Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage

Caroline Townsend Stork, Michael Bocek, Madzia P. Crossley, Julie Sollier, Lionel A. Sanz, Frederic Chedin, Tomek Swigut, Karlene A. Cimprich

Research output: Contribution to journalArticle

76 Scopus citations

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.

Original languageEnglish (US)
Article numbere17548
JournaleLife
Volume5
Issue numberAUGUST
DOIs
StatePublished - Aug 23 2016

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Stork, C. T., Bocek, M., Crossley, M. P., Sollier, J., Sanz, L. A., Chedin, F., Swigut, T., & Cimprich, K. A. (2016). Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage. eLife, 5(AUGUST), [e17548]. https://doi.org/10.7554/eLife.17548