Letter | Published:

Nucleotide excision repair is impaired by binding of transcription factors to DNA

Nature volume 532, pages 264267 (14 April 2016) | Download Citation

Abstract

Somatic mutations are the driving force of cancer genome evolution1. The rate of somatic mutations appears to be greatly variable across the genome due to variations in chromatin organization, DNA accessibility and replication timing2,3,4,5. 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) 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. 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.

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Acknowledgements

We acknowledge funding from the Spanish Ministry of Economy and Competitiveness (grant number SAF2012-36199), the Marató de TV3 Foundation, and the Spanish National Institute of Bioinformatics (INB). R.S. is supported by an EMBO Long-Term Fellowship (ALTF 568-2014) co-funded by the European Commission (EMBOCOFUND2012, GA-2012-600394) support from Marie Curie Actions. A.G.-P. is supported by a Ramón y Cajal contract (RYC-2013-14554).

Author information

Affiliations

  1. Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain

    • Radhakrishnan Sabarinathan
    • , Loris Mularoni
    • , Jordi Deu-Pons
    • , Abel Gonzalez-Perez
    •  & Núria López-Bigas
  2. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain

    • Núria López-Bigas

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Contributions

N.L.-B. conceived and supervised the study. N.L.-B. and R.S. designed the analyses. R.S. performed the analyses with contributions from L.M. and J.D.-P. All authors participated in the discussion of the results. N.L.-B., A.G.-P. and R.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Núria López-Bigas.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This file contains the results of mutation rate enrichment at the binding sites of individual TFs in melanoma.

  2. 2.

    Supplementary Table 2

    This file contains the results of sample-wise analysis of mutation rate enrichment at the active TFBS for 38 melanoma samples and one normal skin sample.

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DOI

https://doi.org/10.1038/nature17661

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