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

0538129 - ÚMG 2021 RIV GB eng J - Journal Article
Bauer m, M. - Naščáková, Zuzana - Mihai, A.I. - Cheng p, P.F. - Levesque, M.P. - Lampart, S. - Hurwitz, R. - Pfannkuch, L. - Dobrovolná, Jana - Jacobs, M. - Bartfeld, S. - Dohlman, A. - Shen, X. - Gall, A.A. - Salama, N.R. - Toepfer, A. - Weber, A. - Meyer, T.F. - Janščák, Pavel - Mueller, A.
The ALPK1/TIFA/NF-kappa B axis links a bacterial carcinogen to R-loop-induced replication stress.
Nature Communications. Roč. 11, č. 1 (2020), č. článku 5117. E-ISSN 2041-1723
R&D Projects: GA ČR GA19-07674S; GA MŠMT LTAUSA19096; GA MŠMT(CZ) EF16_013/0001775; GA MŠMT LO1419; GA MŠMT(CZ) LM2018129
Institutional support: RVO:68378050
Keywords : helicobacter-pylori infection * nf-kappa-b * double-strand breaks * gastric-cancer * mouse model * inflammation * colonization * metaanalysis * contributes * eradication
OECD category: Biochemistry and molecular biology
Impact factor: 14.919, year: 2020
Method of publishing: Open access
https://www.nature.com/articles/s41467-020-18857-z

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-kappa B signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate betaADP-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 betaADP-heptose/ ALPK1/TIFA/NF-kappa B 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-kappa B-driven innate immune responses to R-loop-dependent replication stress and DNA damage. The bacterial pathogen Helicobacter pylori is known for its ability to induce DNA double-strand breaks in the genome of its target cells. Here, we show that H. pylori-induced DNA damage and replication stress occurs in S-phase cells as a result of R-loop-mediated transcription/replication conflicts that are triggered by activation of the ALPK1/TIFA/NF-kappa B signaling axis.
Permanent Link: http://hdl.handle.net/11104/0315950