Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage
Year: 2016
Type: article
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.
Source: eLife
DOI: 10.7554/elife.17548
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: G2882558110, Mechanisms Linking Genome Stability to RNA Metabolism, Cellular and Molecular Biology Training Program, "R-loop formation protects CpG islands against epigenetic silencing"., Stanford Cancer Institute, Cancer Center Support Grant P30, Mechanisms of R-loop-Associated Genome Instability
OpenAlex ID: W2515159273