Key Points
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Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that accelerates the decay of transcripts in which translation termination has occurred prematurely.
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NMD can be initiated by mRNA decapping, accelerated poly(A) shortening or endonucleolytic cleavage and is completed subsequently by the exonucleolytic decay pathways.
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NMD activation depends on UPF proteins and SMG factors, as well as the presence of inappropriate messenger ribonucleoprotein (mRNP) structures neighbouring the premature termination codon (PTC). Depending on the species, such structures may include a proximal exon junction complex (EJC) or the absence of poly(A)-binding proteins (PABPs) or other 3′ untranslated region-associated factors.
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NMD is triggered by premature translation termination, a response that stands in striking contrast to stop codon recognition by the ribosome at the end of each round of normal translation. Premature termination is mechanistically distinct from normal termination.
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NMD encompasses multiple ancillary functions, including the promotion of ribosome release and recycling, translational repression, decay of the nascent peptide and accumulation of the PTC-containing pre-mRNA at its site of transcription.
Abstract
Although most mRNA molecules derived from protein-coding genes are destined to be translated into functional polypeptides, some are eliminated by cellular quality control pathways that collectively perform the task of mRNA surveillance. In the nonsense-mediated decay (NMD) pathway premature translation termination promotes the recruitment of a set of factors that destabilize a targeted mRNA. The same factors also seem to have key roles in repressing the translation of the mRNA, dissociating its terminating ribosome and messenger ribonucleoproteins (mRNPs), promoting the degradation of its truncated polypeptide product and possibly even feeding back to the site of transcription to interfere with splicing of the primary transcript.
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Acknowledgements
Research in the authors' laboratories was supported by grants from the US National Institutes of Health (NIH), the Human Frontier Science Program and the US–Israel Binational Science Foundation. The authors thank J. Piton for help with drafting Figure 1 and F. He for useful comments on the manuscript.
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In 1998, Allan Jacobson co-founded PTC Therapeutics, a company that has developed ataluren (PTC124) as a novel, orally bioavailable small molecule that selectively promotes readthrough of premature nonsense codons. He remains affiliated with PTC Therapeutics, serving as director, consultant and SAB chair. Stephanie Kervestin declares no competing financial interests.
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Glossary
- Nonsense codon
-
A codon located at the normal end of an open reading frame of an mRNA that provides a stop signal for the elongation of protein synthesis by the ribosome. When a nonsense codon occurs before that site it promotes premature translation termination and nonsense-mediated mRNA decay activation.
- A-site
-
A ribosomal site that binds aminoacyl-tRNAs. During translational elongation, tRNAs move successively from the A-site to the P-site (which binds peptidyl-tRNA) to the E site (which binds deacylated tRNA), always in response to specific codon–anticodon pairing.
- Nonsense suppression
-
(also known as translational readthrough). If a stop codon is 'read' by a near-cognate aminoacyl-tRNA, the ribosome will insert an amino acid residue and continue to translate sequences downstream of the nonsense codon, usually until it reaches the next stop codon; this is known as nonsense suppression. Its frequency is often monitored as an indicator for the fidelity and efficiency of translation termination.
- Toeprint analysis
-
An in vitro method that identifies the position of ribosomes on an mRNA, on the basis of the inhibition of primer extension by reverse transcriptase from a labelled oligonucleotide hybridized 3′ to the region of interest. Termination codons usually yield a toeprinting fragment that terminates approximately 13 nucleotides downstream of the uracil of the termination codon, spacing that is consistent with ribosomes that have paused with the termination codon in their A-site.
- Zinc-finger domain
-
(CH domain). A protein structural motif that coordinates zinc ions with Cys and His residues. This motif is often central to protein modules that serve as interaction domains or binding sites for DNA or RNA. In UPF1, this domain encompasses a unique combination of three zinc-binding motifs arranged into two tandem modules.
- RNA helicase
-
An enzyme harbouring ATPase and RNA unwinding activity. Cells contain many different RNA helicases that are involved in a wide range of gene expression functions, including pre-mRNA splicing, protein synthesis and mRNA decay.
- P-bodies
-
Cytoplasmic foci that contain high concentrations of factors involved in 5′ to 3′ mRNA decay. The role of P-bodies in mRNA decay has been controversial because these structures are not essential for mRNA decay or microRNA silencing, and mRNAs that enter P-bodies are not necessarily destined for degradation and can exit these foci and reinitiate translation.
- Cycloheximide
-
An inhibitor of protein synthesis in eukaryotes that blocks the translocation of the ribosome during the elongation step. When added to cells or extracts in which translation is underway, this drug will stall elongating ribosomes on the mRNA.
- PIN domain
-
A protein domain of ∼130 amino acids that can function as a ribonuclease and cleave single-stranded RNA. The name is derived from its identification in the amino terminus of the PILT protein.
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Kervestin, S., Jacobson, A. NMD: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol 13, 700–712 (2012). https://doi.org/10.1038/nrm3454
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DOI: https://doi.org/10.1038/nrm3454
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