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Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types

PLoS Genetics, ISSN: 1553-7404, Vol: 12, Issue: 8, Page: e1006207
2016
  • 59
    Citations
  • 0
    Usage
  • 97
    Captures
  • 1
    Mentions
  • 1
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    59
  • Captures
    97
  • Mentions
    1
    • News Mentions
      1
      • News
        1
  • Social Media
    1
    • Shares, Likes & Comments
      1
      • Facebook
        1

Most Recent News

Strand-resolved mutagenicity of DNA damage and repair

Nature, Published online: 12 June 2024; doi:10.1038/s41586-024-07490-1 How strand-asymmetric processes such as replication and transcription interact with DNA damage to drive mechanisms of repair and mutagenesis is explored.

Article Description

Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative rates and impact of the mutational burden at the binding sites of 81 transcription factors (TFs), by comparing the abundance and patterns of single base substitutions within putatively functional binding sites to control sites with matched sequence composition. There is a strong (1.43-fold) and significant excess of mutations at functional binding sites across TFs, and the mutations that accumulate in cancers are typically more disruptive than variants tolerated in extant human populations at the same sites. CTCF binding sites suffer an exceptionally high mutational load in cancer (3.31-fold excess) relative to control sites, and we demonstrate for the first time that this effect is seen in essentially all cancer types with sufficient data. The sub-set of CTCF sites involved in higher order chromatin structures has the highest mutational burden, suggesting a widespread breakdown of chromatin organization. However, we find no evidence for selection driving these distinctive patterns of mutation. The mutational load at CTCF-binding sites is substantially determined by replication timing and the mutational signature of the tumor in question, suggesting that selectively neutral processes underlie the unusual mutation patterns. Pervasive hyper-mutation within transcription factor binding sites rewires the regulatory landscape of the cancer genome, but it is dominated by mutational processes rather than selection.

Bibliographic Details

http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84984873593&origin=inward; http://dx.doi.org/10.1371/journal.pgen.1006207; http://www.ncbi.nlm.nih.gov/pubmed/27490693; https://dx.plos.org/10.1371/journal.pgen.1006207.g002; http://dx.doi.org/10.1371/journal.pgen.1006207.g002; https://dx.plos.org/10.1371/journal.pgen.1006207.g005; http://dx.doi.org/10.1371/journal.pgen.1006207.g005; https://dx.plos.org/10.1371/journal.pgen.1006207; https://dx.plos.org/10.1371/journal.pgen.1006207.g001; http://dx.doi.org/10.1371/journal.pgen.1006207.g001; https://dx.plos.org/10.1371/journal.pgen.1006207.t001; http://dx.doi.org/10.1371/journal.pgen.1006207.t001; https://dx.plos.org/10.1371/journal.pgen.1006207.g004; http://dx.doi.org/10.1371/journal.pgen.1006207.g004; https://dx.plos.org/10.1371/journal.pgen.1006207.g003; http://dx.doi.org/10.1371/journal.pgen.1006207.g003; https://dx.doi.org/10.1371/journal.pgen.1006207.g001; https://journals.plos.org/plosgenetics/article/figure?id=10.1371/journal.pgen.1006207.g001; https://dx.doi.org/10.1371/journal.pgen.1006207.g003; https://journals.plos.org/plosgenetics/article/figure?id=10.1371/journal.pgen.1006207.g003; https://dx.doi.org/10.1371/journal.pgen.1006207.g004; https://journals.plos.org/plosgenetics/article/figure?id=10.1371/journal.pgen.1006207.g004; https://dx.doi.org/10.1371/journal.pgen.1006207.g002; https://journals.plos.org/plosgenetics/article/figure?id=10.1371/journal.pgen.1006207.g002; https://dx.doi.org/10.1371/journal.pgen.1006207.t001; https://journals.plos.org/plosgenetics/article/figure?id=10.1371/journal.pgen.1006207.t001; https://dx.doi.org/10.1371/journal.pgen.1006207; https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006207; https://dx.doi.org/10.1371/journal.pgen.1006207.g005; https://journals.plos.org/plosgenetics/article/figure?id=10.1371/journal.pgen.1006207.g005; http://dx.plos.org/10.1371/journal.pgen.1006207.g005; http://dx.plos.org/10.1371/journal.pgen.1006207.g003; https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006207&type=printable; http://dx.plos.org/10.1371/journal.pgen.1006207.g001; http://dx.plos.org/10.1371/journal.pgen.1006207.g002; http://dx.plos.org/10.1371/journal.pgen.1006207.t001; http://dx.plos.org/10.1371/journal.pgen.1006207.g004; http://www.plosone.org/article/metrics/info:doi/10.1371/journal.pgen.1006207; http://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006207&type=printable; http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006207; http://dx.plos.org/10.1371/journal.pgen.1006207

Vera B. Kaiser; Martin S. Taylor; Colin A. Semple; Jaegil Kim

Public Library of Science (PLoS)

Agricultural and Biological Sciences; Biochemistry, Genetics and Molecular Biology; Medicine

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