ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma

Peng Mao, Alexander J. Brown, Shingo Esaki, Svetlana Lockwood, Gregory M. K. Poon, Michael J. Smerdon, Steven A. Roberts () and John J. Wyrick ()
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Peng Mao: Washington State University
Alexander J. Brown: Washington State University
Shingo Esaki: Georgia State University
Svetlana Lockwood: Washington State University
Gregory M. K. Poon: Georgia State University
Michael J. Smerdon: Washington State University
Steven A. Roberts: Washington State University
John J. Wyrick: Washington State University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Recurrent 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.

Date: 2018
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DOI: 10.1038/s41467-018-05064-0

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