title: 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.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Caroline Townsend
authors.initials: CT
authors.lastname: Stork
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Bocek
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Madzia P
authors.initials: MP
authors.lastname: Crossley
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Sollier
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States.
authors.forename: Lionel A
authors.initials: LA
authors.lastname: Sanz
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chédin
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Tomek
authors.initials: T
authors.lastname: Swigut
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.
authors.forename: Karlene A
authors.identifier: 0000-0002-1937-2969
authors.initials: KA
authors.lastname: Cimprich
mesh_terms: D004247:DNA / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004967:Estrogens / Q000633:toxicity*; D006801:Humans; D061986:MCF-7 Cells; D009153:Mutagens / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004967:Estrogens; D009153:Mutagens; D012333:RNA, Messenger; D004247:DNA
keywords: DNA damage; R-loops; chromosomes; estrogen; genes; genome instability; human; transcription