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. 2010 Nov;11(7):537-61.
doi: 10.2174/138920210793175895.

MicroRNA: Biogenesis, Function and Role in Cancer

Leigh-Ann Macfarlane  1 , Paul R Murphy
Affiliations

MicroRNA: Biogenesis, Function and Role in Cancer

Leigh-Ann Macfarlane et al. Curr Genomics. 2010 Nov.

Abstract

MicroRNAs are small, highly conserved non-coding RNA molecules involved in the regulation of gene expression. MicroRNAs are transcribed by RNA polymerases II and III, generating precursors that undergo a series of cleavage events to form mature microRNA. The conventional biogenesis pathway consists of two cleavage events, one nuclear and one cytoplasmic. However, alternative biogenesis pathways exist that differ in the number of cleavage events and enzymes responsible. How microRNA precursors are sorted to the different pathways is unclear but appears to be determined by the site of origin of the microRNA, its sequence and thermodynamic stability. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC). MicroRNA assembles into RISC, activating the complex to target messenger RNA (mRNA) specified by the microRNA. Various RISC assembly models have been proposed and research continues to explore the mechanism(s) of RISC loading and activation. The degree and nature of the complementarity between the microRNA and target determine the gene silencing mechanism, slicer-dependent mRNA degradation or slicer-independent translation inhibition. Recent evidence indicates that P-bodies are essential for microRNA-mediated gene silencing and that RISC assembly and silencing occurs primarily within P-bodies. The P-body model outlines microRNA sorting and shuttling between specialized P-body compartments that house enzymes required for slicer -dependent and -independent silencing, addressing the reversibility of these silencing mechanisms. Detailed knowledge of the microRNA pathways is essential for understanding their physiological role and the implications associated with dysfunction and dysregulation.

Keywords: Cancer.; MicroRNA; Post-transcriptional gene regulation; RNA interference (RNAi).

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Figures

Fig. (1). MicroRNA maturation and function.
Fig. (1). MicroRNA maturation and function.
The miRNA gene is transcribed to generate a primary microRNA (pri-miRNA) precursor molecule that undergoes nuclear cleavage to form a precursor microRNA (pre-miRNA). The pre-miRNA is cleaved in the cytoplasm to create a microRNA duplex (miRNA:miRNA*, passenger strand designated with asterisk) containing the mature miRNA. The duplex unwinds and the mature miRNA assembles into RISC. The miRNA base-pairs with target mRNA to direct gene silencing via mRNA cleavage or translation repression based on the level of complementarity between the miRNA and the mRNA target.
Fig. (2). Nuclear component of microRNA biogenesis.
Fig. (2). Nuclear component of microRNA biogenesis.
Intergenic miRNAs are transcribed by RNA polymerase II or III generating a primary miRNA (pri-miRNA) molecule, which is processed into a precursor miRNA (pre-miRNA) by the microprocessor complex comprised of DGCR8 and Drosha. Pre-miRNAs are exported to the cytoplasm in a nucleocytoplasmic transporter containing Exportin 5 and Ran-GTP. MiRNA within introns are transcribed as part of precursor mRNA (pre-mRNA) by RNA polymerase II. The miRNA sequence is excised from the pre-mRNA by spliceosomal components or the microprocessor to liberate a mirtron or a pre-miRNA that is exported. Alternatively, a primary miRNA (pri-miRNA) is released which undergoes microprocessor cleavage to generate pre-miRNA.
Fig. (3). Cytoplasmic component of microRNA biogenesis.
Fig. (3). Cytoplasmic component of microRNA biogenesis.
Pre-miRNA is cleaved by Dicer to generate miRNA duplex or by Ago2 to generate an Ago2-cleaved precursor miRNA” (ac-pre-miRNA) that subsequently acts as a substrate for Dicer. The asterisk (*) near a protein symbolizes it is responsible for the cleavage event. The miRNA duplex liberates the mature miRNA to assemble into RISC loading complex comprised of Ago2, TRBP, PACT and Dicer. The mechanism of mature miRNA release is unclear. Possible mechanisms involving RNA Helicase A (RHA), Dicer cleavage, Ago2 cleavage and uncharacterized proteins have been illustrated.
Fig. (4). Slicer-dependent microRNA mediated gene silencing.
Fig. (4). Slicer-dependent microRNA mediated gene silencing.
Extensive base-pairing between the miRNA guide and mRNA target permit Ago2 mRNA cleavage. Subsequently, mRNA is deadenylated by protein complexes comprised of Pop2, Ccr4 and Not1. mRNA is then degraded from 3’ to 5’ by the exosome complex or from 5’ to 3’ by the Xrn1p exonuclease following decapping by Dcp enzymes.
Fig. (5). Slicer-independent microRNA mediated gene silencing.
Fig. (5). Slicer-independent microRNA mediated gene silencing.
Limited base-pairing between the miRNA guide and mRNA target create bulges that inhibit Ago2 mRNA cleavage and propels slicer-independent gene silencing mechanisms. MiRNA can repress translation directly pre- or post- translation initiation which is determined by the target mRNA promoter. Alternatively, miRNA can repress translation indirectly by segregating mRNA away from ribosomes to cytoplasmic foci and accelerating deadenylation and decapping processes. Ultimately, mRNA can be isolated for storage or be targeted for decay via Xrn1p or exosome degradation. Stored mRNA can return to active translation or be targeted for degradation.
Fig. (6). The P-body model.
Fig. (6). The P-body model.
The RISC loading complex containing mature miRNA translocates to a P-body compartment specific for RISC assembly and activation. Upon target recognition the silencing mechanism is determine as slicer -depepndent or –independent, both having distinct functional compartments. Target mRNA will then be redirected for degradation or mRNA storage, which can be later returned to active translation or degraded.
Fig. (7). Proposed microRNA working model.
Fig. (7). Proposed microRNA working model.
duplexes have mismatched pairs an Ago2 independent bypass mechanism will be employed. I hypothesize that this mechanism uses RNA helicase A to unwind the miRNA duplex which permits Ago2 of the RISC loading complex to load the arm with the least stable 5’end, the miRNA guide. Once the mature miRNA guide is bound to Ago2 additional RISC associated proteins, such as GW182, assemble to form the active miRISC which will seek out and bind its target mRNA.
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