Abstract
AbstractRecurrent mutations are frequently associated with transcription factor (TF) binding sites (TFBS) in melanoma, but the mechanism driving mutagenesis at TFBS is unclear. Here, we use a method called CPD-seq to map the distribution of UV-induced cyclobutane pyrimidine dimers (CPDs) across the human genome at single nucleotide resolution. Our results indicate that CPD lesions are elevated at active TFBS, an effect that is primarily due to E26 transformation-specific (ETS) TFs. We show that ETS TFs induce a unique signature of CPD hotspots that are highly correlated with recurrent mutations in melanomas, despite high repair activity at these sites. ETS1 protein renders its DNA binding targets extremely susceptible to UV damage in vitro, due to binding-induced perturbations in the DNA structure that favor CPD formation. These findings define a mechanism responsible for recurrent mutations in melanoma and reveal that DNA binding by ETS TFs is inherently mutagenic in UV-exposed cells.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases
U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
National Science Foundation
U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences
U.S. Department of Health & Human Services | NIH | National Cancer Institute
internal grant from the Washington State University College of Veterinary Medicine
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Cited by
110 articles.
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