Molecular Mechanisms of H. pylori-Induced DNA Double-Strand Breaks

Abstract

Infections contribute to carcinogenesis through inflammation-related mechanisms. H. pylori infection is a significant risk factor for gastric carcinogenesis. However, the molecular mechanism by which H. pylori infection contributes to carcinogenesis has not been fully elucidated. H. pylori-associated chronic inflammation is linked to genomic instability via reactive oxygen and nitrogen species (RONS). In this article, we summarize the current knowledge of H. pylori-induced double strand breaks (DSBs). Furthermore, we provide mechanistic insight into how processing of oxidative DNA damage via base excision repair (BER) leads to DSBs. We review recent studies on how H. pylori infection triggers NF-κB/inducible NO synthase (iNOS) versus NF-κB/nucleotide excision repair (NER) axis-mediated DSBs to drive genomic instability. This review discusses current research findings that are related to mechanisms of DSBs and repair during H. pylori infection.

Keywords: BER; DSBs; H. pylori; NER; NF-κB; RONS.

Figure 1

Molecular mechanisms of H. pylori-induced double strand breaks (DSBs). Schematic representation of how H. pylori induces DSBs. H. pylori infection causes DNA damage in gastric epithelial cells [24]. H. pylori-host cell interaction is a prerequisite for DSBs [25] (top panel). Persistence of the host-bacterium interaction leads to chronic inflammation and the release of inflammatory cytokines and chemokines, which contribute to oxidative DNA damage that is processed via base excision repair (BER) pathways (bottom panel). Processing oxidative DNA damage by DNA glycosylase (e.g., OGG1, NEIL1, etc.) contributes to accumulation of apurinic/apyrimidinic (AP) sites that are eventually converted to DSBs [26]. In addition, some cytokines (e.g., TNF-α) inhibit BER proteins to exacerbate genomic instability. The second pathway associated with H. pylori-mediated NF-κB activation leads to formation of a protein complex with nucleotide excision repair proteins (XPF and XPG), cleaves the promoter regions, and alters gene expression [11] including HR DNA repair proteins (Rad51). Alternatively, NF-κB/iNOS-mediated NO production leads to DNA damage and/or inhibits DNA repair proteins (AAG) that likely impact BER and cause DSBs. Note that solid arrow and dot arrow shows activation and alternative avenue for the down stream events respectively; T bar shows inhibition or suppression of protein activity or gene expression.