Key Points
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Nonsense-mediated mRNA decay (NMD) is a translation-dependent mechanism of RNA decay that probably evolved to eliminate abnormal transcripts that are a consequence of routine abnormalities in gene expression. However, NMD also targets naturally occurring transcripts, such as certain alternatively spliced RNAs and some selenoprotein mRNAs.
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Generally, premature termination codons (PTCs) that are located within mRNA at a position that is more than 50–55 nucleotides (nt) upstream of a splicing-generated exon–exon junction elicit NMD. However, there are exceptions to the rule. For example, edited apolipoprotein B mRNA is immune to NMD. Furthermore, PTCs within the 5′ end of exon 1 of triosephosphate isomerase mRNA fail to elicit NMD because translation reinitiates at an AUG in the middle of exon 1. Also, PTCs within the 3′ end of T-cell receptor-β mRNA elicit NMD, despite the absence of an exon–exon junction located more than 50–55 nt downstream.
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The role of a splicing-generated exon–exon junction complex in NMD reflects the splicing-dependent deposition of an exon junction complex (EJC) ∼20–24 nt upstream of an exon–exon junction. The EJC recruits up-frameshift (UPF) proteins that are required for NMD.
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NMD, which is restricted to newly synthesized mRNA, targets mRNA bound by the mostly nuclear cap-binding proteins CBP80 and CBP20 during a pioneer round of translation. After the pioneer round of translation, CBP80–CBP20 is replaced by eukaryotic initiation factor eIF4E, which is mostly cytoplasmic but also nuclear. By the time eIF4E binds to the mRNA cap, the EJC and associated UPF proteins have been removed so that eIF4E-bound mRNA is immune to NMD.
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Most mRNAs are subject to NMD at a point when they co-purify with nuclei. Nucleus-associated NMD has been proposed to involve translation by nuclear ribosomes or, alternatively, translation by cytoplasmic ribosomes either during the process of mRNA export to the cytoplasm or in a mechanism that feeds back to nuclei. Other mRNAs are subject to NMD in the cytoplasm.
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NMD is mediated by four UPF proteins (UPF1, UPF2, UPF3 and UPF3X), and four SMG proteins (SMG1, SMG5, SMG6 and SMG7). UPF2, UPF3 and UPF3X are mRNP proteins, whereas UPF1 is not. Evidence indicates that SMG proteins function to phosphorylate or dephosphorylate UPF1.
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NMD degrades mRNA from both ends and involves decapping, deadenylating and exonucleolytic activities.
Abstract
Studies of nonsense-mediated mRNA decay in mammalian cells have proffered unforeseen insights into changes in mRNA–protein interactions throughout the lifetime of an mRNA. Remarkably, mRNA acquires a complex of proteins at each exon–exon junction during pre-mRNA splicing that influences the subsequent steps of mRNA translation and nonsense-mediated mRNA decay. Complex-loaded mRNA is thought to undergo a pioneer round of translation when still bound by cap-binding proteins CBP80 and CBP20 and poly(A)-binding protein 2. The acquisition and loss of mRNA-associated proteins accompanies the transition from the pioneer round to subsequent rounds of translation, and from translational competence to substrate for nonsense-mediated mRNA decay.
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Acknowledgements
I thank B. Lehner, J. Lykke-Andersen, J. Mendell and N. Sonenberg for communicating unpublished data, F. Lejeune for generating figures, and members of the Maquat laboratory for their comments on the manuscript. This work was supported by Public Health Service Grants from the National Institutes of Health.
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Glossary
- PREMATURE TERMINATION CODON
-
(PTC). A UAA, UAG or UGA codon that is located within an mRNA upstream of the normal site of translation termination. The PTC directs the premature termination of translation.
- SELENOPROTEIN mRNA
-
An mRNA that has one or more UGA codons and that, together with a cis-residing selenocysteine insertion element, competes with the process of translation termination to direct the incorporation of the amino acid selenocysteine into the growing polypeptide chain.
- mRNA RIBONUCLEOPROTEIN PARTICLE
-
(mRNP). The composite of mRNA and associated proteins. mRNPs can affect mRNA localization, mRNA translation or mRNA half-life.
- NONSENSE CODON RECOGNITION
-
The process by which UAA, UAG or UGA codons direct translation termination, which is mediated by eukaryotic release factors eRF1 and eRF3.
- EXON JUNCTION COMPLEX
-
(EJC). A complex of proteins that is deposited as a consequence of pre-mRNA splicing ∼20–24 nucleotides upstream of splicing-generated exon–exon junctions of newly synthesized mRNA.
- C-TO-U EDITING
-
A post-transcriptional process that involves the deamination of a cytidine (C) nucleotide to a uridine (U) nucleotide within pre-mRNA that, in the case of apolipoprotein B transcripts, converts a glutamine codon (CAA) to a termination codon (UAA).
- APOBEC1–ACF
-
Apolipoprotein B mRNA editing catalytic polypeptide 1 (APOBEC1) in complex with the RNA-binding protein APOBEC1 complementation factor (ACF). APOBEC1–ACF is required for the C-to-U editing of apoliproprotein B transcripts.
- CYTIDINE DEAMINASES
-
A family of enzymes, one member of which is the 27-kDa apolipoprotein B mRNA editing catalytic polypeptide 1 (APOBEC1), that catalyse the C-to-U editing of apolipoprotein pre-mRNA.
- BALBIANI RING mRNA
-
A 35–40-kilobase mRNA in the insect Chironomus tentans that, as shown by electron-microscopy studies, is exported from nuclei to the cytoplasm 5′-end first, and becomes associated with cytoplasmic ribosomes before nuclear export is complete.
- EUKARYOTIC RELEASE FACTOR
-
(eRF). eRF1 and eRF3 function in translation termination at the A site of the 80S ribosome: eRF1 recognizes all three termination codons, and eRF3 functions as a ribosome-dependent GTPase that helps eRF1 to release the newly synthesized polypeptide.
- EXOSOME
-
A complex of at least 11 3′-to-5′ exonucleases that functions in nuclei and the cytoplasm in several different RNA-processing and RNA-degradation pathways.
- DEADENYLASE
-
An enzyme that functions to remove the 3′ poly(A) tail from RNA in a 3′-to-5′ direction.
- SM-LIKE LSM PROTEIN
-
A subunit of a heptameric complex that functions in RNA metabolism. LSM2–8 functions in pre-mRNA splicing in nuclei, and LSM1–7 functions in mRNA decay in the cytoplasm.
- PH DOMAIN
-
A protein domain that is characteristic of the RNase PH family of bacterial phosphate-dependent ribonucleases.
- S1 DOMAIN
-
An RNA-binding domain that is characteristic of the small ribosomal subunit protein S1.
- KH DOMAIN
-
An RNA-binding domain that typifies hnRNP K (hnRNP K homology).
- RNASE D DOMAIN
-
A protein domain that is characteristic of bacterial RNase D.
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Maquat, L. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 5, 89–99 (2004). https://doi.org/10.1038/nrm1310
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DOI: https://doi.org/10.1038/nrm1310
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