The H.pylori CagA oncoprotein induces replication fork collapse and DNA double strand breaks through Fanconi Anemia pathway downregulation

Although H.pylori infection is known to induce host genomic double strand breaks, (DSBs), the role of CagA, a central virulence factor with oncogenic properties in DSB generation remains unclear. Here, using transcriptomic and proteomic analyses, we show that CagA downregulates the expression of major DNA repair factors such as FANCD2, BRCA1 and BRCA2 of the Fanconi Anemia (FA) pathway of DNA repair and leads to compromised host replication fork speed, stability and toxic DSB induction. Our results highlight the mechanism of CagA-mediated genome instability at the level of replication forks and can be used to devise strategies that mitigate the genotoxic effects of H.pylori-infection. Overall design: WTA10 cells are modified MKN-28 cells where CagA is induced in the absence of Doxycycline in the culture medium. Cells were cultured either in the presence of Doxycycline (WTA10-Pos1 and WTA10-Pos2 are biological replicates) or in the absence of Doxycycline (WTA10-Neg1 and WTA10-Neg2 are biological replicates)