Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 36; pp. 14944 - 14949
• Main Authors: Toller, Isabella M, Neelsen, Kai J, Steger, Martin, Hartung, Mara L, Hottiger, Michael O, Stucki, Manuel, Kalali, Behnam, Gerhard, Markus, Sartori, Alessandro A, Lopes, Massimo, Müller, Anne
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06.09.2011; National Acad Sciences
• Series: From the Cover
• Subjects: Adhesins; Animals; Antigens, Bacterial - genetics; Antigens, Bacterial - metabolism; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins; Bacteria; Bacterial Adhesion; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biological Sciences; blood; Blood groups; Carcinogenesis; carcinogenicity; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell lines; Cell nucleus; Cells; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Chromosome Aberrations; Chromosomes; Cultured cells; Cytotoxins; direct contact; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - microbiology; Epithelial Cells - pathology; gamma -Glutamyltransferase; Gastric cancer; Gastric mucosa; Gel electrophoresis; genes; Genomic Islands; genomics; Gram-negative bacteria; Helicobacter Infections - complications; Helicobacter Infections - metabolism; Helicobacter Infections - pathology; Helicobacter pylori; Helicobacter pylori - metabolism; Histone H2A; histones; Histones - genetics; Histones - metabolism; Humans; Infection; Infections; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Mammalian cells; Mesenchyme; Metaphase; Mice; Microscopy; Molecular modelling; mutagenicity; nuclear genome; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; pathogenicity islands; Pathogens; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; pulsed-field gel electrophoresis; recruitment; Risk factors; Rodents; stomach neoplasms; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - microbiology; Stomach Neoplasms - pathology; Trans-Activators - genetics; Trans-Activators - metabolism; Tumor Suppressor p53-Binding Protein 1; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; virulence; virulence factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1100959108

The bacterial pathogen Helicobacter pylori chronically infects the human gastric mucosa and is the leading risk factor for the development of gastric cancer. The molecular mechanisms of H. pylori-associated gastric carcinogenesis remain ill defined. In this study, we examined the possibility that H. pylori directly compromises the genomic integrity of its host cells. We provide evidence that the infection introduces DNA double-strand breaks (DSBs) in primary and transformed murine and human epithelial and mesenchymal cells. The induction of DSBs depends on the direct contact of live bacteria with mammalian cells. The infection-associated DNA damage is evident upon separation of nuclear DNA by pulse field gel electrophoresis and by high-magnification microscopy of metaphase chromosomes. Bacterial adhesion (e.g., via blood group antigen-binding adhesin) is required to induce DSBs; in contrast, the H. pylori virulence factors vacuolating cytotoxin A, γ-glutamyl transpeptidase, and the cytotoxin-associated gene (Cag) pathogenicity island are dispensable for DSB induction. The DNA discontinuities trigger a damage-signaling and repair response involving the sequential ataxia telangiectasia mutated (ATM)-dependent recruitment of repair factors—p53-binding protein (53BP1) and mediator of DNA damage checkpoint protein 1 (MDC1)—and histone H2A variant X (H2AX) phosphorylation. Although most breaks are repaired efficiently upon termination of the infection, we observe that prolonged active infection leads to saturation of cellular repair capabilities. In summary, we conclude that DNA damage followed by potentially imprecise repair is consistent with the carcinogenic properties of H. pylori and with its mutagenic properties in vitro and in vivo and may contribute to the genetic instability and frequent chromosomal aberrations that are a hallmark of gastric cancer.