title: Drosha regulates gene expression independently of RNA cleavage function.
abstract: Drosha is the main RNase III-like enzyme involved in the process of microRNA (miRNA) biogenesis in the nucleus. Using whole-genome ChIP-on-chip analysis, we demonstrate that, in addition to miRNA sequences, Drosha specifically binds promoter-proximal regions of many human genes in a transcription-dependent manner. This binding is not associated with miRNA production or RNA cleavage. Drosha knockdown in HeLa cells downregulated nascent gene transcription, resulting in a reduction of polyadenylated mRNA produced from these gene regions. Furthermore, we show that this function of Drosha is dependent on its N-terminal protein-interaction domain, which associates with the RNA-binding protein CBP80 and RNA Polymerase II. Consequently, we uncover a previously unsuspected RNA cleavage-independent function of Drosha in the regulation of human gene expression.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Electronic address: natalia.gromak@path.ox.ac.uk.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gromak
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Dienstbier
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Macias
authors.affiliation: Computational Genomics Group, Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain; The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Mireya
authors.initials: M
authors.lastname: Plass
authors.affiliation: Computational Genomics Group, Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Eyras
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Javier F
authors.initials: JF
authors.lastname: Cáceres
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Electronic address: nicholas.proudfoot@path.ox.ac.uk.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Proudfoot
mesh_terms: D001665:Binding Sites; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D039502:Nuclear Cap-Binding Protein Complex / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D043244:Ribonuclease III / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D061805:Transcription Elongation, Genetic
chemical_list: D035683:MicroRNAs; D039502:Nuclear Cap-Binding Protein Complex; D012319:RNA Polymerase II; C517918:DROSHA protein, human; D043244:Ribonuclease III