Translational control by the 3′-UTR: the ends specify the means

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Abstract

In most cases, translational control mechanisms result from the interaction of RNA-binding proteins with 5′- or 3′-untranslated regions (UTRs) of mRNA. In organisms ranging from viruses to humans, protein-mediated interactions between transcript termini result in the formation of an RNA loop. Such RNA ‘circularization’ is thought to increase translational efficiency and, in addition, permits regulation by novel mechanisms, particularly 3′-UTR-mediated translational control. Two general mechanisms of translational inhibition by 3′-UTR-binding proteins have been proposed, one in which mRNA closure is disrupted and another in which mRNA closure is required. Experimental evidence for the latter is provided by studies of interferon-γ-mediated translational silencing of ceruloplasmin expression in monocytic cells. A multi-species analysis has shown that, in most vertebrates, 3′-UTRs are substantially longer than their 5′ counterparts, indicating a significant potential for regulation. In addition, the average length of 3′-UTR sequences has increased during evolution, suggesting that their utilization might contribute to organism complexity.

Section snippets

Translational control mechanisms

We are beginning to understand the control processes and molecular mechanisms that regulate translation. Translational regulation can be subdivided into two groups, global and transcript-specific control. Global control enables vertebrate cells to utilize strategies that offer temporal, and possibly spatial, co-regulation of many, or most, expressed transcripts. Such control is used in cellular responses to a threatening stress, such as viral infection, ultraviolet irradiation, hypoxia and

The ‘closed-loop’ or ‘circular’ structure of mRNA

How 3′-UTR-binding proteins regulate the initiation of translation at the distant 5′ terminus is less obvious than how 5′-UTR-binding proteins regulate initiation. However, experiments in several different areas of mRNA biology have led investigators to arrive at a common conclusion: the ‘head’ and ‘tail’ of a transcript might be spatially proximate as a result of interactions between the ends 15, 16. An early indication of a functional interaction between transcript termini came from the

Circularization of mRNA: variations on a theme

The biological importance of 5′–3′ interactions of coding RNA is underscored by the diversity of mechanisms of transcript closure that have evolved in organisms ranging from viruses to humans. In the simplest example yet described, the positive-strand RNA genome of barley yellow dwarf virus (Fig. 2b) forms a closed loop in the absence of either a cap or a poly(A) tail, by direct base-pairing (‘kissing’) between a 105-nt translation element in the 3′-UTR and the 5′-UTR; an as-yet unidentified

Transcript circularization in translational control

Several mechanisms have been proposed for the regulation of initiation by transcript circularization. The observation that eIF4G mediates poly(A)-tail-dependent translation suggests that the eIF4G–PABP complex enhances ribosome recruitment, possibly by directed recycling of the 40S ribosomal subunit from the 3′-UTR to the 5′ terminus (Fig. 3a) [30]. In this case, disruption of the 5′–3′ interaction – by intercepting the interaction of PABP either with the poly(A) tail (Fig. 3bi) or with eIF4G (

Transcript 3′-UTRs: regions of opportunity and risk

Binding of the IRE-binding protein to the 5′-UTR IRE of ferritin and binding of hnRNP K and hnRNP E1 to the 3′-UTR DICE of 15-lipoxygenase are the prototypic, and perhaps best-understood, mechanisms of translational control by trans-acting factors. In the past six years, we have begun to appreciate the diversity of translational control mechanisms, many of them involving protein interactions at the 3′-UTR. At the same time, substantial biochemical, morphological and functional evidence has

Acknowledgements

Our work was supported by Public Health Service grants HL-29582 and HL-52692 from the National Heart Lung and Blood Institute, National Institutes of Health (to P.L.F.), and by a Scientist Development Grant from the American Heart Association, National Affiliate (to B.M.). We are grateful to Ken Kula for artistry.

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