Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage
- Stanford University School of Medicine, United States
- University of California, Davis, United States
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
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Genome-wide DRIP-seq in E2 stimulated MCF7 cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE81851).
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Global Analysis of the Immediate Transcriptional Effects of Estrogen Signaling Reveals a Rapid, Extensive, and Transient ResponsePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE27463).
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Genome-wide modelling of transcription kinetics reveals patterns of RNA processing delaysPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE62789).
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High-throughput sequencing of DNA G-quadruplex structures in the human genomePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE63874).
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Landscape of somatic mutations in 560 breast cancer whole-genome sequencesPublicly available at the European Genome-phenome Archive (accession no. EGAS00001001178).
Article and author information
Author details
Karlene A Cimprich
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.
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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Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage
eLife 5:e17548.
https://doi.org/10.7554/eLife.17548
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