Patterns of bezo[a]pyrene-induced mutagenesis are dictated by epigenetic influences on the efficiency of nucleotide excision repair and DNA damage susceptibility.

Lung cancer sequencing efforts have uncovered mutational signatures that have been attributedto exposure to the cigarette smoke carcinogen benzo[a]pyrene. Benzo[a]pyrene metabolizes incells to Benzo[a]pyrene diol expoxide (BPDE), and reacts with guanine nucleotides to formbulky BPDE adducts. These DNA adducts block transcription and replication, compromising cellfunction and survival, and are repaired in human cells by the nucleotide excision repair pathway.Here, we applied high-resolution genomic assays to measure BPDE-induced damage formationand mutagenesis in human cells. We integrated the damage and mutagenesis data wegenerated with previous repair, DNA methylation, RNA expression, and chromatin componentmeasurements in the same cell lines, along with lung cancer mutagenesis data. BPDE damageformation is significantly enhanced by DNA methylation and in active and accessible chromatinregions. Transcription factor binding can both induce or repress damage formation, dependingon the factor. While DNA methylation does not appear to influence repair efficiency, BPDEdamage repair was significantly elevated in accessible chromatin regions, which indeedaccumulated less mutations. Thus, when driving mutagenesis in opposing directions, the finalmutational patterns appear to be dictated by the efficiency of repair rather than the frequencyof underlying damages.