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