Altered benzo[a]pyrene adduct formation in nucleosomes establishes distinct mutational patterns in lung cancer

Benzo[a]pyrene is a carcinogen in tobacco smoke that, when metabolized to benzo[a]pyrene diol epoxide (BPDE), induces mutagenic DNA lesions that promote the development of lung cancer. In lung cells, BPDE damages DNA packaged in nucleosomes, but the impact of nucleosomes on BPDE adduct formation is unclear. Here, we analyze genome-wide maps of BPDE adduct formation and repair in human cells. Our analysis indicates that BPDE adduct formation is suppressed in nucleosomes and enriched in adjacent linker DNA. Within nucleosomes, BPDE adduct formation is specifically elevated at minor-out rotational settings, where the minor groove of the DNA faces outward from the histone octamer. Structural analysis indicates that the solvent accessibility of the reactive exocyclic N2 amino group in guanine bases is elevated at minor-out rotational settings, potentially accounting for elevated BPDE damage at these locations. These damage patterns coincide with and can explain elevated somatic mutation rates in lung cancers at linker DNA and minor-out rotational settings in nucleosomes. While BPDE damage formation in nucleosomes strongly correlates with mutation patterns in lung cancers, the repair of these adducts does not. Analysis of damage patterns at CCCTC-binding factor and SP1 transcription factor binding sites indicates that BPDE damage formation is also suppressed by these DNA-bound proteins, and this damage modulation correlates with mutation patterns at these binding sites in lung cancers. These data indicate that altered BPDE adduct formation in chromatin can explain the distinct patterns of somatic mutations in lung cancers.