RT Journal Article SR Electronic T1 Nucleotide excision repair is impaired by binding of transcription factors to DNA JF bioRxiv FD Cold Spring Harbor Laboratory SP 028886 DO 10.1101/028886 A1 Radhakrishnan Sabarinathan A1 Loris Mularoni A1 Jordi Deu-Pons A1 Abel Gonzalez-Perez A1 Núria López-Bigas YR 2015 UL http://biorxiv.org/content/early/2015/10/13/028886.abstract AB Somatic mutations are the driving force of cancer genome evolution1. The rate of somatic mutations appears in great variability across the genome due to chromatin organization, DNA accessibility and replication timing2-5. However, other variables that may influence the mutation rate locally, such as DNA-binding proteins, are unknown. Here we demonstrate that the rate of somatic mutations in melanoma tumors is highly increased at active Transcription Factor binding sites (TFBS) and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data6, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Therefore, our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of mutations at their binding sites. This finding has important implications in our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.