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ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma

Author

Listed:
  • Peng Mao

    (Washington State University)

  • Alexander J. Brown

    (Washington State University)

  • Shingo Esaki

    (Georgia State University)

  • Svetlana Lockwood

    (Washington State University)

  • Gregory M. K. Poon

    (Georgia State University
    Georgia State University)

  • Michael J. Smerdon

    (Washington State University)

  • Steven A. Roberts

    (Washington State University
    Washington State University)

  • John J. Wyrick

    (Washington State University
    Washington State University)

Abstract

Recurrent mutations are frequently associated with transcription factor (TF) binding sites (TFBS) in melanoma, but the mechanism driving mutagenesis at TFBS is unclear. Here, we use a method called CPD-seq to map the distribution of UV-induced cyclobutane pyrimidine dimers (CPDs) across the human genome at single nucleotide resolution. Our results indicate that CPD lesions are elevated at active TFBS, an effect that is primarily due to E26 transformation-specific (ETS) TFs. We show that ETS TFs induce a unique signature of CPD hotspots that are highly correlated with recurrent mutations in melanomas, despite high repair activity at these sites. ETS1 protein renders its DNA binding targets extremely susceptible to UV damage in vitro, due to binding-induced perturbations in the DNA structure that favor CPD formation. These findings define a mechanism responsible for recurrent mutations in melanoma and reveal that DNA binding by ETS TFs is inherently mutagenic in UV-exposed cells.

Suggested Citation

  • Peng Mao & Alexander J. Brown & Shingo Esaki & Svetlana Lockwood & Gregory M. K. Poon & Michael J. Smerdon & Steven A. Roberts & John J. Wyrick, 2018. "ETS transcription factors induce a unique UV damage signature that drives recurrent mutagenesis in melanoma," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05064-0
    DOI: 10.1038/s41467-018-05064-0
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    Cited by:

    1. Miranda V. Hunter & Reuben Moncada & Joshua M. Weiss & Itai Yanai & Richard M. White, 2021. "Spatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Martin Boström & Erik Larsson, 2022. "Somatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    3. Sebastian Carrasco Pro & Heather Hook & David Bray & Daniel Berenzy & Devlin Moyer & Meimei Yin & Adam Thomas Labadorf & Ryan Tewhey & Trevor Siggers & Juan Ignacio Fuxman Bass, 2023. "Widespread perturbation of ETS factor binding sites in cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Kathiresan Selvam & Smitha Sivapragasam & Gregory M. K. Poon & John J. Wyrick, 2023. "Detecting recurrent passenger mutations in melanoma by targeted UV damage sequencing," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Kerryn Elliott & Vinod Kumar Singh & Martin Boström & Erik Larsson, 2023. "Base-resolution UV footprinting by sequencing reveals distinctive damage signatures for DNA-binding proteins," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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