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

• DOI: 10.1371/journal.pgen.1007849
• Publication Date: 2018-12-26T13:42:20Z
• Authors: Kerryn Elliott; Martin Boström; Stefan Filges; Markus Lindberg; Jimmy Van den Eynden; Anders Ståhlberg; Anders R. Clausen; Erik Larsson
• Keywords: Pyrimidine dimer

Sequencing of whole cancer genomes has revealed an abundance recurrent mutations in gene-regulatory promoter regions, particular melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these commonly believed be due locally inhibited DNA repair. Here, we first show that low-dose UV light induces preferably at a known ETS hotspot cultured cells even the absence global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping cyclobutane pyrimidine dimers (CPDs) shortly after exposure and thus before repair, find ETS-related exhibit increases CPD formation efficacy manner consistent with tumor data single-base level. Analysis large genome cohort illustrates widespread contribution this effect melanoma. NER underlies general increase somatic burden regulatory elements including sites, our supports elevated damage specific genomic bases is core prominent seen skin cancers, explaining key phenomenon whole-genome analyses.