title: Redox Signaling by the RNA Polymerase III TFIIB-Related Factor Brf2.
abstract: TFIIB-related factor 2 (Brf2) is a member of the family of TFIIB-like core transcription factors. Brf2 recruits RNA polymerase (Pol) III to type III gene-external promoters, including the U6 spliceosomal RNA and selenocysteine tRNA genes. Found only in vertebrates, Brf2 has been linked to tumorigenesis but the underlying mechanisms remain elusive. We have solved crystal structures of a human Brf2-TBP complex bound to natural promoters, obtaining a detailed view of the molecular interactions occurring at Brf2-dependent Pol III promoters and highlighting the general structural and functional conservation of human Pol II and Pol III pre-initiation complexes. Surprisingly, our structural and functional studies unravel a Brf2 redox-sensing module capable of specifically regulating Pol III transcriptional output in living cells. Furthermore, we establish Brf2 as a central redox-sensing transcription factor involved in the oxidative stress pathway and provide a mechanistic model for Brf2 genetic activation in lung and breast cancer.
authors.affiliation: Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Jerome
authors.initials: J
authors.lastname: Gouge
authors.affiliation: Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Karishma
authors.initials: K
authors.lastname: Satia
authors.affiliation: Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guthertz
authors.affiliation: Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Marcella
authors.initials: M
authors.lastname: Widya
authors.affiliation: Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Andrew James
authors.initials: AJ
authors.lastname: Thompson
authors.affiliation: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Cousin
authors.affiliation: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Dergai
authors.affiliation: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Nouria
authors.initials: N
authors.lastname: Hernandez
authors.affiliation: Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, UK. Electronic address: alessandro.vannini@icr.ac.uk.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vannini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D012320:RNA Polymerase III / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D016415:Sequence Alignment; D015398:Signal Transduction; D035361:Transcription Factor TFIIIB / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C416185:BRF2 protein, human; D035361:Transcription Factor TFIIIB; D004247:DNA; D012320:RNA Polymerase III