Abstract 3154: Integrating DNA damage and mutation enrichment to understand mutagenesis at transcription factor binding sites

Abstract The buildup of ultraviolet (UV) light-induced DNA damage, such as Cyclobutane Pyrimidine Dimers (CPDs), is a crucial precursor to genetic mutations and the development of skin melanoma. These damaged sites and mutations are known to not be randomly distributed; in fact, previous research suggests potential relationships between damaged/mutated sites and transcription factors (TFs), proteins that regulate gene expression by binding to target sequences across the genome. To examine relationships between UV damages and TF binding sites on a genomic level, we integrated data from the Duke iMADS database of TF binding sites, CPD damage maps across the human genome, ATAC-seq accessibility data from the Cistrome database, and mutation data from Australian melanoma patients (from the ICGC consortium). We developed a computational workflow to measure the spatial distribution of damage/mutations at TF binding sites. Our analysis showed a strong association between the positions of CPD damages and mutations within the binding sites of ETS1, but not E2F or c-Myc, with the peaks in damage/mutations primarily residing at the central core of the ETS1 binding sites. The creation of such an analytic pipeline will enable the further quantitative genome-wide study of the relationships between the degrees of damages/mutations within TF binding sites, chromatin accessibility, and other genomic contexts. With these results, we can better understand the mechanisms involved in accumulating damages and mutations and how they progress to cancer, aging, and senescence. Citation Format: Bo Chi, Raluca Gordan. Integrating DNA damage and mutation enrichment to understand mutagenesis at transcription factor binding sites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3154.