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How to get away with nonsense: Mechanisms and consequences of escape from nonsense‐mediated RNA decay

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Abstract Nonsense‐mediated RNA decay (NMD) is an evolutionarily conserved RNA quality control process that serves both as a mechanism to eliminate aberrant transcripts carrying premature stop codons, and to regulate expression of some normal transcripts. For a quality control process, NMD exhibits surprising variability in its efficiency across transcripts, cells, tissues, and individuals in both physiological and pathological contexts. Whether an aberrant RNA is spared or degraded, and by what mechanism, could determine the phenotypic outcome of a disease‐causing mutation. Hence, understanding the variability in NMD is not only important for clinical interpretation of genetic variants but also may provide clues to identify novel therapeutic approaches to counter genetic disorders caused by nonsense mutations. Here, we discuss the current knowledge of NMD variability and the mechanisms that allow certain transcripts to escape NMD despite the presence of NMD‐inducing features. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA in Disease and Development > RNA in Disease RNA Turnover and Surveillance > Regulation of RNA Stability
Mammalian model of nonsense‐mediated RNA decay (NMD) activation. (a) During translation of a normal mRNA the ribosome dislodges exon junction complexes (EJCs) as it traverses the RNA molecule up until the NTC. (b) Activation of NMD on a premature termination codon (PTC)‐containing mRNA can occur by at least two mechanisms: (a) during EJC‐dependent NMD, a PTC found more than 50–55 nucleotides upstream of a downstream exon–exon junction triggers NMD. (b) EJC‐independent NMD relies on proteins other than the EJC found downstream of the PTC, including UPF1. Red ovals represent NMD‐associated factors
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Varying RNA quality control efficiency modulates expression of protein‐truncating variants
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Cellular contexts that induce variability in NMD. (a) Cell stresses including oxidative stress, unfolded protein response (UPR), viral infection and the tumor microenvironment can induce phosphorylation of the translation initiation factor, eIF2α, and lead to translation attenuation and consequently, NMD inhibition. (b) Variability in the level of exon junction complexes (EJCs) and associated factors as well as the efficiency of EJC deposition can vary NMD. (c) Cellular states such precursor versus differentiated cells, cells undergoing apoptosis, and cells derived from disease states (e.g., facioscapulohumeral muscular dystrophy [FSHD]) show characteristic modulation of NMD factor levels that allows variation in NMD efficiency. Red ovals represent NMD‐associated factors
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Graphical illustration of the different gene‐specific molecular events that promote escape from nonsense‐mediated RNA decay (NMD). Premature termination codon (PTC)‐containing mRNAs can be generated via multiple mechanisms. Among co‐transcriptional mechanisms that prevent the production of an NMD isoform, an alternative splicing decision that leads to the exclusion of an exon containing an in‐frame PTC is shown. Not shown are alternative transcription initiation and alternative polyadenylation, both of which can allow the exclusion of a PTC from the final transcript. Post‐transcriptional escape from NMD can be mediated by gene‐specific elements such as nucleotide sequences or mRNA structure and may facilitate mRNA escape from NMD by two potential mechanisms: (a) facilitating recruitment of RNA‐binding factors that can modulate NMD, or (b) by stimulating non‐canonical translation at the PTC which causes removal of downstream exon junction complexes (EJCs) and inhibition of NMD, including translation readthrough and translation reinitiation. Red oval represents NMD‐associated factors; blue oval represents NMD‐modifying factors.
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RNA Turnover and Surveillance > Regulation of RNA Stability
RNA in Disease and Development > RNA in Disease
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

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