Infection with the gastric bacterium Helicobacter pylori can cause chromosomal instability (CIN) and promote tumorigenesis. Koeppel et al. compared the DNA damage response (DDR) following H. pylori infection with that induced by other genotoxic treatments in human gastric cells and observed reduced activation of the DDR components ATR and the MRN complex, but not of 53BP1, following infection. Furthermore, the expression of 58 DDR genes was downregulated, indicating that H. pylori can systematically reduce DNA damage repair capacities. Measuring genome-wide localization of the DDR factor γH2AX revealed that by 18 hours following infection, damage induced by ionizing radiation shifted from being randomly localized to being localized to genic regions, especially to actively transcribed genes, and to telomere-proximal regions. This is similar to CIN patterns observed in H. pylori-associated gastric cancers.