Abstract
BackgroundDuring microRNA (miRNA) maturation in humans and flies, Drosha and Dicer cut the precursor transcript, thereby producing a short RNA duplex. One strand of this duplex becomes a functional component of the RNA-Induced Silencing Complex (RISC), while the other is eliminated. While thermodynamic asymmetry of the duplex ends appears to play a decisive role in the strand selection process, the details of the selection mechanism are not yet understood.ResultsHere, we assess miRNA strand selection bias in humans and fruit flies by analyzing the sequence composition and relative expression levels of the two strands of the precursor duplex in these species. We find that the sequence elements associated with preferential miRNA strand selection and/or rejection differ between the two species. Further, we identify another feature that distinguishes human and fly miRNA processing machinery: the relative accuracy of the Drosha and Dicer enzymes.ConclusionOur result provides clues to the mechanistic aspects of miRNA strand selection in humans and other mammals. Further, it indicates that human and fly miRNA processing pathways are more distinct than currently recognized. Finally, the observed strand selection determinants are instrumental in the rational design of efficient miRNA-based expression regulators.
Highlights
During microRNA maturation in humans and flies, Drosha and Dicer cut the precursor transcript, thereby producing a short RNA duplex
MicroRNAs are small single-stranded endogenous RNAs, approximately 22 nucleotides in length, which are involved in posttranscriptional gene regulation in a wide variety of species [1,2,3,4]. miRNAs function as a component of an RNA-Induced Silencing Complex (RISC) by guiding it to specific targets through base-pairing interaction between the miRNA seed region and a complementary sequence in the 3'-UTR of a target transcript [5,6]
Analyzing sequence features underlying miRNA strand selection bias in humans and flies, we find several outstanding features characterising human, but not fly miRNAs. These features include a bias towards specific nucleotides at the 5-ends of both selected and excluded strands (U and C, respectively), and a pronounced purine/pyrimidine content difference between the two strands. We speculate that these additional sequence features may have evolved to facilitate discrimination between the two stands of the precursor duplex
Summary
During microRNA (miRNA) maturation in humans and flies, Drosha and Dicer cut the precursor transcript, thereby producing a short RNA duplex One strand of this duplex becomes a functional component of the RNA-Induced Silencing Complex (RISC), while the other is eliminated. The hairpin is excised from a longer precursor by Drosha and subsequently cut by Dicer, which produces an RNA duplex with 3' overhanging ends, each 2 nucleotides long [8,10,11,12,13]. This duplex structure is shared between miRNA and small interfering RNA (siRNA) processing pathways [14,15]. Since the selected strand determines the functional specificity of an RISC, this is a crucial step in the RNA interference (RNAi) pathway
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