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• W2565643732 abstract "In this issue of Molecular Cell, Jankevicius et al., 2016Jankevicius G. Ariza A. Ahel M. Ahel I. Mol. Cell. 2016; 64 (this issue): 1109-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar characterize the DarTG toxin-antitoxin module in which the DarT toxin ADP-ribosylates single-stranded DNA and the DarG antitoxin counteracts DarT by direct binding and by enzymatic removal of the ADP-ribosylation. In this issue of Molecular Cell, Jankevicius et al., 2016Jankevicius G. Ariza A. Ahel M. Ahel I. Mol. Cell. 2016; 64 (this issue): 1109-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar characterize the DarTG toxin-antitoxin module in which the DarT toxin ADP-ribosylates single-stranded DNA and the DarG antitoxin counteracts DarT by direct binding and by enzymatic removal of the ADP-ribosylation. ADP-ribosylation denotes the transfer of an ADP-ribose moiety from NAD+ onto macromolecules, and many biologists are familiar with the classical textbook examples of bacterial exotoxins, e.g., cholera toxin, diphtheria toxin, or pertussis toxin, that ADP-ribosylate host factors to promote bacterial infection (Simon et al., 2014Simon N.C. Aktories K. Barbieri J.T. Nat. Rev. Microbiol. 2014; 12: 599-611Crossref PubMed Scopus (147) Google Scholar). These exotoxins are used abundantly as tools to study signaling or trafficking in eukaryotic cells and, like the far majority of ADP-ribosylating proteins, belong to the large PARP/ARTD (poly ADP-ribose polymerase/diphteria toxin-like ADP-ribosyltransferase) domain family (Aravind et al., 2015Aravind L. Zhang D. de Souza R.F. Anand S. Iyer L.M. Curr. Top. Microbiol. Immunol. 2015; 384: 3-32PubMed Google Scholar, Simon et al., 2014Simon N.C. Aktories K. Barbieri J.T. Nat. Rev. Microbiol. 2014; 12: 599-611Crossref PubMed Scopus (147) Google Scholar). Apart from host-targeted exotoxins, previous research has primarily focused on the endogenous PARP/ARTD proteins of humans and other eukaryotes that play important roles in cellular stress responses, DNA repair/cancer, and antiviral defenses (Kuny and Sullivan, 2016Kuny C.V. Sullivan C.S. PLoS Pathog. 2016; 12: e1005453Crossref PubMed Scopus (31) Google Scholar, Sharifi et al., 2013Sharifi R. Morra R. Appel C.D. Tallis M. Chioza B. Jankevicius G. Simpson M.A. Matic I. Ozkan E. Golia B. et al.EMBO J. 2013; 32: 1225-1237Crossref PubMed Scopus (217) Google Scholar). However, it is believed that this domain family had originally emerged in bacteria and that different PARP/ARTD proteins were subsequently acquired by eukaryotic lineages through horizontal gene transfer (Aravind et al., 2015Aravind L. Zhang D. de Souza R.F. Anand S. Iyer L.M. Curr. Top. Microbiol. Immunol. 2015; 384: 3-32PubMed Google Scholar). Compared to their relatives with activities in eukaryotic cells, the genuine bacterial PARP/ARTD proteins have been sparsely studied and their evolutionary history and functional diversity have remained elusive. In this issue of Molecular Cell, Jankevicius et al., 2016Jankevicius G. Ariza A. Ahel M. Ahel I. Mol. Cell. 2016; 64 (this issue): 1109-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar now characterize one of these proteins, DarT, and show that it ADP-ribosylates single-stranded DNA to cause bacterial growth inhibition as the toxin of the DarTG toxin-antitoxin (TA) module (Figure 1). Similar to the well-known examples of host-targeted exotoxins, the diversity of molecular functions employed by bacterial TA modules has made their exploration a valuable source of versatile tools for molecular biology and biotechnology (Unterholzner et al., 2013Unterholzner S.J. Poppenberger B. Rozhon W. Mob. Genet. Elements. 2013; 3: e26219Crossref PubMed Google Scholar). These small genetic elements are composed of a toxin protein that inhibits bacterial growth through interference with basic cellular processes and an antitoxin that blocks or counteracts the activity of the toxin. In their current study, Jankevicius et al., 2016Jankevicius G. Ariza A. Ahel M. Ahel I. Mol. Cell. 2016; 64 (this issue): 1109-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar show that the bacterial bona fide PARP/ARTD protein DarT is a toxin that specifically ADP-ribosylates the second thymidine of a TNTC motif in single-stranded DNA. DarT is controlled by its antitoxin DarG that can strip off the ADP-ribosylation from experimentally modified DNA in test tubes and consequently abolish the growth arrest caused by DarT in bacterial cells. In its N-terminal part, DarG contains a so-called macrodomain that is well known as a module interacting with—and frequently removing—ADP-ribosylation (Rack et al., 2016Rack J.G. Perina D. Ahel I. Annu. Rev. Biochem. 2016; 85: 431-454Crossref PubMed Scopus (136) Google Scholar), while the C-terminal region of the antitoxin does not display any known protein domains. As expected, expression of the DarG macrodomain alone was sufficient to reverse DarT-mediated DNA ADP-ribosylation and could restore the growth of bacteria that had previously been stalled by DarT. Consistently, catalytically inactive DarG was barely able to counteract DarT expression in vivo but, surprisingly, still caused significant inhibition of the DarT ADP-ribosylation activity in vitro. This effect depended on the C-terminal region of DarG, suggesting that the two parts of the antitoxin represent two separate layers of DarT regulation. The authors therefore hypothesized that, beyond enzymatic reversal, DarG may additionally inhibit DarT through direct protein-protein interactions, and they could indeed demonstrate that the two proteins form a complex. Such a direct inhibition of toxin activities is widely prevalent as the defining feature of type II TA module antitoxins, though the antitoxin-mediated regeneration of the toxin’s target would also suggest classification as a type IV TA module (Unterholzner et al., 2013Unterholzner S.J. Poppenberger B. Rozhon W. Mob. Genet. Elements. 2013; 3: e26219Crossref PubMed Google Scholar). DarTG can therefore be seen as a type II/IV TA module hybrid, a setup that may have evolved because the reversal of DNA ADP-ribosylation is likely critical to ensure the reversibility of DarT-mediated growth arrest. Open questions remain regarding the precise chain of events that underlie the growth inhibition caused by DarT as well as regarding the biological function(s) of the DarTG TA module. Jankevicius et al., 2016Jankevicius G. Ariza A. Ahel M. Ahel I. Mol. Cell. 2016; 64 (this issue): 1109-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar show that the expression of DarT inhibits chromosome replication, likely because the toxin modifies unprotected single-stranded DNA at replication forks and other sites of genome functioning. However, it will be interesting to see if other processes, e.g., transcription, are also affected and whether the SOS response, a set of DNA repair systems that is induced by DarT, can alleviate the effects of DNA ADP-ribosylation. While the molecular mechanism of DarT is unprecedented for TA modules, it is reminiscent of the pierisin family of exotoxins that kill eukaryotic cells by excessively ADP-ribosylating guanines in both single-stranded and double-stranded DNA (Nakano et al., 2015Nakano T. Takahashi-Nakaguchi A. Yamamoto M. Watanabe M. Curr. Top. Microbiol. Immunol. 2015; 384: 127-149PubMed Google Scholar). However, unlike these lethal toxins, DarT is bacteriostatic and appears to be carefully controlled by two layers of DarG-mediated regulation. It is therefore difficult to imagine that the evolved biological function(s) of the DarTG TA module could involve toxin-mediated cell killing as it is known for TA modules acting in plasmid addiction or altruistic suicide for phage defense (Unterholzner et al., 2013Unterholzner S.J. Poppenberger B. Rozhon W. Mob. Genet. Elements. 2013; 3: e26219Crossref PubMed Google Scholar). Instead, Jankevicius et al., 2016Jankevicius G. Ariza A. Ahel M. Ahel I. Mol. Cell. 2016; 64 (this issue): 1109-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar speculate that DarTG may rather ramp down bacterial physiology to increase stress tolerance or induce bacterial persistence, a dormant state that is notorious for conferring antibiotic tolerance in clinical settings (Gerdes and Maisonneuve, 2012Gerdes K. Maisonneuve E. Annu. Rev. Microbiol. 2012; 66: 103-123Crossref PubMed Scopus (289) Google Scholar). A potential role of DarTG in bacterial persistence would expand our view on the physiological basis of this phenomenon, since so far only TA modules with toxins that target protein translation or the proton-motive force have been shown to be involved (Gerdes and Maisonneuve, 2015Gerdes K. Maisonneuve E. Mol. Cell. 2015; 59: 1-3Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Beyond these biological roles that have been classically associated with TA modules, another fascinating hypothesis proposed by Jankevicius et al., 2016Jankevicius G. Ariza A. Ahel M. Ahel I. Mol. Cell. 2016; 64 (this issue): 1109-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar is that DarTG may somehow act in conjunction with restriction-modification (R-M) systems. They convincingly argue that DarTG homologs are frequently encoded together with these bacterial immunity systems and that they share the direct modification of cellular DNA as their molecular function. It will therefore be interesting to see whether future studies can corroborate a link between DarTG and R-M systems as a truly new aspect of TA module functioning. As a final note, the way DarTG uses ADP-ribosylation to control bacterial physiology is strikingly reminiscent of how ADP-ribosylation is regulated even in humans. Jankevicius et al., 2016Jankevicius G. Ariza A. Ahel M. Ahel I. Mol. Cell. 2016; 64 (this issue): 1109-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar present the crystal structure of the DarG macrodomain and show that it is very similar to the macrodomain of human TARG1. Like DarG, this protein controls PARP/ARTD enzymes by hydrolyzing ADP-ribosylation from their targets, and the abrogation of this control through mutations in TARG1 appears to cause neurodegenerative disease (Sharifi et al., 2013Sharifi R. Morra R. Appel C.D. Tallis M. Chioza B. Jankevicius G. Simpson M.A. Matic I. Ozkan E. Golia B. et al.EMBO J. 2013; 32: 1225-1237Crossref PubMed Scopus (217) Google Scholar). The study by Jankevicius et al., 2016Jankevicius G. Ariza A. Ahel M. Ahel I. Mol. Cell. 2016; 64 (this issue): 1109-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar therefore reveals how processes in cells from bacteria to humans are controlled by essentially the same interplay between PARP/ARTD enzymes and their macrodomain counterparts. The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNAJankevicius et al.Molecular CellDecember 8, 2016In BriefToxin-antitoxin systems are important regulators of bacterial survival. Jankevicius et al. present a structural and biochemical analysis of DarTG and identify its role in reversible ADP-ribosylation of DNA. Their findings may lead to new developments in biotechnology and therapeutic opportunities in the fight against bacterial infections. Full-Text PDF Open Access" @default.
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• W2565643732 title "Back to the Roots: Deep View into the Evolutionary History of ADP-Ribosylation Opened by the DNA-Targeting Toxin-Antitoxin Module DarTG" @default.
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