Figure 1

Figure illustrates the biogenesis of miRNAs in the cellular nucleous, its transport to the cytoplasm, and processing by Drosha and Dicer Enzymes. The figure also illustrates the RISC incorporation of miRNAs for functional activity in different pathways of translational inhibition or activation. In brief, miRNAs are mostly transcribed from intragenic or intergenic regions by RNA polymerase II into primary transcripts (pri-miRNAs) of variable length (1 kb- 3 kb). In the nucleus Pri-miRNA transcript is further processed by the nuclear ribo-nuclease enzyme ‘Drosha’ thereby resulting in a hairpin intermediate of about 70–100 nucleotides, called pre-miRNA. The pre-miRNA is then transported out of the nucleus by a transporting protein exportin-5. In the cytoplasm, the pre-miRNA is once again processed by another ribonuclease enzyme ‘Dicer’ into a mature double-stranded miRNA. Two strands of double stranded miRNA (miRNA/miRNA* complex) are separated by Dicer processing. After strand separation, mature miRNA strand (miRNA- also called the guide strand) is incorporated into the RNA-induced silencing complex (RISC), whereas the passenger strand, denoted with a star (miRNA*) is commonly degraded. This miRNA/RISC complex is responsible for miRNA function. If on miRNA cloning, or miRNA array, the passenger strand is found at low frequency (less than 15% of the guide strand) it is named miR*. However, if both passenger and guide strand are equal in distribution, then these two strands are named the 3p and 5p version of miRNA depending on their location to either 5' or 3' of the miRNA molecule. In this case both strands can potentially incorporate in position into the RISC complex and have a biological role [9–14]. The specificity of miRNA targeting is defined by Watson–Crick complementarities between positions 2 to 8 from the 5 primed end of the miRNA sequence with the 3′ untranslated region (UTR) of their target mRNAs. When miRNA and its target mRNA sequence show perfect complementarities, the RISC induces mRNA degradation. Should an imperfect miRNA–mRNA target pairing occur, translation into a protein is blocked [9, 10]. Regardless of which of these two events occur, the net result is a decrease in the amount of protein encoded by the mRNA targets. Each miRNA has the potential to target a large number of genes (on average about 500 for each miRNA family). Conversely, an estimated 60% of the mRNAs have one or more evolutionarily conserved sequence that is predicted to interact with miRNAs [9, 10, 15]. miRNAs have been shown to bind to the open reading frame or to the 5′ UTR of the target genes and, in some cases, they have been shown to activate rather than to inhibit gene expression [16]. Researchers have also reported that miRNAs can bind to ribonucleoproteins in a seed sequence and a RISC-independent manner and then interfere with their RNA binding functions (decoy activity) [17]. MiRNAs can also regulate gene expression at the transcriptional level by binding directly to the DNA [18].