High-throughput characterization of transcription factors that modulate UV damage formation and repair at single-nucleotide resolution.

Genomic studies revealed elevated DNA damage and mutation rates at transcription factor (TF) binding sites in UV-linked cancers. While TFs can promote UV-induced mutagenesis by altering both damage formation and repair, these mechanisms have not been systematically characterized across TFs at high resolution. Using genome-wide UV damage maps from skin fibroblasts, we develop a scalable statistical framework to analyze TF-mediated mutagenic mechanisms across hundreds of TFs. We identify numerous previously unreported TFs that significantly enhance or suppress UV damage formation within their binding sites. A systematic survey of TF-DNA complexes reveals that damage modulation often coincides with TF-induced DNA distortions that either protect against or promote photodimer formation. Additionally, we analyze repair efficiency in TF binding sites at high resolution, identifying TFs likely to compete with repair. Comparisons with skin cancer mutations distinguish mutation enrichment driven by increased damageability versus attenuated repair, revealing the highly contextual nature of TF-mediated mutagenesis.