title: H. pylori-Induced DNA Strand Breaks Are Introduced by Nucleotide Excision Repair Endonucleases and Promote NF-κB Target Gene Expression.
abstract: The human bacterial pathogen Helicobacter pylori exhibits genotoxic properties that promote gastric carcinogenesis. H. pylori introduces DNA double strand breaks (DSBs) in epithelial cells that trigger host cell DNA repair efforts. Here, we show that H. pylori-induced DSBs are repaired via error-prone, potentially mutagenic non-homologous end-joining. A genome-wide screen for factors contributing to DSB induction revealed a critical role for the H. pylori type IV secretion system (T4SS). Inhibition of transcription, as well as NF-κB/RelA-specific RNAi, abrogates DSB formation. DSB induction further requires β1-integrin signaling. DSBs are introduced by the nucleotide excision repair endonucleases XPF and XPG, which, together with RelA, are recruited to chromatin in a highly coordinated, T4SS-dependent manner. Interestingly, XPF/XPG-mediated DNA DSBs promote NF-κB target gene transactivation and host cell survival. In summary, H. pylori induces XPF/XPG-mediated DNA damage through activation of the T4SS/β1-integrin signaling axis, which promotes NF-κB target gene expression and host cell survival.
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Mara L
authors.initials: ML
authors.lastname: Hartung
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Dorothea C
authors.initials: DC
authors.lastname: Gruber
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Katrin N
authors.initials: KN
authors.lastname: Koch
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Livia
authors.initials: L
authors.lastname: Grüter
authors.affiliation: Functional Genomics Center Zurich, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Rehrauer
authors.affiliation: Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstrasse 5, 91085 Erlangen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Tegtmeyer
authors.affiliation: Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstrasse 5, 91085 Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Backert
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland. Electronic address: mueller@imcr.uzh.ch.
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D000069319:Type IV Secretion Systems / Q000235:genetics / Q000378:metabolism; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D004720:Endonucleases; D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D019012:Integrin beta1; D016209:Interleukin-8; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000069319:Type IV Secretion Systems; D000099250:DNA Excision Repair Protein ERCC-5; C000606204:NFKBIA protein, human; C498143:RELA protein, human; C095888:xeroderma pigmentosum group F protein