Abstract
The ribonuclease Dicer plays a central role in the microRNA pathway by catalyzing the formation of 19–24-nucleotide (nt) long microRNAs. Subsequently incorporated into Argonaute 2 (Ago2) effector complexes, microRNAs are known to regulate messenger RNA (mRNA) translation. Whether shorter RNA species derived from microRNAs exist and play a role in mRNA regulation remains unknown. Here, we report the serendipitous discovery of a 12-nt long RNA species corresponding to the 5′ region of the microRNA let-7, and tentatively termed semi-microRNA, or smiRNA. Using a smiRNA derived from the precursor of miR-223 as a model, we show that 12-nt long smiRNA species are devoid of any direct mRNA regulatory activity, as assessed in a reporter gene activity assay in transfected cultured human cells. However, smiR-223 was found to modulate the ability of the microRNA from which it derives to mediate translational repression or cleavage of reporter mRNAs. Our findings suggest that the 12-nt RNA species, generated along the microRNA pathway, may participate to the control of gene expression by regulating the activity of the related full-length mature microRNA in vivo.
Highlights
Small non-coding RNAs, such as microRNAs, have recently evolved as key players in the fine tuning of gene expression, which is required for preserving well balanced protein levels and maintaining normal cellular functions
While using a high-throughput sequencing (HTS) approach aimed to elucidate the small RNA profile of human platelets, which contain an abundant and diverse array of microRNAs (Landry et al, 2009), we serendipitously discovered a significant number of 12-nt long RNA sequences
Direct messenger RNA (mRNA) regulatory activity, a 12-nt model smiRNA was found to modulate the ability of the microRNA from which it derives to mediate translational repression or cleavage of reporter mRNAs
Summary
Small non-coding RNAs, such as microRNAs, have recently evolved as key players in the fine tuning of gene expression, which is required for preserving well balanced protein levels and maintaining normal cellular functions. Dicer forms a complex with transactivating response (TAR) RNA binding protein (TRBP; Chendrimada et al, 2005; Haase et al, 2005) and processes microRNA precursors (pre-microRNAs), through the concerted action of its C-terminal RNase IIIa and IIIb motifs, to generate a microRNA duplex composed of a 5p and 3p microRNA strand. Recent studies have shown that either strand may subsist and nucleate the formation of Argonaute 2 (Ago2) silencing complexes competent in the regulation of specific messenger RNAs (mRNAs; Okamura et al, 2008; Guo and Lu, 2010; Mah et al, 2010; Yang et al, 2011). MicroRNAs have been shown to activate the expression of a target gene (Vasudevan et al, 2007)
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