Drosha Regulates Gene Expression Independently of RNA Cleavage Function

Summary

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.

Graphical Abstract

Highlights

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  Drosha binds promoter-proximal regions of transcribed human genes

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  Drosha binding is not associated with RNA cleavage or miRNA processing

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  Drosha regulates nascent gene transcription

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  Drosha interacts with CBP80 and RNA Pol II through its N-terminal domain

Abstract

In higher eukaryotes, the Microprocessor complex (Drosha endonuclease and DGCR8 RNA-binding protein) recognizes and excises RNA hairpins from larger nuclear transcripts. This ultimately leads to cytoplasmic microRNA production or, in some cases, direct downregulation of gene expression through RNA cleavage. In this study, Gromak, Proudfoot, and colleagues show that Drosha-DGCR8 binds numerous gene promoters not to cleave RNA but, rather, to form a molecular interaction surface. This helps recruit additional factors to gene promoters with a consequent increase in gene activity.