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Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers.

Journal article
Authors Kerryn Elliott
Martin Boström
Stefan Filges
Markus Lindberg
Jimmy Van den Eynden
Anders Ståhlberg
Anders R Clausen
Erik Larsson
Published in PLoS genetics
Volume 14
Issue 12
Pages e1007849
ISSN 1553-7404
Publication year 2018
Published at Institute of Biomedicine, Department of Pathology
Sahlgrenska Cancer Center
Institute of Biomedicine
Wallenberg Centre for Molecular and Translational Medicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages e1007849
Language en
Subject categories Functional genomics, Molecular biology, Cell and molecular biology, Genetics, Medical Genetics, Cell and Molecular Biology


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.

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