title: Nucleotide excision repair is impaired by binding of transcription factors to DNA.
abstract: Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears to be greatly variable across the genome due to variations in chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally are unknown, such as a role for DNA-binding proteins, for example. Here we demonstrate that the rate of somatic mutations in melanomas is highly increased at active transcription factor binding sites and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of DNA mutations at the protein binding sites. This finding has important implications for our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.
authors.affiliation: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Sabarinathan
authors.affiliation: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Loris
authors.initials: L
authors.lastname: Mularoni
authors.affiliation: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Deu-Pons
authors.affiliation: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Gonzalez-Perez
authors.affiliation: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: López-Bigas
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008545:Melanoma / Q000235:genetics*; D016296:Mutagenesis / Q000235:genetics*; D059645:Mutation Rate; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009707:Nucleosomes; D014157:Transcription Factors; D004247:DNA