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; John J Wyrick

doi:10.1038/s41467-018-05064-0

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

Journal article

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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

Nature communications, Vol.9(1), pp.2626-13

07/06/2018

DOI: https://doi.org/10.1038/s41467-018-05064-0

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https://hdl.handle.net/2376/106179

PMCID: PMC6035183

PMID: 29980679

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https://doi.org/10.1038/s41467-018-05064-0View

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Abstract

Pyrimidine Dimers - metabolism

Proto-Oncogene Protein c-ets-1 - metabolism

Humans

Mutagenesis - genetics

DNA - metabolism

Melanoma - pathology

Mutation - genetics

DNA - chemistry

Ultraviolet Rays

Melanoma - genetics

Models, Biological

Base Sequence

Protein Binding

Nucleic Acid Conformation

Binding Sites

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.

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Title: ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma
Creators: Peng Mao - School of Molecular Biosciences, Washington State University, Pullman, WA, 99164, USA
Alexander J Brown - School of Molecular Biosciences, Washington State University, Pullman, WA, 99164, USA
Shingo Esaki - Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
Svetlana Lockwood - Paul G. Allen School for Global Animal Health, Washington State University, Pullman, WA, 99164, USA
Gregory M K Poon - Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA
Michael J Smerdon - School of Molecular Biosciences, Washington State University, Pullman, WA, 99164, USA
Steven A Roberts - Center for Reproductive Biology, Washington State University, Pullman, WA, 99164, USA. sroberts@vetmed.wsu.edu
John J Wyrick - Center for Reproductive Biology, Washington State University, Pullman, WA, 99164, USA. jwyrick@vetmed.wsu.edu
Publication Details: Nature communications, Vol.9(1), pp.2626-13
Academic Unit: Paul G. Allen School for Global Animal Health; Molecular Biosciences, School of
Publisher: England
Grant note: R00 ES022633 / NIEHS NIH HHS R00ES022633 / U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS) R01ES002614 / U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS) R01CA218112 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R21HL129063 / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) T32AI07025 / U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) T32 GM008336 / NIGMS NIH HHS T32 AI007025 / NIAID NIH HHS R01 ES002614 / NIEHS NIH HHS R01 CA218112 / NCI NIH HHS R21 HL129063 / NHLBI NIH HHS MCB 15451600 / National Science Foundation (NSF) R21ES027937 / U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS) R21 ES027937 / NIEHS NIH HHS
Identifiers: 99900546609701842
Language: English
Resource Type: Journal article