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 attributed to exposure to the cigarette smoke carcinogen benzo[a]pyrene. Benzo[a]pyrene metabolizes in cells to Benzo[a]pyrene diol expoxide (BPDE), and reacts with guanine nucleotides to form bulky BPDE adducts. These DNA adducts block transcription and replication, compromising cell function 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 formation and mutagenesis in human cells. We integrated the damage and mutagenesis data we generated with previous repair, DNA methylation, RNA expression, and chromatin component measurements in the same cell lines, along with lung cancer mutagenesis data. BPDE damage formation is significantly enhanced by DNA methylation and in active and accessible chromatin regions. Transcription factor binding can both induce or repress damage formation, depending on the factor. While DNA methylation does not appear to influence repair efficiency, BPDE damage repair was significantly elevated in accessible chromatin regions, which indeed accumulated less mutations. Thus, when driving mutagenesis in opposing directions, the final mutational patterns appear to be dictated by the efficiency of repair rather than the frequency of underlying damages.