Adaptation delay causes a burst of mutations in bacteria responding to oxidative stress

Understanding the interplay between phenotypic and genetic adaptation is a focus of evolutionary biology. In bacteria, the oxidative stress response prevents mutagenesis by reactive oxygen species (ROS). We hypothesise that the stress response dynamics can therefore affect the timing of the mutation supply that fuels genetic adaptation to oxidative stress. We uncover that sudden hydrogen peroxide stress causes a burst of mutations. By developing single-molecule and single-cell microscopy methods, we determine how these mutation dynamics arise from phenotypic adaptation mechanisms. H₂ O₂ signalling by the transcription factor OxyR rapidly induces ROS-scavenging enzymes. However, an adaptation delay leaves cells vulnerable to the mutagenic and toxic effects of hydroxyl radicals generated by the Fenton reaction. Resulting DNA damage is counteracted by a spike in DNA repair activities during the adaptation delay. Absence of a mutation burst in cells with prior stress exposure or constitutive OxyR activation shows that the timing of phenotypic adaptation directly controls stress-induced mutagenesis. Similar observations for alkylation stress show that mutation bursts are a general phenomenon associated with adaptation delays.