Gromak, Natalia2; Dienstbier, Martin2; Macias, Sara5; Plass, Mireya6; Eyras, Eduardo7; Cáceres, Javier F.5; Proudfoot, Nicholas J.2
1 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet2 University of Oxford3 University of Edinburgh4 Universitat Pompeu Fabra5 University of Edinburgh6 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet7 Universitat Pompeu Fabra
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.