Abstract 5044: Whole-genome investigation of transcription factors that promote UV damage and mutation

Abstract Understanding the spatial distribution of ultraviolet light (UV)-induced damage and mutation across the genome is an important question due to their oncogenic role in melanoma and other cancers. Previous research suggests UV-induced Cyclobutane Pyrimidine Dimer (CPD) damage lesions and mutations are enriched at transcription factor (TF) binding sites, genomic locations where TFs bind to regulate gene expression. However, current studies of the links between observed enrichment and TF activity revolve around individual qualitative studies with a control sample (often naked DNA) representing sequence effects. With many TFs, damaged sites, and other contributory factors, we seek to quantitatively assess the genome-wide relationship between TF activity, damage formation, and mutagenesis. To accomplish this, we designed a distribution-free simulation pipeline to model the baseline effects of the underlying nucleotide sequence on damage and mutation accumulation by connecting TF binding sites, ATAC-seq chromatin accessibility, CPD lesions in cellular and naked DNA, and mutations from melanoma patients. This analysis reveals that CPDs exhibit varying patterns at the binding sites of TFs relative to what would be expected based on sequence context alone. While some TFs show no additional association with CPD damage, others demonstrate either an enrichment or a reduction in CPDs at their binding sites. Specifically, the top TF clusters associated with UV damage enrichment at a position are ETS, NFY, SPI, and MBD2. ETS, in particular, is consistent with previous studies as a suggested damage driver. In contrast, the top TF clusters associated with reduced damage are AP1, CCAAT_CEBP, NR (including NR1H3 and NR1I2), NFY, and IRF. Using a similar simulation approach, we identified that the most damaged positions in most of the top TF clusters had corresponding mutational enrichment. However, NFY, with damage enrichment at a non-mutagenic TT dimer, showed no mutational enrichment. These clusters can serve as a preliminary list for experimental validation of the modulation of UV-induced damage and mutagenesis driven by TF binding. Our findings and further study will reveal novel insights into the role of TFs in DNA damage accumulation and mutagenesis, which may be vital in reducing cancer incidence. Citation Format: Bo Chi, Raluca Gordan. Whole-genome investigation of transcription factors that promote UV damage and mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5044.