MicroRNA Biogenesis and Its Functions

The first miRNA, lin-4, was initially discovered over a decade ago in Caenorhabditis elegans [6, 7]. Because of the versatile functions, miRNAs were widely recognized in 2001 [8-10]. Currently, miRNAs have been identified in a wide array of organisms, including plants, zebrafish, Drosophila, and mammals [11]. The expression of miRNAs in multicellular organisms exhibits spatiotemporal, tissue- and cell-specificity, suggesting their involvement in tissue morphogenesis and cell differentiation [12]. To date, the public miRNA database, MIRBase, has collected 462 human and 340 mouse miRNA sequences (http://microrna.sanger.ac.uk; release 8.1).

miRNA biogenesis is a comprehensive biochemical process [13]. Briefly, miRNAs are transcribed by RNA polymerase II and initially generated by a large RNA precursor—a primary transcript RNA (pri-miRNA). The pri-miRNA precessed into a stem-loop structure of about 70-100 nt (pre-miRNA) by a double-strand RNA-specific ribonuclease, Drosha, and its interaction partner DGCR8/pasha [14, 15]. These pre-miRNAs are transported into the cytoplasm via an Exportin-5-RanGTP dependent mechanism [16]. In the cytoplasm, the pre-miRNAs are cleaved by a second, dsRNA-specific ribonuclease called Dicer with the help of

TRBP and AGO2 [17]. In Drosophila, there are two distinct Dicers (Dcr1/2). Dcr1 specializes in processing endogenous hairpin RNA precursors into miRNAs, and Dcr2 specializes in the cleavage of double stranded RNAs (dsRNAs) that are destined to function as siRNAs [18]. Loss of dicer-1 completely disrupts the miRNA pathway and only has a weak effect on the siRNA pathway. Dicer-1 also interacts with Loquacious, the double-stranded RNA-binding domain protein to mediate pre-miRNA process [19]. The Loquacious appears to be required for normal miRNA maturation and germ line stem cell maintenance [20].

The mature miRNA (17-25 nt) is bound by a complex called miRNA-associated RNA-induced silencing complex (miRISC). This complex binds to 3' UTR of target mRNA, either degrades mRNA or represses translation of mRNA depending on the degree of complementarity. Most animal miRNAs act as inhibitor in translation of mRNA; however, miRNA-directed mRNA cleavage has also been shown to occur in mammals [21-23]. Therefore, miRNA may share with siRNA pathway in certain cell content.

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