Drosha Regulates Gene Expression Independently of RNA Cleavage Function

•Drosha binds promoter-proximal regions of transcribed human genes•Drosha binding is not associated with RNA cleavage or miRNA processing•Drosha regulates nascent gene transcription•Drosha interacts with CBP80 and RNA Pol II through its N-terminal domain

SummaryDrosha 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.

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