Genome-wide mapping reveals determinants of DNA damage sensitivity

DNA damages post a hazard to genome function and stability as they block RNA and DNA polymerases and may lead to cell death, mutations, and cancer. Bulky DNA damages include the cyclobutane pyrimidine dimers (CPDs) induced by ultraviolet (UV) radiation and the BaP diol epoxide-deoxyguanosine (BPDE-dG) induced by smoking. Recent mutagenesis studies have found that UV-induced mutational patterns are asymmetric along transcribed genes, with lower mutagenesis on transcribed strand attributed to transcription-coupled repair. High resolution maps of CPDs revealed that the major determinant of CPD formation is the primary sequence of the DNA. We analyzed the patterns of CPDs at transcribed regions and reveal a transcriptional asymmetry in DNA damage formation, that is explained by the asymmetric distribution of damage-forming di-nucleotides. This asymmetry is conserved in vertebrates and invertebrates and is completely reversed between introns and exons. In introns, the transcriptional asymmetry is linked to the transcription process, while in exons the asymmetry is associated with codon usage preferences. Reanalysis of nucleotide excision repair, normalizing repair to the damage-forming di-nucleotide frequencies, discovered that repair of CPDs is more efficient in exons compared to introns, contributing to the maintenance and integrity of coding regions.

Expanding our research to additional damage types, we have generated the first BPDE Damage-seq maps across the human genome. Preliminary results indicate a relationship between BPDE damage formation and DNA methylation, which we are currently investigating.

Our work mapping DNA damages at single nucleotide resolution provide valuable new insight to understanding DNA damage sensitivity and mutagenic potential.