Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-κB signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate β-ADP-heptose by the ALPK1/TIFA signaling pathway. DNA damage depends on the bi-functional RfaE enzyme and the Cag pathogenicity island of H. pylori, is accompanied by replication fork stalling and can be observed also in primary cells derived from gastric organoids. Importantly, H. pylori-induced replication stress and DNA damage depend on the presence of co-transcriptional RNA/DNA hybrids (R-loops) that form in infected cells during S-phase as a consequence of β-ADP-heptose/ ALPK1/TIFA/NF-κB signaling. H. pylori resides in close proximity to S-phase cells in the gastric mucosa of gastritis patients. Taken together, our results link bacterial infection and NF-κB-driven innate immune responses to R-loop-dependent replication stress and DNA damage.
- MeSH
- adaptorové proteiny signální transdukční genetika metabolismus MeSH
- bakteriální proteiny metabolismus MeSH
- DNA chemie genetika MeSH
- floxuridin MeSH
- glykosyltransferasy metabolismus MeSH
- Helicobacter pylori metabolismus patogenita MeSH
- infekce vyvolané Helicobacter pylori metabolismus mikrobiologie MeSH
- interakce hostitele a patogenu fyziologie MeSH
- lidé MeSH
- lipopolysacharidy metabolismus MeSH
- mutace MeSH
- nádorové buněčné linie MeSH
- nádory žaludku genetika mikrobiologie patologie MeSH
- NF-kappa B genetika metabolismus MeSH
- poškození DNA MeSH
- proteinkinasy genetika metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- replikace DNA účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH