UV irradiation remodels the specificity landscape of transcription factors.

Proceedings of the National Academy of Sciences of the United States of America 2023 Mar 14

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Somatic mutations are highly enriched at transcription factor (TF) binding sites, with the strongest trend being observed for ultraviolet light (UV)-induced mutations in melanomas. One of the main mechanisms proposed for this hypermutation pattern is the inefficient repair of UV lesions within TF-binding sites, caused by competition between TFs bound to these lesions and the DNA repair proteins that must recognize the lesions to initiate repair. However, TF binding to UV-irradiated DNA is poorly characterized, and it is unclear whether TFs maintain specificity for their DNA sites after UV exposure. We developed UV-Bind, a high-throughput approach to investigate the impact of UV irradiation on protein-DNA binding specificity. We applied UV-Bind to ten TFs from eight structural families, and found that UV lesions significantly altered the DNA-binding preferences of all the TFs tested. The main effect was a decrease in binding specificity, but the precise effects and their magnitude differ across factors. Importantly, we found that despite the overall reduction in DNA-binding specificity in the presence of UV lesions, TFs can still compete with repair proteins for lesion recognition, in a manner consistent with their specificity for UV-irradiated DNA. In addition, for a subset of TFs, we identified a surprising but reproducible effect at certain nonconsensus DNA sequences, where UV irradiation leads to a high increase in the level of TF binding. These changes in DNA-binding specificity after UV irradiation, at both consensus and nonconsensus sites, have important implications for the regulatory and mutagenic roles of TFs in the cell.

Citation

Zachery Mielko, Yuning Zhang, Harshit Sahay, Yiling Liu, Matthew A Schaich, Brittani Schnable, Abigail M Morrison, Debbie Burdinski, Sheera Adar, Miles Pufall, Bennett Van Houten, Raluca Gordân, Ariel Afek. UV irradiation remodels the specificity landscape of transcription factors. Proceedings of the National Academy of Sciences of the United States of America. 2023 Mar 14;120(11):e2217422120