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Cell Rep. 2015 Oct 6;13(1):70-79. doi: 10.1016/j.celrep.2015.08.074. Epub 2015 Sep 24.

H. pylori-Induced DNA Strand Breaks Are Introduced by Nucleotide Excision Repair Endonucleases and Promote NF-κB Target Gene Expression.

Author information

1
Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
2
Functional Genomics Center Zurich, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
3
Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstrasse 5, 91085 Erlangen, Germany.
4
Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland. Electronic address: mueller@imcr.uzh.ch.

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.

PMID:
26411687
DOI:
10.1016/j.celrep.2015.08.074
[Indexed for MEDLINE]
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