A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems

Zhang, Dapeng; Iyer, Lakshminarayan M.; Aravind, L.

The use of toxins as a defensive, offensive or selfish addictive strategy is observed across the tree of life. Interestingly, a diverse set of protein toxins from distantly related organisms have a propensity to catalyze nucleic acid modifying or cleaving reactions in their target cells. Well-known examples are currently known from across the phylogenetic spectrum: plants deploy toxins such as ricin, abrin and modeccin to protect their seeds, which are RNA N-glycosidases that remove a specific purine *To whom correspondence should be addressed. Tel: [phone]; Fax: [phone]; Email: [e-mail] base from eukaryotic 28S rRNA to render it non-functional (1, 2) . In a similar vein, the fungal toxin a-sarcin, produced by fungi such as Aspergillus giganteus, acts as a specific endonuclease that cleaves the 28S rRNA at a position close to the site of action of the above plant toxins (3) . Among animals the use of nucleic acid-targeting enzymes is observed in the venoms of snakes (4) . Several animals, including vertebrates, are known to deploy cytotoxic RNases, such as RNase A, which potentially target RNA from bacteria and viruses (5) . Bacteria are a particularly rich source of nucleic acid-targeting toxins, which are deployed in various contexts. Pathogenic bacteria secrete RNA N-glycosidases that target the 28S rRNA of eukaryotic hosts similar to the ricin-like plant toxins (6) . Bacteria are also known to deploy RNase and DNase bacteriocins in intra-and possibly inter-specific competition that target molecules such as tRNA and genomic DNA (7) . The best known are the plasmid-borne toxins of the model bacterium Escherichia coli, which kill closely related competing strains. Of these colicins E3, E4 and E6 cleave rRNA, colicins E5 and D cleave tRNA and colicins E2, E7, E8 and E9 cleave DNA (8) . Additionally, bacterial genomes are also colonized by systems such as the toxin-antitoxin systems and restriction-modification systems which produce enzymes that function as nucleic acid-targeting toxins (9) (10) (11) (12) . In these systems the primary function of the toxin is to kill the host bacterial cell if the toxin encoding system is genetically disrupted in some way (10, 11) . Thus, they act as selfish elements that forcibly 'addict' the host to maintain them in genomes or plasmids. In many of these cases, organisms or genetic elements that produce the toxin also produce an antitoxin or immunity protein that renders the 'self' resistant to the action of the toxin. The study of these toxins and antitoxins or immunity proteins has not only expanded our understanding of the evolution of inter-species competition but also thrown considerable light on the biochemistry of nucleic acids and other molecules that interact with them (9) (10) (11) (12) . In practical terms these nucleic acid-targeting toxins and antitoxins/immunity proteins are potential reagents that could be utilized in numerous biotechnological contexts ranging from chemical analysis of nucleic acids to bio-defense.