The ALPK1/TIFA/NF-kB axis links a bacterial carcinogen to replication stress and DNA damage.

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-kB signaling upon innate immune recognition of LPS biosynthetic intermediates, such as ADP-heptose, by the ALPK1/TIFA pathway. DNA damage is accompanied by replication fork stalling as determined by DNA fiber assay and can be observed also in gastric organoids derived from bariatric surgery patients. We link H. pylori-induced DNA damage to the formation of RNA/DNA hybrids (R-loops), as overexpression of the R-loop-processing enzyme RNAse H1 prevents DNA damage and replication stress. R-loops form in infected cells as a consequence of ADP-heptose/ALPK1/TIFA/NF-kB signaling. Factors associated with R-loop processing and prevention are recurrently mutated in gastric cancer. In summary, our results link bacterial infection and NF-kB-driven innate immune responses to DNA damage, replication stress, and carcinogenesis. Citation Format: Michael Bauer, Zuzana Nascakova, Anca Mihai, Anne Muller. The ALPK1/TIFA/NF-kB axis links a bacterial carcinogen to replication stress and DNA damage [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B34.