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  • Review Article
  • Published:

Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?

Key Points

  • MicroRNAs (miRNAs) — approximately 21-nucleotide-long, genome-encoded RNAs — have emerged as key regulators of gene expression in eukaryotes.

  • miRNAs represent just one class of small RNA regulators, the others being small interfering RNAs (siRNAs) and PIWI-associated RNAs (piRNAs), all of which operate in processes that are collectively referred to as RNA silencing.

  • miRNAs control gene expression post-transcriptionallly, by hybridizing to target mRNAs and thereby regulating their translation or stability.

  • By targeting dozens or even hundreds of different mRNAs, individual miRNAs have the potential to fine-tune or modulate the expression of genes that participate in a specific metabolic or developmental pathway; but they can also act as reversible switches to turn on and off mRNA translation.

  • miRNAs function as components of ribonucleoprotein (RNP) complexes, referred to as either miRNPs or miRNA-induced silencing complexes (miRISCs), with proteins of the Argonaute (AGO) family being the most important and best characterized components.

  • Studies performed both in vivo and in cell-free extracts have provided some mechanistic insights into the miRNA-mediated repression, although many details of the repression are still poorly understood.

Abstract

MicroRNAs constitute a large family of small, approximately 21-nucleotide-long, non-coding RNAs that have emerged as key post-transcriptional regulators of gene expression in metazoans and plants. In mammals, microRNAs are predicted to control the activity of approximately 30% of all protein-coding genes, and have been shown to participate in the regulation of almost every cellular process investigated so far. By base pairing to mRNAs, microRNAs mediate translational repression or mRNA degradation. This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of microRNA function.

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Figure 1: Examples of reporters used in studies of microRNA function.
Figure 2: Domain organization of Argonaute and GW182 proteins.
Figure 3: Possible mechanisms of the microRNA-mediated post-transcriptional gene repression in animal cells.
Figure 4: Possible interplay between RNA binding proteins and micro-ribonucleoproteins interacting with the mRNAs 3′ UTR.

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Acknowledgements

We thank R. Jackson for drawing our attention to the bypass suppressors of the yeast Pab1 deletion. We thank H. Grosshans, N. Standart, R. Jackson and members of the Filipowicz and Sonenberg groups for their comments. S.N.B is a recipient of Human Frontier Science Program Organization (HFSPO) long-term fellowship. The Friedrich Miescher Institute is supported by the Novartis Research Foundation. N.S. was supported by grants from the HFSPO and the Canadian Institute of Health Research and is a Howard Hughes Medical Institute International Scholar. Research by W.F. is also supported by the EC FP6 Program 'Sirocco'.

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Correspondence to Witold Filipowicz or Nahum Sonenberg.

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Supplementary information S1 (table)

Examples of miRNA-targeted mRNAs, repression of which is associated with no or only minimal mRNA degradation. (PDF 228 kb)

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Glossary

Dicer

An RNase III family endonuclease that processes dsRNA and pre-miRNAs into small interfering RNAs and microRNAs, respectively.

Small interfering RNAs

(siRNAs). Small RNAs that are similar in size to microRNAs but are derived from the progressive cleavage of long dsRNA by Dicer. Upon incorporation into an RISC, siRNAs guide the endonucleolytic cleavage of the target mRNA.

RNA interference

The dsRNA-induced, sequence-homology dependent gene-silencing mechanism. The dsRNA is processed to siRNAs, which, upon incorporation into an RISC, guide the endonucleolytic cleavage of the target mRNA.

RNA-induced silencing complex

(RISC). The ribonucleoprotein complex, consisting of small interfering RNA and an AGO protein, that harbours the 'slicer' activity, which cleaves an mRNA target in the middle of siRNA–mRNA complementarity.

micro-ribonucleoprotein

(miRNP). A ribonucleoprotein complex containing a miRNA and one of the AGO proteins. Depending on the identity of the associated AGO, it might harbour a 'slicer' activity, characteristic of an RISC.

m7G cap

The 7-methylguanosine (m7G) that is linked by a 5–5′ triphosphate bridge to the first transcribed nucleoside at the 5′ end of eukaryotic mRNAs.

Internal ribosomal entry site

(IRES). An RNA element, usually present in the 5′ UTR, that allows m7G-cap-independent association of ribosome with mRNA.

ApppN cap

An unmethylated cap analogue that is not bound by eIF4E. The mRNAs with an artificially introduced ApppN cap instead of a physiological m7GpppN cap are translated inefficiently.

Polysome gradient analysis

A technique that involves the sedimentation of cell extracts through a gradient of sucrose or glycerol, thereby allowing the determination of the number of ribosomes that are associated with a specific mRNA. Repression of translational initiation, which results in the less efficient loading of ribosomes onto mRNA, is usually associated with a shift of mRNA towards the top of the gradient.

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Filipowicz, W., Bhattacharyya, S. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?. Nat Rev Genet 9, 102–114 (2008). https://doi.org/10.1038/nrg2290

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