Fig. 8: Model of Pol IV-mutagenesis across bacterial genomes.

Stressful conditions, such those found in the Cystic Fibrosis airway environment, increase the production of reactive oxygen species (ROS), leading to the oxidation of the nucleotide pool. Fork arrest at replication termination sites and highly transcribed zones of the genome facilitates Pol IV molecules enrich near replisomes. This enzyme gains access to the processivity β clamp factor and catalyzes the erroneous insertion of oxodGTP opposite a template A surrounded by a 5’G and/or 3’C. As MutS is unable to regulate the low fidelity DNA synthesis by Pol IV under stress, these errors are fixed as AT to CG mutations. Consequently, Pol IV can drive rapid genomic evolution of genes located in difficult-to-replicate regions of the bacterial chromosome, giving rise to highly inactivated genetic variants that could enhance pathogen survival under hostile conditions.