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Regulation of nonsense‐mediated mRNA decay

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Abstract Nonsense‐mediated mRNA decay (NMD) is a highly conserved pathway that was originally identified as a RNA surveillance mechanism that degrades aberrant mRNAs harboring premature termination (nonsense) codons. Recently, it was discovered that NMD also regulates normal gene expression. Genome‐wide studies showed that ablation of NMD alters the expression of ∼10% of transcripts in a wide variety of eukaryotes. In general, NMD specifically targets normal transcripts that harbor a stop codon in a premature context. The finding that NMD regulates normal gene expression raises the possibility that NMD itself is subject to regulation. Indeed, recent studies have shown that NMD efficiency varies in different cell types and tissues. NMD is also subject to developmental control in both higher and lower eukaryotic species. Molecular mechanisms have been defined—including those involving microRNAs and other RNA decay pathways—that regulate the magnitude of NMD in some developmental settings. This developmental regulation of NMD appears to have physiological roles, at least in some model systems. In addition to mechanisms that modulate the efficiency of NMD, mechanisms have recently been identified that serve the opposite purpose: to maintain the efficiency of NMD in the face of insults. This ‘buffering’ is achieved by feedback networks that serve to regulate the stability of NMD factors. The discovery of NMD homeostasis and NMD regulatory mechanisms has important implications for how NMD acts in biological processes and how its magnitude could potentially be manipulated for clinical benefit. WIREs RNA 2012. doi: 10.1002/wrna.1137 This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Development

Feedback regulation of nonsense‐mediated mRNA decay (NMD). (a) The NMD factors depicted are repressed in level by NMD.140,95 This is because these NMD factors are encoded by mRNAs that are themselves NMD substrates. This repression is lifted in response to insults that perturb NMD (depicted as a lightning bolt), which, in turn, permits an upregulation of NMD factors and the potential for restoration of NMD. (b) The weak NMD protein encoded by the UPF3A gene is destabilized by the presence of the strong NMD factor encoded by its paralog UPF3B.61 Loss of UPF3B, which occurs in a subset of intellectual disability patients, permits UPF3A to accumulate, thereby partially restoring NMD.61,146

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Developmental regulation of nonsense‐mediated mRNA decay (NMD) activity. (a) The NMD‐factor UPF2 and the STAU1‐mediated mRNA decay (SMD)‐factor STAU1 compete for binding to UPF1, which is essential for both NMD and SMD. During myogenesis, UPF2 protein level decreases, leading to less binding of UPF2 to UPF1, and increased binding of STAU1 to UPF1. This shift decreases NMD activity and increases SMD activity.120 By an unknown mechanism, UPF3B protein level increases during myogenesis, leading to higher association of UPF3B with UPF1, and consequent increased activity of the UPF3B‐dependent branch of NMD.120 (b) A brain‐enriched microRNA, miR‐128, dramatically increases in level during brain development. Because miR‐128 suppresses the expression of the NMD factors, UPF1 and MLN51, this leads to downregulation of NMD activity during brain development.122

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Modulation of nonsense‐mediated mRNA decay (NMD) activity during development. Evidence suggests that the magnitude of NMD is downregulated (green) or upregulated (red) in the biological contexts shown (see text for details).

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Nonsense‐mediated mRNA decay (NMD) is a branched pathway. The four branches of the NMD pathway that have been so far identified are depicted.51,10 Note that these branches are likely to have overlapping mRNA substrate specificity. Some of the factors required for these branches are shown, but more probably remain to be identified (see Table 1 for list of NMD factors).

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Nonsense‐mediated RNA decay (NMD)‐inducing features. NMD can be elicited by (a) an upstream open reading frame (uORF), (b) a stop codon followed by an intron, (c) an alternative splicing event that generates a premature termination codon (PTC), or (d) a long 3′ untranslated region (UTR). See text for details.

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The dual role of nonsense‐mediated RNA decay (NMD). NMD is both an RNA surveillance pathway that degrades aberrant mRNAs harboring premature nonsense codons and a posttranscriptional regulatory pathway that regulates and degrades a subset of normal mRNAs from wild‐type genes.

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Cell type and tissue‐specific nonsense‐mediated mRNA decay (NMD) feedback regulation. Cells differ in the NMD factors feedback regulated by NMD.95 Depicted are the NMD factor mRNAs downregulated by the UPF3B‐dependent branch of NMD in the cell types and tissues shown (note that HeLa and lymphoblastoid cells are human and purified normal T cells and adult brain are from mice).

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RNA in Disease and Development > RNA in Development
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Turnover and Surveillance > Regulation of RNA Stability

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