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

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.

SUBMITTER: Stork CT

PROVIDER: S-EPMC5030092 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Stork Caroline Townsend CT Bocek Michael M Crossley Madzia P MP Sollier Julie J Sanz Lionel A LA Chédin Frédéric F Swigut Tomek T Cimprich Karlene A KA

eLife 20160823

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 highl ...[more]

PMID: 27552054

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

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

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