Expanding roles for miRNAs and siRNAs in cell regulation

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Abstract

The role of small RNAs as key regulators of mRNA turnover and translation has been well established. Recent advances indicate that the small RNAs termed microRNAs play important roles in cell proliferation, apoptosis and differentiation. Moreover, the microRNA mechanism is an efficient means to regulate production of a diverse range of proteins. As new microRNAs and their mRNA targets rapidly emerge, it is becoming apparent that RNA-based regulation of mRNAs may rival ubiquitination as a mechanism to control protein levels.

Introduction

Gene expression influences so many cellular activities that the study of gene regulation has exerted a siren song over many of us who are interested in cell biology. Although the role that proteins play in this process is well understood, it is becoming clear that small RNAs are also important gene regulatory factors. Small RNAs, including microRNAs (miRNAs) and short interfering RNAs (siRNAs), are components of a RNA-based mechanism of gene regulation found in eukaryotes [1]. siRNAs are utilized throughout the Eukaryota to inhibit viruses and transposable elements 2., 3.. They also play a role in chromosome organization and in silencing the expression of protein-coding genes 4., 5., 6., 7.. The miRNA branch of RNA-based gene regulation is less widespread; miRNAs are found in plants and animals but are apparently absent in fungi such Schizosaccharomyces pombe [5]. Another class of small RNAs, tiny noncoding RNAs (tncRNAs), are related in structure to siRNAs and miRNAs, but their function is unknown 8., 9..

Section snippets

siRNAs

siRNAs have a specific size of ∼22 nucleotides and are produced from double-stranded RNA precursor molecules of varying length and origin [2]. Precursor RNAs are processed by members of the RNase III family of Dicer or Dicer-like (DCL) enzymes [1]; the resulting siRNAs are duplex in structure. They are then incorporated into a RNA-induced silencing complex (RISC) composed of numerous cellular proteins [10]. Incorporation is coupled with duplex unwinding to generate two single-stranded siRNAs,

miRNAs and their biogenesis

Although chemically similar to siRNAs, miRNAs are formed by Dicer cleavage of hairpin-loop RNA precursors rather than long double-stranded RNAs [1]. These precursors are transcribed from genes within the genome. The first two miRNA genes were identified by forward genetics 16., 17., and other miRNA genes have been identified either by direct cloning of processed miRNAs 9., 18., 19., 20., 21., 22., 23., 24. or by computational prediction and validation 8., 25., 26., 27.. The number of miRNA

miRNA activities

Like siRNAs, miRNAs repress gene expression by negatively regulating complementary mRNAs. Plant miRNAs generally trigger target mRNA degradation by base-pairing with near-perfect complementarity 32., 33., 34., 35.•. Conversely, several miRNAs from animals repress gene expression primarily by blocking the translation of mRNA transcripts into protein 17., 36., 37., 38., 39.••. They interact with their targets by imperfect base-pairing to mRNA sequences within 3′ untranslated regions. The exact

Biological regulation by miRNAs

A question of great interest concerns the function of miRNAs in metazoans. Although the functions of only a few miRNAs are known, evidence suggests that miRNAs play diverse but important roles in the development of organisms (Table 1). Mutations in Dicer genes have been isolated in several plant and animal species and, as predicted, these mutants exhibit severely reduced levels of miRNAs. Partial loss of dcl1 activity in Arabidopsis results in delayed flower timing, loss of meristem identity,

Conclusions

It is most likely that gene silencing based on siRNAs arose early in eukaryote evolution. This then provided the means for metazoans to evolve another mechanism based on endogenous genes encoding miRNAs. Given the many levels of gene regulation that already existed when Metazoa first appeared, why did the miRNA-based mechanism arise? In plants, most miRNAs appear to degrade target mRNAs using a siRNA-like mechanism. This implies that a single plant miRNA molecule can repress multiple

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

The authors thank Takashi Hayashi for help with Figure 3, and Erik Sontheimer for helpful comments. The authors are supported by a grant from the National Institutes of Health GM68743.

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