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.

The work was supported by a Wellcome Trust Programme Grant to N.J.P. and Royal Society University Research fellowship and MRC NIRG MR/J007870/1 to N.G. J.F.C. and S.M. were supported by the Medical Research Council and Wellcome Trust (grant 095518/Z/11/Z). E.E. was supported by grants from the Spanish Ministry of Science and by the Sandra Ibarra Foundation (BIO2008-01091, BIO2011-23920, and CSD2009-00080). M.P. is supported by the Novo Nordisk Foundation