Trends in Cell Biology
Volume 25, Issue 11, November 2015, Pages 651-665
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Review
The Functions of MicroRNAs: mRNA Decay and Translational Repression

https://doi.org/10.1016/j.tcb.2015.07.011Get rights and content

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Animal miRNAs promote mRNA decay by recruiting deadenylases and decapping factors onto the target mRNAs through GW182/TNRC6.

Plant miRNAs do not promote deadenylation but cleave nearly perfectly complementary targets. The 3′ end of the 5′ fragment is uridylated, and both the 5′ and 3′ fragments are decayed by the 5′-to-3′ exoribonuclease.

Animal miRNAs repress translation initiation by promoting dissociation of eIF4F through GW182-mediated displacement of PABP, recruitment of translational inhibitors via GW182, and displacement of the ATP-dependent RNA helicase eIF4A from the translation initiation complex eIF4F.

Plant miRNAs repress translation via various organelle-bound factors. Although the mechanism is unclear, in vitro studies suggest that AGO1–RISC can block translation initiation and ribosome movement.

MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs, which regulate complementary mRNAs by inducing translational repression and mRNA decay. Although this dual repression system seems to operate in both animals and plants, genetic and biochemical studies suggest that the mechanism underlying the miRNA-mediated silencing is different in the two kingdoms. Here, we review the recent progress in our understanding of how miRNAs mediate translational repression and mRNA decay, and discuss the contributions of the two silencing modes to the overall silencing effect in both kingdoms.

Section snippets

miRNAs Mediate Two Modes of Silencing

miRNAs are endogenous, small noncoding RNAs approximately 20–22 nucleotides (nt) long that regulate gene expression by binding to their complementary target mRNAs. To date, over 2000 miRNAs have been identified in the human genome, while the model plant Arabidopsis thaliana has ∼300 miRNAs [1]. They control a broad array of biological processes, including development, differentiation, proliferation, and stress responses 2, 3, 4, 5, 6.

miRNAs cannot work alone. To silence target mRNAs, they need

Mechanism of miRNA-Mediated mRNA Decay in Animals

Although animal miRNAs were initially thought to repress translation of target mRNAs with little or no decrease in mRNA abundance 13, 14, later studies revealed that miRNAs can also promote mRNA destabilization by recruiting deadenylases onto target mRNAs through GW182 protein (TNRC6A–C in mammals and GW182 or Gawky in Drosophila) 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. GW182 protein plays key roles in the animal miRNA pathway through interaction with Ago. Biochemical and structural

Mechanism of miRNA-Mediated mRNA Decay in Plants

In contrast to animal miRNAs, plant miRNAs cannot promote deadenylation [64]; instead, they can direct target RNA cleavage (Figure 2) 8, 65. In the model plant A. thaliana, there are ten Ago proteins (AGO1–10) 66, 67, of which miRNAs are mainly sorted into AGO1. AGO1 has a catalytic tetrad in its PIWI domain and cleaves target mRNAs with fully or nearly fully complementary sequence to the miRNA 65, 68, 69, 70. Although it is unknown how quickly miRNAs cleave their target mRNAs in vivo, in vitro

miRNA-Mediated Translational Repression in Animals

To date, many studies using different organisms and methods have suggested that miRNAs inhibit the initiation step of translation (Box 2) 76, 77, 78, 79. Translational repression at the initiation step is also supported by recent genome-wide analyses of endogenous miRNA targets 80, 81, 82. Although it is still unclear exactly how miRNAs repress translation, three major mechanisms have been proposed in the past few years, including (i) GW182-mediated PABP displacement 48, 49, (ii) recruitment of

Evidence for Translational Silencing and Introduction of Factors Involved

Initially, plant miRNAs were thought to silence target genes only through endonucleolytic activity of Argonaute proteins. Contrary to animal miRNAs, however, which silence many partially complementary target mRNAs without cleavage, each plant miRNA has a few specific target mRNAs with fully or nearly fully complementary sequence [11]. Indeed, plant miRNA-mediated target cleavage has been validated with Northern blotting, 5’-Rapid Amplification of cDNA Ends (RACE) analyses and other assays in

In Animals

Although genetic, biochemical, and structural analyses have uncovered the intricate mechanisms of miRNA-mediated silencing, the relative contributions of mRNA decay and translational repression to the overall silencing remain under debate. Of course the relative contributions of the two pathways should vary depending on the concentration of RISC components, the sequence of target mRNAs (e.g., number or position of miRNA-binding sites), or cell types, but recent genome-wide analyses have

Concluding Remarks

Over the past years, much progress has been achieved in understanding the effector step of animal and plant miRNA pathways. Accordingly, our understanding of the mechanism of miRNA-mediated mRNA decay in animals and target cleavage in plants has significantly matured. In contrast to this, there are many unanswered questions regarding the mechanism of miRNA-mediated translational repression (see Outstanding Questions). In animals, it remains unclear at which step(s) of translation is blocked by

Acknowledgments

We thank Shintaro Iwasaki, Takashi Fukaya, and members of the Tomari laboratory for discussions and critical reading of the manuscript. This work was supported in part by Grant-in-Aids for Scientific Research on Innovative Areas to Y.T. (‘Non-coding RNA neo-taxonomy’) and H-o.I. (‘Nascent-chain biology’).

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