Abstract
Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations are commonly believed to be due to locally inhibited DNA repair. Here, we first show that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit strong increases in CPD formation efficacy in a manner consistent with tumor mutation data at the single-base level. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory elements including ETS sites, our data supports that elevated DNA damage formation at specific genomic bases is at the core of the prominent promoter mutation hotspots seen in skin cancers, thus explaining a key phenomenon in whole-genome cancer analyses.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Binding Sites / genetics
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Cell Line, Tumor
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DNA Damage
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DNA, Neoplasm / genetics
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Humans
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Melanoma / etiology*
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Melanoma / genetics*
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Melanoma / metabolism
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Mutation*
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Neoplasms, Radiation-Induced / etiology*
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Neoplasms, Radiation-Induced / genetics*
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Neoplasms, Radiation-Induced / metabolism
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-ets / metabolism
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Pyrimidine Dimers / biosynthesis*
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Pyrimidine Dimers / genetics
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Pyrimidine Dimers / radiation effects
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Skin Neoplasms / etiology*
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Skin Neoplasms / genetics*
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Skin Neoplasms / metabolism
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Ultraviolet Rays / adverse effects*
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Whole Genome Sequencing
Substances
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DNA, Neoplasm
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Proto-Oncogene Proteins c-ets
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Pyrimidine Dimers
Grants and funding
This work was supported by grants from the Knut and Alice Wallenberg Foundation (EL, AS;
www.kaw.wallenberg.org), the Swedish Foundation for Strategic Research (EL, ARC;
www.strategiska.se), the Wenner-Gren Foundation (EL;
www.wenner-gren.se), the Swedish Medical Research Council (EL, AS, ARC;
www.vr.se), the Swedish Cancer Society (EL, AS;
www.cancerfonden.se), the Swedish Childhood Cancer Foundation (A.S), Sahlgrenska Academy (ALF) at University of Gothenburg (AS), the Åke Wiberg foundation (EL;
www.ake-wiberg.se), and the Lars Erik Lundberg Foundation for Research and Education (EL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.