively. We directly observed that the ADP-ribosylating toxin turn-turn (ARTT)-loop including Trp159 and Gln162 plays a key role in the specificity of DNA-targeting guanine-specific ART as well as protein-targeting ARTs such as C3 exoenzyme. We propose that the ARTT-loop recognition is a common substrate recognition mechanism in the pierisin family. Furthermore, this complex structure sheds light on similarities and differences among two subclasses that are distinguished by conserved structural motifs: H-Y-E in the ARTD subfamily and R-S-E in the ARTC subfamily. The spatial arrangements of the electrophile and nucleophile were the same, providing the first evidence for a common reaction mechanism in these ARTs. ARTC (including ScARP) uses the ARTT-loop for substrate recognition, whereas ARTD (represented by Arr) uses the C-terminal helix instead of the ARTT-loop. These observations could help inform efforts to improve ART inhibitors. ADP-ribosylationis an important post-translational modification observed in all living organisms. Many bacterial mono-ADP-ribosyltransferases (ARTs) are known to attach the ADP-ribosyl moiety to specific target proteins and residues (1,2). The cholera toxin ADP-ribosylates arginine residues in G proteins (3), whereas the pertussis toxin ADP-ribosylates a cysteine residue (4). Diphtheria toxin and Pseudomonas aeruginosa exotoxin ADP-ribosylate diphthamide, a modified histidine in elongation factor 2 (5,6). Furthermore, Clostridium botulinum C3 exoenzyme ADP-ribosylates Asn41 of RhoA (7,8) and Clostridium perfringens Iota toxin A subunit (Ia) ADP-ribosylates Arg177 of actin (9,10 ARTs fall into two major subclasses that are distinguished by conserved structural motifs: H-Y-E in the ARTD subfamily (related to Diphtheria toxin) and R-S-E in the ARTC subfamily (related to cholera toxin and clostridial toxins (C3 and Ia)). Traditionally, ADP-ribosylation has been considered a protein modification. However, emerging evidence suggests that DNA ADP-ribosylation is also common. The first DNA-targeting ART was found in pierid butterflies and was thus named pierisin (11,12). Pierisin ADP-ribosylates calf thymus DNA containing dG-dC and N 2 amino group of the guanine residue in DNA to yield N 2 -(ADP-ribos-1-yl)...

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The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA

Cited by 161 publications

References 26 publications

Bifunctional Immunity Proteins Protect Bacteria against FtsZ-Targeting ADP-Ribosylating Toxins

Bifunctional Immunity Proteins Protect Bacteria against FtsZ-Targeting ADP-Ribosylating Toxins

ADP‐ribosylation: new facets of an ancient modification

Substrate N2 atom recognition mechanism in pierisin family DNA-targeting, guanine-specific ADP-ribosyltransferase ScARP

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