title: Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability.
abstract: R-loops, consisting of an RNA-DNA hybrid and displaced single-stranded DNA, are physiological structures that regulate various cellular processes occurring on chromatin. Intriguingly, changes in R-loop dynamics have also been associated with DNA damage accumulation and genome instability; however, the mechanisms underlying R-loop-induced DNA damage remain unknown. Here we demonstrate in human cells that R-loops induced by the absence of diverse RNA processing factors, including the RNA/DNA helicases Aquarius (AQR) and Senataxin (SETX), or by the inhibition of topoisomerase I, are actively processed into DNA double-strand breaks (DSBs) by the nucleotide excision repair endonucleases XPF and XPG. Surprisingly, DSB formation requires the transcription-coupled nucleotide excision repair (TC-NER) factor Cockayne syndrome group B (CSB), but not the global genome repair protein XPC. These findings reveal an unexpected and potentially deleterious role for TC-NER factors in driving R-loop-induced DNA damage and genome instability.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Sollier
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Caroline Townsend
authors.initials: CT
authors.lastname: Stork
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avenida Américo Vespucio, 41092 Seville, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: García-Rubio
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Renee D
authors.initials: RD
authors.lastname: Paulsen
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avenida Américo Vespucio, 41092 Seville, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Aguilera
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: cimprich@stanford.edu.
authors.forename: Karlene A
authors.initials: KA
authors.lastname: Cimprich
mesh_terms: D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D015894:Genome, Human; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D012331:RNA, Fungal; D012324:RNA-Dependent RNA Polymerase; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5; C095888:xeroderma pigmentosum group F protein