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Nonsense‐mediated mRNA decay: novel mechanistic insights and biological impact

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Nonsense‐mediated mRNA decay (NMD) was originally coined to define a quality control mechanism that targets mRNAs with truncated open reading frames due to the presence of a premature termination codon. Meanwhile, it became clear that NMD has a much broader impact on gene expression and additional biological functions beyond quality control are continuously being discovered. We review here the current views regarding the molecular mechanisms of NMD, according to which NMD ensues on mRNAs that fail to terminate translation properly, and point out the gaps in our understanding. We further summarize the recent literature on an ever‐rising spectrum of biological processes in which NMD appears to be involved, including homeostatic control of gene expression, development and differentiation, as well as viral defense. WIREs RNA 2016, 7:661–682. doi: 10.1002/wrna.1357 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability
Schematic illustration of domains and motifs of important mammalian NMD factors. Amino acid numbering relates to the human proteins. All proteins are drawn to the same scale except for SMG1. CH: cysteine‐histidine rich domain; SQ: serine‐glutamine rich domain; MIF4G: middle of 4G‐like domains; UBD: UPF1‐binding domain; RRM: RNA recognition motif; EBM: exon junction binding motif; HEAT: Huntingtin, elongation factor 3 (EF3), A (PP2A), yeast kinase TOR1 domain; FAT: focal adhesion kinase domain; PIKK: phosphatidylinositol 3‐kinase‐related protein kinase domain; FATC: C‐terminal FAT domain; PIN: PilT N‐terminus domain; PC: C‐terminal proline‐rich region.
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NMD as a cell‐intrinsic viral defense mechanism. NMD can restrict RNA+ alphavirus replication by targeting the viral genome for degradation during early cytosolic steps of the infection. When NMD is impaired (e.g., by depletion of UPF1, SMG5, or SMG7), all steps in the replication cycle are stimulated, leading to the production and release of more virus progeny.
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NMD activity is regulated during stress response. Under normal conditions (green) NMD destabilizes IRE1α mRNA, a central UPR component, thereby preventing UPR activation. Under ER stress (red) UPR is activated and inhibits NMD via eIF2α phosphorylation, triggering IRE1α accumulation and hence a robust UPR activation. Stress‐induced inhibition of NMD also results in a higher accumulation of ATF4, a transcriptional activator of the integrated stress response (ISR) with uORFs in its mRNA. Therefore, modulation of NMD activity plays a key role in the initial phase of the stress response. In conditions of prolonged stress, the UPR and ISR pathways activate a proapoptotic program. In cells undergoing apoptosis, NMD activity can be further downregulated by the production of caspase‐derived proteolytic forms of UPF1. This establishes a reinforcing feedback loop that will irreversibly commit the cell to apoptosis.
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Suggested roles for NMD in stem cell differentiation. (a) NMD promotes the differentiation of ESCs into the three germ layers, at least partially, by downregulating the mRNA levels of pluripotency genes, like c‐Myc. (b) UPF1 promotes the proliferative, undifferentiated state of neuronal stem cells, by inducing the decay of mRNAs encoding proneural factors and proliferation inhibitors. Neuronal differentiation is triggered when a neurogenic signal causes a rapid increase in the levels of the neuronally expressed miR‐128, which downregulates UPF1 mRNA by binding to the 3′ UTR of the UPF1 mRNA, and consequently represses NMD. UPF1 and miR‐128, a part of a self‐reinforcing negative feedback control system, can act as a molecular switch to lock in the different cellular states.
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Homeostatic regulation of splicing factor levels by AS‐NMD. Splicing activators and repressors can autoregulate their own protein levels through alternative splicing of their cognate pre‐mRNAs. When the splicing factor is present at high levels in the cell, it inhibits its own expression by stimulating the production of mRNA splice variants that will be targeted for degradation by NMD. Splicing activators stimulate the inclusion of stop codon exons, whereas splicing inhibitors repress the inclusion of a coding exon and hence generate PTC+ mRNAs. The relative levels of splicing activators and inhibitors further impact the alternative splicing of all other pre‐mRNAs in the cell.
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Nonsense‐mediated mRNA decay activation and target degradation. (a) Aberrant translation termination occurs when the termination codon (TC) is distant to the poly(A) tail. NMD licensing includes the interaction of ribosome‐bound ERF3 with UPF1 instead of PABP, and UPF1 activation relies on the recruitment of UPF2 and/or UPF3. In this model, UPF1 is proposed to initially bind mRNA nonspecifically and interact with ERFs on aberrantly terminating ribosomes. UPF1 is activated by UPF2 and/or UPF3 (EJC‐independent NMD activation). Adjacent EJCs enhance UPF2/UPF3 recruitment and therefore facilitate NMD activation (EJC‐enhanced NMD activation). (b) SMG1 kinase is activated when its inhibitory counterparts SMG8 and SMG9 are released, which is facilitated by UPF2 and DHX34. SMG1 phosphorylates UPF1 on N‐ and C‐terminal Ser and Thr residues followed by Gln (S/T‐Q). The helicase activity of UPF1 stimulates downstream NMD events. (c) Phosphorylated UPF1 (p‐UPF1) can promote mRNA degradation by at least three distinct mechanisms: SMG6‐mediated endonucleolytic cleavage (a), recruitment of the decapping complex (DCPC) directly by UPF1 or via PNRC2 (b), or SMG7‐mediated recruitment of the CCR4‐NOT complex (c). NMD‐targeted mRNAs are further degraded by general cellular exonucleolytic activities.
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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Regulation of RNA Stability

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