Multiple species of pathogenic bacteria have been shown in recent years to damage the nuclear DNA of their host cells, often resulting in particularly hazardous DNA double strand breaks (DSBs). The carcinogenic bacterial pathogen H. pylori, which causes chronic gastritis and is the most important risk factor for the development of peptic ulcer disease and gastric cancer, also exhibits genotoxic activity. Exposure of gastric epithelial cells to H. pylori induces DNA fragmentation in a contact-dependent manner that is detectable by pulsed field gel electrophoresis (PFGE) and can be visualized by high resolution microscopy of metaphase chromosomes; the DSB repair factor p53 binding protein 1 (53BP1) and others are recruited to the sites of DSBs, and, together with the phosphorylation of histone H2A variant X (γH2AX), indicate the initiation of DSB repair by the host cell repair machinery. We have begun to investigate the mechanistic basis of H. pylori-induced DNA DSBs and to elucidate key host and bacterial factors contributing to DSB induction (summarized in Figure 1). By screening an H. pylori transposon library for mutants lacking the ability to induce host cell DNA DSBs, we have identified the cag pathogenicity island (cagPAI)-encoded T4SS as being critically involved in H. pylori-induced DNA damage. We have further found active transcription and the T4SS/b1 integrin-induced activation of nuclear factor kappa B (NF-kB) to be important prerequisites of DSB induction and have identified the nucleotide excision repair (NER) endonucleases XPF and XPG as critical enzymes introducing the strand breaks. XPF/XPG-mediated DSBs serve to amplify NF-kB target gene expression and to promote host cell survival. Ongoing projects are designed to further elucidate the mechanistic basis and functional consequences of H. pylori induced DNA DSBs for the host/H. pylori interaction and gastric carcinogenesis. See Hartung et al., Cell Reports, 2015.
Figure. The human bacterial pathogen Helicobacter pylori exhibits genotoxic properties that potentially promote gastric carcinogenesis. H. pylori introduces DNA double strand breaks (DSBs) in epithelial cells that trigger host cell DNA repair efforts. H. pylori-induced DSBs are repaired via error-prone, potentially mutagenic non-homologous end joining. The H. pylori type IV secretion system is required for DNA double strand breaks (DSBs). DSBs are introduced by the nucleotide excision repair endonucleases XPF and XPG and promote NF-kB target gene transactivation.