1. Chromosomes and Gene Expression
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Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage

  1. Caroline Townsend Stork
  2. Michael Bocek
  3. Madzia P Crossley
  4. Julie Sollier
  5. Lionel A Sanz
  6. Frédéric Chédin
  7. Tomek Swigut
  8. Karlene A Cimprich  Is a corresponding author
  1. Stanford University School of Medicine, United States
  2. University of California, Davis, United States
Research Article
  • Cited 108
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Cite this article as: eLife 2016;5:e17548 doi: 10.7554/eLife.17548
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Abstract

The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in some instances have been linked to DNA damage. We show that E2-dependent R-loop formation and breast cancer rearrangements are highly enriched at E2-responsive genomic loci and that E2 induces DNA replication-dependent double-strand breaks (DSBs). Strikingly, many DSBs that accumulate in response to E2 are R-loop dependent. Thus, R-loops resulting from the E2 transcriptional response are a significant source of DNA damage. This work reveals a novel mechanism by which E2 stimulation leads to genomic instability and highlights how transcriptional programs play an important role in shaping the genomic landscape of DNA damage susceptibility.

Data availability

The following data sets were generated
    1. Stork CT
    2. Bocek M
    3. Swigut T
    4. Cimprich K
    (2016) Genome-wide DRIP-seq in E2 stimulated MCF7 cells
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE81851).
The following previously published data sets were used

Article and author information

Author details

  1. Caroline Townsend Stork

    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Michael Bocek

    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Madzia P Crossley

    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Julie Sollier

    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lionel A Sanz

    Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Frédéric Chédin

    Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Tomek Swigut

    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Karlene A Cimprich

    Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States
    For correspondence
    cimprich@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1937-2969

Funding

Susan G. Komen (IIR 12222368)

  • Karlene A Cimprich

National Institutes of Health (R01 GM119334)

  • Karlene A Cimprich

National Institutes of Health (R01 GM100489)

  • Karlene A Cimprich

National Institutes of Health (R01 GM094299)

  • Frédéric Chédin

National Science Foundation (Graduate Research Fellowship)

  • Caroline Townsend Stork

National Institutes of Health (Training Grant T32GM007276)

  • Caroline Townsend Stork

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrés Aguilera, CABIMER, Universidad de Sevilla, Spain

Publication history

  1. Received: May 5, 2016
  2. Accepted: August 18, 2016
  3. Accepted Manuscript published: August 23, 2016 (version 1)
  4. Version of Record published: September 20, 2016 (version 2)

Copyright

© 2016, Stork et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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