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  • Review Article
  • Published:

Early nonsense: mRNA decay solves a translational problem

Key Points

  • Cells use several different mechanisms to ensure the fidelity of gene expression, including processes that monitor the integrity of RNA synthesis and processing, transfer RNA aminoacylation, peptide elongation and protein folding. The process known as nonsense-mediated mRNA decay (NMD) ensures that mRNAs harbouring premature translation-termination codons are targeted for rapid degradation.

  • NMD has been extensively studied in yeast, worms, flies and mammals, leading to the identification of some basic parameters of the process and a key set of regulatory factors. NMD depends on concurrent mRNA translation and on nonsense-codon recognition by the translational apparatus. At least in yeast, recognition of an mRNA as an NMD substrate can occur at any time during the cellular lifetime of the transcript. The principal NMD regulators in all eukaryotes are encoded by the UPF1, NMD2 (also known as UPF2) and UPF3 genes.

  • Premature termination triggers NMD but normal termination does not. Although premature termination has generally been considered to be the mechanistic equivalent of normal termination, recent experiments in yeast indicate that this conclusion is unwarranted. Premature termination appears to be much less efficient than normal termination and might be the only one of the two translation-termination processes that uses the factors that are encoded by the UPF and NMD genes.

  • The 3′-UTR of an mRNA has an important role in termination-codon function. In some cases, the NMD phenotype of a premature terminator can be alleviated by deleting the downstream coding-region sequences, by tethering poly(A)-binding protein (PABP) close to the premature termination codon, or by placing natural 3′-UTR sequences immediately distal to a premature termination codon.

  • The faux UTR model for NMD in yeast postulates that the mRNA sequence distal to a premature terminator, which forms an unconventional 3′-UTR, is not the functional equivalent of a normal 3′-UTR. Proximity to the poly(A) tail (and its bound PABP) is thought to have a qualitative and/or quantitative influence on the nature of the termination event, probably as a consequence of the PABP interaction with the release factor eRF3. In turn, the absence of proximal PABP at a premature termination codon is hypothesized to facilitate the binding of the NMDfactors to the termination complex, leading to the dissociation of the 60S ribosomal subunit and to the recruitment of the Dcp1–Dcp2 decapping enzyme complex. The recruitment of Dcp1–Dcp2 promotes decapping and thereby renders the transcript susceptible to complete degradation by the 5′-to-3′ decay pathway.

  • Although current models for NMD in mammalian cells appear to differ significantly from the faux UTR model, these differences are reconcilable.

Abstract

Gene expression is highly accurate and rarely generates defective proteins. Several mechanisms ensure this fidelity, including specialized surveillance pathways that rid the cell of mRNAs that are incompletely processed or that lack complete open reading frames. One such mechanism, nonsense-mediated mRNA decay, is triggered when ribosomes encounter a premature translation-termination — or nonsense — codon. New evidence indicates that the specialized factors that are recruited for this process not only promote rapid mRNA degradation, but are also required to resolvea poorly dissociable termination complex.

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Figure 1: The mRNA 'life cycle' in the cytoplasm.
Figure 2: Model for the regulation of CPA1 upstream open reading frame translation and mRNA degradation.
Figure 3: Stabilization of nonsense-containing mRNA by tethered Pab1.
Figure 4: Proposed mechanistic differences between normal and premature translation termination in yeast.

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Acknowledgements

Research in the authors' laboratories was supported by grants from the National Institutes of Health. We are indebted to F. He, S. Ghosh, S. Kervestin and D. Mangus for critical comments on the manuscript and for numerous stimulating discussions.

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Glossary

Nonsense codon

An alternative name for the codons that do not designate the insertion of a specific amino acid during protein synthesis in the standard genetic code. Since UAA, UAG and UGA also promote the termination of protein synthesis, these three codons have also been termed stop codons.

Messenger ribonucleoprotein particle

An mRNA molecule and the proteins that are bound to it.

Closed loop

An mRNP structure in which the interaction of the mRNA 5′ and 3′ ends is promoted, in part, by interactions between the poly(A)-binding protein (PABP), the initiation factor eIF4G and the cap-binding protein eIF4E.

Initiator methionyl transfer RNA

A tRNA that, when aminoacylated with methionine, functions specifically in the translation of mRNA to place the first amino acid of the nascent polypeptide into the ribosome when a start codon (typically AUG) is decoded.

Upstream open reading frame

(uORF). Most mRNAs contain a single open reading frame (ORF); that is, an AUG start codon, followed by a sizeable number of in-frame codons that designate specific amino acids, followed by a termination codon. In some mRNAs, the ORF is preceded by one or more small ORFs, designated uORFs.

Bicistronic mRNA

Also known as dicistronic mRNA. An mRNA that contains two independently translated open reading frames (two cistrons) that are typically non-overlapping.

Untranslated regions

(UTRs). The segments of mRNA that do not usually code for proteins, namely the 5′ segment that precedes the start codon, which is used for translational initiation (5′-UTR), and the 3′ segment that follows the nonsense codon, which signals normal translation termination (3′-UTR). Internal segments of mRNAs can become de facto 3′-UTRs if preceded by a premature termination codon.

Pseudogene

A segment of DNA in the genome that resembles a functional gene but is not functional because of the absence of appropriate regulatory sequences or a complete open reading frame.

Decapping

The process of removing the 5′ cap structure from an mRNA, usually as a step prior to further 5′-to-3′ exonucleolytic digestion of the remainder of the mRNA. In yeast, decapping is catalysed by the Dcp1–Dcp2 complex, of which Dcp2 is thought to be the catalytic component.

Exosome

A complex of exonucleases that functions in the nucleus and cytoplasm to degrade several classes of RNA (including pre-mRNA, pre-ribosomal RNA and mRNA) from the 3′ end.

Deadenylation

The process of shortening of the 3′ poly(A) tail that is present on most eukaryotic mRNAs. Although many deadenylases have been described, the principal cytoplasmic activity in yeast seems to be from the CCR4–NOT complex.

Nonsense suppression

A term that is used to describe the failure of the ribosome to terminate at a nonsense codon and instead to read through it as if the insertion of an amino acid had been specified. Often, the amino acid that is inserted arises from a 'near cognate transfer RNA', that is, one in which two of three codon–anti-codon base pairs are still in place.

Polysome

Also known as polyribosome. It is a complex with two or more ribosomes that are associated with an mRNA.

A site

The site on the ribosome to which aminoacyl-transfer RNA will normally bind.

P site

The site on the ribosome that accommodates peptidyl-transfer RNA.

Exon junction complex

A complex of proteins that is deposited on a transcript as a consequence of pre-mRNA splicing 22–24 nt 5′ to an exon–exon junction.

P body

(Processing body). A site within the cytoplasm that localizes the processes of RNA metabolism and inactivation, including RNA degradation and silencing. mRNA that is sequestered in P bodies is not available for translation.

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Amrani, N., Sachs, M. & Jacobson, A. Early nonsense: mRNA decay solves a translational problem. Nat Rev Mol Cell Biol 7, 415–425 (2006). https://doi.org/10.1038/nrm1942

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