NMD: a multifaceted response to premature translational termination

• Published in: Nature reviews. Molecular cell biology Vol. 13; no. 11; pp. 700 - 712
• Main Authors: Kervestin, Stephanie, Jacobson, Allan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2012; Nature Publishing Group
• Subjects: 631/337/1645/2020; 631/337/574; Biochemistry; Biochemistry, Molecular Biology; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cell cycle; Codon, Nonsense; Decay; Developmental Biology; Enzymes; Gene expression; Genetic translation; Humans; Life Sciences; Messenger RNA; Nonsense Mediated mRNA Decay; Peptide Chain Termination, Translational - genetics; Peptide Termination Factors - genetics; Peptide Termination Factors - metabolism; Physiological aspects; Polypeptides; Protein Biosynthesis; Protein synthesis; Proteins; Quality control; review-article; Ribonucleic acid; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; Ribosomes; Ribosomes - genetics; Ribosomes - metabolism; RNA; RNA Stability - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - metabolism; Stem Cells; Trans-Activators - metabolism; Transcription Factors - metabolism; Transfer RNA; Yeast; France; United States
• ISSN: 1471-0072; 1471-0080; 1471-0080
• DOI: 10.1038/nrm3454

Key Points Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that accelerates the decay of transcripts in which translation termination has occurred prematurely. NMD can be initiated by mRNA decapping, accelerated poly(A) shortening or endonucleolytic cleavage and is completed subsequently by the exonucleolytic decay pathways. 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. 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. 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. Nonsense-mediated decay (NMD) is one of the surveillance pathways that ensure fidelity in gene expression by recognizing and degrading aberrant mRNAs. How the factors involved in NMD discriminate between normal and prematurely terminated mRNAs, and how they carry out their functions downstream of recognition, has been the subject of intense investigation. 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.