The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress

Michael Bauer, Zuzana Nascakova, Anca-Irina Mihai, Phil F. Cheng, Mitchell P. Levesque, Simon Lampart, Robert Hurwitz, Lennart Pfannkuch, Jana Dobrovolna, Melanie Jacobs, Sina Bartfeld, Anders Dohlman, Xiling Shen, Alevtina A. Gall, Nina R. Salama, Antonia Töpfer, Achim Weber, Thomas F. Meyer, Pavel Janscak () and Anne Müller ()
Additional contact information
Michael Bauer: University of Zurich
Zuzana Nascakova: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic
Anca-Irina Mihai: University of Zurich
Phil F. Cheng: University Hospital Zurich
Mitchell P. Levesque: University Hospital Zurich
Simon Lampart: University of Zurich
Robert Hurwitz: Max Planck Institute for Infection Biology, Department of Molecular Biology
Lennart Pfannkuch: Max Planck Institute for Infection Biology, Department of Molecular Biology
Jana Dobrovolna: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic
Melanie Jacobs: Research Center for Infectious Diseases, Institute for Molecular Infection Biology, University of Würzburg
Sina Bartfeld: Research Center for Infectious Diseases, Institute for Molecular Infection Biology, University of Würzburg
Anders Dohlman: Duke University
Xiling Shen: Duke University
Alevtina A. Gall: Division of Human Biology, Fred Hutchinson Cancer Research Center
Nina R. Salama: Division of Human Biology, Fred Hutchinson Cancer Research Center
Antonia Töpfer: University Hospital Zurich and University of Zurich
Achim Weber: University of Zurich
Thomas F. Meyer: Max Planck Institute for Infection Biology, Department of Molecular Biology
Pavel Janscak: University of Zurich
Anne Müller: University of Zurich

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18857-z

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