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Gene silencing by microRNAs: contributions of translational repression and mRNA decay

Nature Reviews Genetics volume 12, pages 99–110 (2011)Cite this article

Subjects

Key Points

  • MicroRNAs (miRNAs) repress the expression of mRNA targets by promoting translational repression and mRNA degradation.

  • In animals, target degradation is initiated by accelerated deadenylation, which is normally followed by decapping and subsequent degradation of the mRNA body. However, some deadenylated targets may not be further degraded.

  • In plants, target degradation is initiated by endonucleolytic cleavage catalysed by the Argonaute proteins.

  • Although translational repression and mRNA degradation have both been reported in animals and plants, recent evidence indicates that target degradation provides a major contribution to silencing in both kingdoms.

  • An important difference between the mechanisms of miRNA-mediated silencing in animals and plants is the requirement, in animals, for proteins of the GW182 family.

  • GW182 proteins are essential for silencing in animal cells. They interact with Argonaute proteins through an amino-terminal domain and with the cytoplasmic poly(A)-binding protein (PABPC) through a carboxy-terminal silencing domain.

  • Current models suggest that GW182 proteins interfere with PABPC function in translation and/or mRNA stabilization and promote mRNA deadenylation.

  • A remaining open question is whether silencing of miRNA targets can be entirely attributed to deadenylation or whether additional mechanisms are involved in repressing protein production.

  • Moreover, the contribution of translational repression to silencing in plants remains unknown.

Abstract

Despite their widespread roles as regulators of gene expression, important questions remain about target regulation by microRNAs. Animal microRNAs were originally thought to repress target translation, with little or no influence on mRNA abundance, whereas the reverse was thought to be true in plants. Now, however, it is clear that microRNAs can induce mRNA degradation in animals and, conversely, translational repression in plants. Recent studies have made important advances in elucidating the relative contributions of these two different modes of target regulation by microRNAs. They have also shed light on the specific mechanisms of target silencing, which, although it differs fundamentally between plants and animals, shares some common features between the two kingdoms.

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Figure 1: RNA-target recognition in plants and animals.
Figure 2: Mechanisms of microRNA-mediated gene silencing in animals.
Figure 3: Proteins involved in the effector step of microRNA-mediated gene silencing.
Figure 4: Mechanisms of microRNA-mediated gene silencing in plants.

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Acknowledgements

The research in this laboratory is supported by the Max Planck Society, by grants from the Deutsche Forschungsgemeinschaft (DFG, FOR855 and the Gottfried Wilhelm Leibniz Program awarded to E.I.), and by the Sixth Framework Programme of the European Commission through the SIROCCO Integrated Project LSHG-CT-2006-037900.

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    Eric Huntzinger & Elisa Izaurralde

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Correspondence to Elisa Izaurralde.

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Glossary

Argonaute family proteins

The effectors of RNA-mediated gene-silencing pathways. Small RNAs (for example, small interfering RNAs or microRNAs) guide Argonautes to their RNA targets; Argonautes carry out regulation either directly or by recruiting additional factors. Most multicellular eukaryotes have several Argonaute paralogues.

5′-cap

Eukaryotic mRNA is modified by the addition of an m7G(5′)ppp(5′)N structure at the 5′ terminus. Capping is essential for several important steps of gene expression — for example, mRNA stabilization, splicing, mRNA export from the nucleus and translation initiation.

Polysome

A functional unit of protein synthesis that consists of several ribosomes attached along the length of a single molecule of RNA.

Internal ribosome entry site

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

Krebs-2 ascites tumour cells

Tumour cells grown in vivo in the peritoneal cavity of the mouse.

5′-to-3′ mRNA decay pathway

A major decay pathway for bulk mRNA that is initiated by the removal of the poly(A) tail by deadenylases and is followed by decapping and subsequent 5′-to-3′ exonucleolytic digestion of the mRNA body.

Ribozyme

An RNA molecule with a catalytic activity.

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Huntzinger, E., Izaurralde, E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12, 99–110 (2011). https://doi.org/10.1038/nrg2936

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