Shiga toxin (Stx) from Shigella dysenteriae and the structurally and functionally related cytotoxins (Stx1, Stx2) produced by some Escherichia coli serotypes have a main role in the pathogenesis of human diseases such as bacillary dysentery, enterohemorrhagic colitis and hemolytic uremic syndrome. Ricin, from Ricinus communis seeds, is highly toxic and has been used in criminal and terrorist acts. These toxins belong to the large family of ribosome inactivating proteins (RIPs) with RNA-N-glycosidase activity which irreversibly inactivate eukaryotic ribosomes by removing a specific adenine from a highly conserved loop present in 28S rRNA. Both Stx1 and ricin, known as type 2 RIPs, consist of a single A chain containing the catalytic site and a second B chain which binds to cell surface receptors mediating endocytosis. In Stx1, the enzymatic A chain is non-covalently associated to five B chains. For almost two decades it has been largely assumed that RIPs acted only on 28S rRNA within ribosomes. However, a growing body of evidence suggests that RIPs remove adenine moieties not only from rRNA, but also from DNA – an effect leading to DNA damage in cultured cells. We herein report that two distinct RIPs of bacterial (shiga toxin 1, Stx1) and plant (ricin) origin, inhibit the repair of the DNA lesions generated by hydrogen peroxide in cultured human cells. This effect is unrelated either to inhibition of protein synthesis or to depletion of cellular antioxidant defenses and is likely to derive from direct interactions with cellular DNA repair machinery. Therefore, the genotoxicity of these toxins on mammalian cells seems to be a complex phenomenon resulting from the balance between direct (DNA damaging activity), indirect (DNA repair inhibition) effects and the eventual presence of other DNA damaging species. In particular, with regard to Stx1, it could be hypothesized that Stx-producing bacteria increase the risk of transformation of surrounding, inflamed tissues in the course of human infections.
Shiga toxin 1 and ricin inhibit the repair of H2O2-induced DNA single strand breaks in cultured mammalian cells.
SESTILI, PIERO
;MARTINELLI, CHIARA;
2005
Abstract
Shiga toxin (Stx) from Shigella dysenteriae and the structurally and functionally related cytotoxins (Stx1, Stx2) produced by some Escherichia coli serotypes have a main role in the pathogenesis of human diseases such as bacillary dysentery, enterohemorrhagic colitis and hemolytic uremic syndrome. Ricin, from Ricinus communis seeds, is highly toxic and has been used in criminal and terrorist acts. These toxins belong to the large family of ribosome inactivating proteins (RIPs) with RNA-N-glycosidase activity which irreversibly inactivate eukaryotic ribosomes by removing a specific adenine from a highly conserved loop present in 28S rRNA. Both Stx1 and ricin, known as type 2 RIPs, consist of a single A chain containing the catalytic site and a second B chain which binds to cell surface receptors mediating endocytosis. In Stx1, the enzymatic A chain is non-covalently associated to five B chains. For almost two decades it has been largely assumed that RIPs acted only on 28S rRNA within ribosomes. However, a growing body of evidence suggests that RIPs remove adenine moieties not only from rRNA, but also from DNA – an effect leading to DNA damage in cultured cells. We herein report that two distinct RIPs of bacterial (shiga toxin 1, Stx1) and plant (ricin) origin, inhibit the repair of the DNA lesions generated by hydrogen peroxide in cultured human cells. This effect is unrelated either to inhibition of protein synthesis or to depletion of cellular antioxidant defenses and is likely to derive from direct interactions with cellular DNA repair machinery. Therefore, the genotoxicity of these toxins on mammalian cells seems to be a complex phenomenon resulting from the balance between direct (DNA damaging activity), indirect (DNA repair inhibition) effects and the eventual presence of other DNA damaging species. In particular, with regard to Stx1, it could be hypothesized that Stx-producing bacteria increase the risk of transformation of surrounding, inflamed tissues in the course of human infections.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.