Abstract
SummaryWe recently found that hnRNP A1, a protein implicated in many aspects of RNA processing, acts as an auxiliary factor for the Drosha-mediated processing of a microRNA precursor, pri-miR-18a. Here, we provide the mechanism by which hnRNP A1 regulates this event. We show that hnRNP A1 binds to the loop of pri-miR-18a and induces a relaxation at the stem, creating a more favorable cleavage site for Drosha. We found that approximately 14% of all pri-miRNAs have highly conserved loops, which we predict act as landing pads for trans-acting factors influencing miRNA processing. In agreement, we show that 2′O-methyl oligonucleotides targeting conserved loops (LooptomiRs) abolish miRNA processing in vitro. Furthermore, we present evidence to support an essential role of conserved loops for pri-miRNA processing. Altogether, these data suggest the existence of auxiliary factors for the processing of specific miRNAs, revealing an additional level of complexity for the regulation of miRNA biogenesis.
Highlights
MicroRNAs are small noncoding RNAs that negatively regulate gene expression of complementary mRNAs (Ambros, 2004; Bartel, 2004; He and Hannon, 2004)
We have recently shown that hnRNP A1, a protein implicated in many aspects of RNA processing, binds to a miRNA cluster containing pri-miR-18a and promotes production of miR-18a above other members of the cluster (Guil and Caceres, 2007)
We show that hnRNP A1 binds to the loop of this pri-miRNA and induces a relaxation at the stem, which is important for its processing
Summary
MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression of complementary mRNAs (Ambros, 2004; Bartel, 2004; He and Hannon, 2004). We have recently shown that hnRNP A1, a protein implicated in many aspects of RNA processing, binds to a miRNA cluster containing pri-miR-18a and promotes production of miR-18a above other members of the cluster (Guil and Caceres, 2007). This miRNA is expressed as a cluster of intronic RNAs, the miR-17$18a$19a$20a$19b-1$92 microRNA polycistron, and overexpression of this cluster accelerates c-myc-induced tumor development in a mouse B cell lymphoma model (He et al, 2005). The general RNA-binding hnRNP A1 protein acts as an auxiliary factor for the processing of a miRNA precursor, premiR-18a, at the level of Drosha processing (Guil and Caceres, 2007)
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