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NMD: a multifaceted response to premature translational termination

Nature Reviews Molecular Cell Biology volume 13, pages 700–712 (2012)Cite this article

Subjects

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.

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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Figure 1: Structures and consequences of interactions between factors involved in NMD.
Figure 2: Activation of metazoan NMD by EJC-dependent interactions.
Figure 3: Alternative models for NMD activation by premature termination.
Figure 4: Ancillary processes that accompany NMD.
Figure 5: mRNA biogenesis and decay.

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References

  1. Ghosh, S. & Jacobson, A. RNA decay modulates gene expression and controls its fidelity. Wiley Interdiscip. Rev. RNA 1, 351–361 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Garneau, N. L., Wilusz, J. & Wilusz, C. J. The highways and byways of mRNA decay. Nature Rev. Mol. Cell Biol. 8, 113–126 (2007).

    CAS  Google Scholar 

  3. Frischmeyer, P. A. et al. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science 295, 2258–2261 (2002).

    CAS  PubMed  Google Scholar 

  4. Schaeffer, D. & van Hoof, A. Different nuclease requirements for exosome-mediated degradation of normal and nonstop mRNAs. Proc. Natl Acad. Sci. USA 108, 2366–2371 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Klauer, A. A. & van Hoof, A. Degradation of mRNAs that lack a stop codon: a decade of nonstop progress. Wiley Interdiscip. Rev. RNA 3, 649–660 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Graille, M. & Seraphin, B. Surveillance pathways rescuing eukaryotic ribosomes lost in translation. Nature Rev. Mol. Cell Biol. 17 Oct 2012 (doi:10.1038/nrm3457).

    CAS  PubMed  Google Scholar 

  7. Shoemaker, C. J., Eyler, D. E. & Green, R. Dom34:Hbs1 promotes subunit dissociation and peptidyl-tRNA drop-off to initiate no-go decay. Science 330, 369–372 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Doma, M. K. & Parker, R. Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature 440, 561–564 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Isken, O. & Maquat, L. E. Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function. Genes Dev. 21, 1833–1856 (2007).

    CAS  PubMed  Google Scholar 

  10. Jacobson, A. & Izaurralde, E. in Translational Control in Biology and Medicine (eds Mathews, M. B., Sonenberg, N. & Hershey, J.W.B.) 659–691 (Cold Spring Harbor Laboratory Press, 2007).

    Google Scholar 

  11. Nicholson, P. & Muhlemann, O. Cutting the nonsense: the degradation of PTC-containing mRNAs. Biochem. Soc. Trans. 38, 1615–1620 (2010).

    CAS  PubMed  Google Scholar 

  12. Rebbapragada, I. & Lykke-Andersen, J. Execution of nonsense-mediated mRNA decay: what defines a substrate? Curr. Opin. Cell Biol. 21, 394–402 (2009).

    CAS  PubMed  Google Scholar 

  13. Shoemaker, C. J. & Green, R. Translation drives mRNA quality control. Nature Struct. Mol. Biol. 19, 594–601 (2012).

    CAS  Google Scholar 

  14. Kuroha, K., Tatematsu, T. & Inada, T. Upf1 stimulates degradation of the product derived from aberrant messenger RNA containing a specific nonsense mutation by the proteasome. EMBO Rep. 10, 1265–1271 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. He, F. et al. Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5′ to 3′ mRNA decay pathways in yeast. Mol. Cell 12, 1439–1452 (2003).

    CAS  PubMed  Google Scholar 

  16. He, F., Peltz, S. W., Donahue, J. L., Rosbash, M. & Jacobson, A. Stabilization and ribosome association of unspliced pre-mRNAs in a yeast upf1-mutant. Proc. Natl Acad. Sci. USA 90, 7034–7038 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang, J., Vock, V. M., Li, S., Olivas, O. R. & Wilkinson, M. F. A quality control pathway that down-regulates aberrant T-cell receptor (TCR) transcripts by a mechanism requiring UPF2 and translation. J. Biol. Chem. 277, 18489–18493 (2002).

    CAS  PubMed  Google Scholar 

  18. Welch, E. M. & Jacobson, A. An internal open reading frame triggers nonsense-mediated decay of the yeast SPT10 mRNA. EMBO J. 18, 6134–6145 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Mitrovich, Q. M. & Anderson, P. Unproductively spliced ribosomal protein mRNAs are natural targets of mRNA surveillance in C. elegans. Genes Dev. 14, 2173–2184 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Marquardt, S., Hazelbaker, D. Z. & Buratowski, S. Distinct RNA degradation pathways and 3′ extensions of yeast non-coding RNA species. Transcription 2, 145–154 (2011).

    PubMed  PubMed Central  Google Scholar 

  21. Thompson, D. M. & Parker, R. Cytoplasmic decay of intergenic transcripts in Saccharomyces cerevisiae. Mol. Cell. Biol. 27, 92–101 (2007).

    CAS  PubMed  Google Scholar 

  22. Muhlrad, D. & Parker, R. Aberrant mRNAs with extended 3′ UTRs are substrates for rapid degradation by mRNA surveillance. RNA 5, 1299–1307 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kebaara, B. W. & Atkin, A. L. Long 3′-UTRs target wild-type mRNAs for nonsense-mediated mRNA decay in Saccharomyces cerevisiae. Nucleic Acids Res. 37, 2771–2778 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Johansson, M. J., He, F., Spatrick, P., Li, C. & Jacobson, A. Association of yeast Upf1p with direct substrates of the NMD pathway. Proc. Natl Acad. Sci. USA 104, 20872–20877 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Mendell, J. T., Sharifi, N. A., Meyers, J. L., Martinez-Murillo, F. & Dietz, H. C. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nature Genet. 36, 1073–1078 (2004).

    CAS  PubMed  Google Scholar 

  26. Rehwinkel, J., Letunic, I., Raes, J., Bork, P. & Izaurralde, E. Nonsense-mediated mRNA decay factors act in concert to regulate common mRNA targets. RNA 11, 1530–1544 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wittmann, J. Hol, E.M. & Jack, H.M. hUPF2 silencing identifies physiologic substrates of mammalian nonsense-mediated mRNA decay. Mol. Cell. Biol. 26, 1272–1287 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Guan, Q. et al. Impact of nonsense-mediated mRNA decay on the global expression profile of budding yeast. PLoS Genet. 2, e203 (2006).

    PubMed  PubMed Central  Google Scholar 

  29. Viegas, M. H., Gehring, N. H., Breit, S., Hentze, M. W. & Kulozik, A. E. The abundance of RNPS1, a protein component of the exon junction complex, can determine the variability in efficiency of the nonsense mediated decay pathway. Nucleic Acids Res. 35, 4542–4551 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yepiskoposyan, H., Aeschimann, F., Nilsson, D., Okoniewski, M. & Muhlemann, O. Autoregulation of the nonsense-mediated mRNA decay pathway in human cells. RNA 17, 2108–2118 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Isken, O. & Maquat, L. E. The multiple lives of NMD factors: balancing roles in gene and genome regulation. Nature Rev. Genet. 9, 699–712 (2008).

    CAS  PubMed  Google Scholar 

  32. Rehwinkel, J., Raes, J. & Izaurralde, E. Nonsense-mediated mRNA decay: target genes and functional diversification of effectors. Trends Biochem. Sci. 31, 639–646 (2006).

    CAS  PubMed  Google Scholar 

  33. Zhang, S. et al. Polysome-associated mRNAs are substrates for the nonsense-mediated mRNA decay pathway in Saccharomyces cerevisiae. RNA 3, 234–244 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gozalbo, D. & Hohmann, S. Nonsense suppressors partially revert the decrease of the mRNA level of a nonsense mutant allele in yeast. Curr. Genet. 17, 77–79 (1990).

    CAS  PubMed  Google Scholar 

  35. Losson, R. & Lacroute, F. Interference of nonsense mutations with eukaryotic messenger RNA stability. Proc. Natl Acad. Sci. USA 76, 5134–5137 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Belgrader, P., Cheng, J. & Maquat, L. E. Evidence to implicate translation by ribosomes in the mechanism by which nonsense codons reduce the nuclear level of human triosephosphate isomerase mRNA. Proc. Natl Acad. Sci. USA 90, 482–486 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Gaba, A., Jacobson, A. & Sachs, M. S. Ribosome occupancy of the yeast CPA1 upstream open reading frame termination codon modulates nonsense-mediated mRNA decay. Mol. Cell 20, 449–460 (2005).

    CAS  PubMed  Google Scholar 

  38. Jackson, R. J., Hellen, C. U. & Pestova, T. V. Termination and post-termination events in eukaryotic translation. Adv. Protein Chem. Struct. Biol. 86, 45–93 (2012).

    CAS  PubMed  Google Scholar 

  39. Frolova, L. et al. A highly conserved eukaryotic protein family possessing properties of polypeptide chain release factor. Nature 372, 701–703 (1994).

    CAS  PubMed  Google Scholar 

  40. Stansfield, I. et al. The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae. EMBO J. 14, 4365–4373 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhouravleva, G. et al. Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3. EMBO J. 14, 4065–4072 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Cheng, Z. et al. Structural insights into eRF3 and stop codon recognition by eRF1. Genes Dev. 23, 1106–1118 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Alkalaeva, E. Z., Pisarev, A. V., Frolova, L. Y., Kisselev, L. L. & Pestova, T. V. In vitro reconstitution of eukaryotic translation reveals cooperativity between release factors eRF1 and eRF3. Cell 125, 1125–1136 (2006).

    CAS  PubMed  Google Scholar 

  44. Salas-Marco, J. & Bedwell, D. M. GTP hydrolysis by eRF3 facilitates stop codon decoding during eukaryotic translation termination. Mol. Cell. Biol. 24, 7769–7778 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Pisarev, A. V., Hellen, C. U. & Pestova, T. V. Recycling of eukaryotic posttermination ribosomal complexes. Cell 131, 286–299 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Pisarev, A. V. et al. The role of ABCE1 in eukaryotic posttermination ribosomal recycling. Mol. Cell 37, 196–210 (2010). References 45 and 46 demonstrate the first in vitro post-termination recycling of eukaryotic ribosomes and elucidate the roles of initiation factors and the ABCE1 ATPase in this process.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Barthelme, D. et al. Ribosome recycling depends on a mechanistic link between the FeS cluster domain and a conformational switch of the twin-ATPase ABCE1. Proc. Natl Acad. Sci. USA 108, 3228–3233 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Becker, T. et al. Structural basis of highly conserved ribosome recycling in eukaryotes and archaea. Nature 482, 501–506 (2012). This cryo-electron microscopy study demonstrates that Rli1 (a homologue of mammalian ABCE1) interacts with and stabilizes Dom34 (a homologue of eRF1 that functions in NGD) in a conformation presumably adopted by eRF1 to activate the peptidyl transferase centre of the ribosome. This suggests that Hbs1 and its homologue, eRF3, might only be required to bring Dom34 (or eRF1) to the A-site of the ribosome, without active roles in peptide release (for eRF1–eRF3) or ribosome dissociation (for both).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Khoshnevis, S. et al. The iron–sulphur protein RNase L inhibitor functions in translation termination. EMBO Rep. 11, 214–219 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Hoshino, S., Imai, M., Kobayashi, T., Uchida, N. & Katada, T. The eukaryotic polypeptide chain releasing factor (eRF3/GSPT) carrying the translation termination signal to the 3′-poly(A) tail of mRNA. Direct association of erf3/GSPT with polyadenylate-binding protein. J. Biol. Chem. 274, 16677–16680 (1999).

    CAS  PubMed  Google Scholar 

  51. Cosson, B. et al. Poly(A)-binding protein acts in translation termination via eukaryotic release factor 3 interaction and does not influence [PSI+] propagation. Mol. Cell. Biol. 22, 3301–3315 (2002). References 50 and 51 show that eRF3 and Pab1 interact and have a role in translation termination.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ivanov, P. V., Gehring, N. H., Kunz, J. B., Hentze, M. W. & Kulozik, A. E. Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways. EMBO J. 27, 736–747 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hilleren, P. & Parker, R. mRNA surveillance in eukaryotes: kinetic proofreading of proper translation termination as assessed by mRNP domain organization? RNA 5, 711–719 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Amrani, N., Sachs, M. S. & Jacobson, A. Early nonsense: mRNA decay solves a translational problem. Nature Rev. Mol. Cell Biol. 7, 415–425 (2006).

    CAS  Google Scholar 

  55. Estrella, L. A., Wilkinson, M. F. & González, C. I. The shuttling protein Npl3 promotes translation termination accuracy in Saccharomyces cerevisiae. J. Mol. Biol. 394, 410–422 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Gross, T. et al. The DEAD-box RNA helicase Dbp5 functions in translation termination. Science 315, 646–649 (2007).

    CAS  PubMed  Google Scholar 

  57. Bolger, T. A., Folkmann, A. W., Tran, E. J. & Wente, S. R. The mRNA export factor Gle1 and inositol hexakisphosphate regulate distinct stages of translation. Cell 134, 624–633 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Amrani, N. et al. A faux 3′-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature 432, 112–118 (2004). Toeprinting and protein-tethering experiments showing that normal termination and premature termination are functionally different events, and that Pab1localized close to a premature termination codon can mimic a normal 3′ UTR and promote mRNA stabilization.

    CAS  PubMed  Google Scholar 

  59. Peixeiro, I. et al. Interaction of PABPC1 with the translation initiation complex is critical to the NMD resistance of AUG-proximal nonsense mutations. Nucleic Acids Res. 40, 1160–1173 (2011). Toeprinting experiments on normal or premature terminators in mammalian cells that confirm the aberrant nature of translation termination at a PTC and a role for PABPC1 in this process.

    PubMed  PubMed Central  Google Scholar 

  60. Welch, E. M. et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 87–91 (2007). Describes the identification and initial characterization of PTC124 (ataluren), a compound that promotes readthrough of premature but not normal termination codons in human cells. The compound underscores the mechanistic differences between premature and normal termination and has the potential to be a clinically useful therapeutic for a broad range of genetic disorders caused by nonsense mutations.

    CAS  PubMed  Google Scholar 

  61. Ghosh, S., Ganesan, R., Amrani, N. & Jacobson, A. Translational competence of ribosomes released from a premature termination codon is modulated by NMD factors. RNA 16, 1832–1847 (2010). Provides two lines of evidence that post-termination ribosome dissociation is altered at premature termination: reinitiation after termination at a PTC is shown to be affected in yeast cells lacking any of the Upf proteins; and ribosome reuse in vitro is shown to be less efficient after premature termination than it is after normal termination.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Franks, T. M., Singh, G. & Lykke-Andersen, J. Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decay. Cell 143, 938–950 (2010). Demonstrates for the first time that the UPF1 ATPase activity disassembles an mRNP substrate prior to promoting mRNA decay and UPF1 recycling.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hodgkin, J., Papp, A., Pulak, R., Ambros, V. & Anderson, P. A new kind of informational suppression in the nematode Caenorhabditis elegans. Genetics 123, 301–313 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Leeds, P., Peltz, S. W., Jacobson, A. & Culbertson, M. R. The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon. Genes Dev. 5, 2303–2314 (1991).

    CAS  PubMed  Google Scholar 

  65. He, F. & Jacobson, A. Identification of a novel component of the nonsense-mediated mRNA decay pathway by use of an interacting protein screen. Genes Dev. 9, 437–454 (1995).

    CAS  PubMed  Google Scholar 

  66. Perlick, H. A., Medghalchi, S. M., Spencer, F. A., Kendzior, R. J. Jr & Dietz, H. C. Mammalian orthologues of a yeast regulator of nonsense transcript stability. Proc. Natl Acad. Sci. USA 93, 10928–10932 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Conti, E. & Izaurralde, E. Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species. Curr. Opin. Cell Biol. 17, 316–325 (2005).

    CAS  PubMed  Google Scholar 

  68. Cui, Y., Hagan, K. W., Zhang, S. & Peltz, S. W. Identification and characterization of genes that are required for the accelerated degradation of mRNAs containing a premature translational termination codon. Genes Dev. 9, 423–436 (1995).

    CAS  PubMed  Google Scholar 

  69. He, F., Brown, A. H. & Jacobson, A. Upf1p, Nmd2p, and Upf3p are interacting components of the yeast nonsense-mediated mRNA decay pathway. Mol. Cell. Biol. 17, 1580–1594 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Chamieh, H., Ballut, L., Bonneau, F. & Le Hir, H. NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity. Nature Struct. Mol. Biol. 15, 85–93 (2008). The first paper to demonstrate that the ATPase and helicase activities of UPF1 are stimulated by the binding of UPF2 and UPF3.

    CAS  Google Scholar 

  71. Serin, G., Gersappe, A., Black, J. D., Aronoff, R. & Maquat, L. E. Identification and characterization of human orthologues to Saccharomyces cerevisiae Upf2 protein and Upf3 protein (Caenorhabditis elegans SMG-4). Mol. Cell. Biol. 21, 209–223 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Leeds, P., Wood, J. M., Lee, B. S. & Culbertson, M. R. Gene products that promote mRNA turnover in Saccharomyces cerevisiae. Mol. Cell. Biol. 12, 2165–2177 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Altamura, N., Groudinsky, O., Dujardin, G. & Slonimski, P. P. NAM7 nuclear gene encodes a novel member of a family of helicases with a Zn-ligand motif and is involved in mitochondrial functions in Saccharomyces cerevisiae. J. Mol. Biol. 224, 575–587 (1992).

    CAS  PubMed  Google Scholar 

  74. Cheng, Z., Muhlrad, D., Lim, M. K., Parker, R. & Song, H. Structural and functional insights into the human Upf1 helicase core. EMBO J. 26, 253–264 (2007).

    CAS  PubMed  Google Scholar 

  75. Bhattacharya, A. et al. Characterization of the biochemical properties of the human Upf1 gene product that is involved in nonsense-mediated mRNA decay. RNA 6, 1226–1235 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Weng, Y., Czaplinski, K. & Peltz, S. W. Genetic and biochemical characterization of mutations in the ATPase and helicase regions of the Upf1 protein. Mol. Cell. Biol. 16, 5477–5490 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Czaplinski, K., Weng, Y., Hagan, K. W. & Peltz, S. W. Purification and characterization of the Upf1 protein: a factor involved in translation and mRNA degradation. RNA 1, 610–623 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Weng, Y., Czaplinski, K. & Peltz, S. W. ATP is a cofactor of the Upf1 protein that modulates its translation termination and RNA binding activities. RNA 4, 205–214 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Mendell, J. T., Medghalchi, S. M., Lake, R. G., Noensie, E. N. & Dietz, H. C. Novel Upf2p orthologues suggest a functional link between translation initiation and nonsense surveillance complexes. Mol. Cell. Biol. 20, 8944–8957 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kadlec, J., Izaurralde, E. & Cusack, S. The structural basis for the interaction between nonsense-mediated mRNA decay factors UPF2 and UPF3. Nature Struct. Mol. Biol. 11, 330–337 (2004).

    CAS  Google Scholar 

  81. Maderazo, A. B., He, F., Mangus, D. A. & Jacobson, A. Upf1p control of nonsense mRNA translation is regulated by Nmd2p and Upf3p. Mol. Cell. Biol. 20, 4591–4603 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. He, F., Brown, A. H. & Jacobson, A. Interaction between Nmd2p and Upf1p is required for activity but not for dominant-negative inhibition of the nonsense-mediated mRNA decay pathway in yeast. RNA 2, 153–170 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kashima, I. et al. Binding of a novel SMG-1–Upf1–eRF1–eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes Dev. 20, 355–367 (2006). A demonstration that NMD activation in mammalian cells involves an interaction of the SURF complex located at a PTC and UPF2–UPF3 bound to the EJC.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Chakrabarti, S. et al. Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2. Mol. Cell 41, 693–703 (2011). The first structure of UPF1 with both the CH and the helicase domain. This structure shows that UPF1 can switch from a closed conformation to an open and active conformation upon UPF2 binding to the UPF1 N-terminal CH domain.

    CAS  PubMed  Google Scholar 

  85. Clerici, M. et al. Unusual bipartite mode of interaction between the nonsense-mediated decay factors, UPF1 and UPF2. EMBO J. 28, 2293–2306 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Durand, S. et al. Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies. J. Cell. Biol. 178, 1145–1160 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang, W., Cajigas, I. J., Peltz, S. W., Wilkinson, M. F. & González, C. I. A role for Upf2p phosphorylation in Saccharomyces cerevisiae nonsense-mediated mRNA decay. Mol. Cell. Biol. 26, 3390–4000 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Luke, B. et al. Saccharomyces cerevisiae Ebs1p is a putative ortholog of human Smg7 and promotes nonsense-mediated mRNA decay. Nucleic Acids Res. 35, 7688–7697 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Le Hir, H., Moore, M. J. & Maquat, L. E. Pre-mRNA splicing alters mRNP composition: evidence for stable association of proteins at exon-exon junctions. Genes Dev. 14, 1098–1108 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Sun, X. & Maquat, L.E. mRNA surveillance in mammalian cells: the relationship between introns and translation termination. RNA 6, 1–8 (2000).

    PubMed  PubMed Central  Google Scholar 

  91. Lykke-Andersen, J., Shu, M. D. & Steitz, J. A. Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1. Science 293, 1836–1839 (2001).

    CAS  PubMed  Google Scholar 

  92. Le Hir, H., Gatfield, D., Izaurralde, E. & Moore, M. J. The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. EMBO J. 20, 4987–4997 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Lejeune, F., Ishigaki, Y., Li, X. & Maquat, L. E. The exon junction complex is detected on CBP80-bound but not eIF4E-bound mRNA in mammalian cells: dynamics of mRNP remodeling. EMBO J. 21, 3536–3545 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kim, V. N., Kataoka, N. & Dreyfuss, G. Role of the nonsense-mediated decay factor hUpf3 in the splicing-dependent exon–exon junction complex. Science 293, 1832–1836 (2001).

    CAS  PubMed  Google Scholar 

  95. Buchwald, G. et al. Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC–UPF3b complex. Proc. Natl Acad. Sci. USA 107, 10050–10055 (2010). References 89, 91, 92, 94 and 95 show that human UPF2 and UPF3 are associated with the components of the EJC and provide a link between NMD activation and intron location in mammalian cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Melero, R. et al. The cryo-EM structure of the UPF–EJC complex shows UPF1 poised toward the RNA 3′ end. Nature Struct. Mol. Biol. 19, 498–505 (2012).

    CAS  Google Scholar 

  97. Kashima, I. et al. SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decay. Genes Dev. 24, 2440–2450 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Chan, W. K. et al. An alternative branch of the nonsense-mediated decay pathway. EMBO J. 26, 1820–1830 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Gehring, N. H. et al. Exon-junction complex components specify distinct routes of nonsense-mediated mRNA decay with differential cofactor requirements. Mol. Cell 20, 65–75 (2005).

    CAS  PubMed  Google Scholar 

  100. Czaplinski, K. et al. The surveillance complex interacts with the translation release factors to enhance termination and degrade aberrant mRNAs. Genes Dev. 12, 1665–1677 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Singh, G., Rebbapragada, I. & Lykke-Andersen, J. A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay. PLoS Biol. 6, e111 (2008).

    PubMed  PubMed Central  Google Scholar 

  102. Yamashita, A. et al. SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay. Genes Dev. 23, 1091–1105 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang, W., Czaplinski, K., Rao, Y. & Peltz, S. W. The role of Upf proteins in modulating the translation read-through of nonsense-containing transcripts. EMBO J. 20, 880–890 (2001). References 100 and 103 demonstrate direct interactions between yeast Upf1 and the release factors.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Kobayashi, T., Funakoshi, Y., Hoshino, S. & Katada, T. The GTP-binding release factor eRF3 as a key mediator coupling translation termination to mRNA decay. J. Biol. Chem. 279, 45693–45700 (2004).

    CAS  PubMed  Google Scholar 

  105. Keeling, K. M. et al. Leaky termination at premature stop codons antagonizes nonsense-mediated mRNA decay in S. cerevisiae. RNA 10, 691–703 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Weng, Y., Czaplinski, K. & Peltz, S. W. Identification and characterization of mutations in the UPF1 gene that affect nonsense suppression and the formation of the Upf protein complex but not mRNA turnover. Mol. Cell. Biol. 16, 5491–5506 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Johansson, M. J. & Jacobson, A. Nonsense-mediated mRNA decay maintains translational fidelity by limiting magnesium uptake. Genes Dev. 24, 1491–1495 (2010). A demonstration that the previously observed role of yeast Upf1 in termination fidelity is largely attributable to an indirect effect on the stability of the uORF-containing ALR1 mRNA.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Ruiz-Echevarria, M. J. & Peltz, S. W. The RNA binding protein Pub1 modulates the stability of transcripts containing upstream open reading frames. Cell 101, 741–751 (2000).

    CAS  PubMed  Google Scholar 

  109. González, C. I., Ruiz-Echevarria, M. J., Vasudevan, S., Henry, M. F. & Peltz, S. W. The yeast hnRNP-like protein Hrp1/Nab4 marks a transcript for nonsense-mediated mRNA decay. Mol. Cell 5, 489–499 (2000).

    PubMed  Google Scholar 

  110. González, C. I., Wang, W. & Peltz, S. W. Nonsense-mediated mRNA decay in Saccharomyces cerevisiae: a quality control mechanism that degrades transcripts harboring premature termination codons. Cold Spring Harb. Symp. Quant. Biol. 66, 321–328 (2001).

    PubMed  Google Scholar 

  111. Czaplinski, K., Ruiz-Echevarria, M. J., González, C. I. & Peltz, S. W. Should we kill the messenger? The role of the surveillance complex in translation termination and mRNA turnover. Bioessays 21, 685–696 (1999).

    CAS  PubMed  Google Scholar 

  112. Carter, M. S., Li, S. & Wilkinson, M. F. A splicing-dependent regulatory mechanism that detects translation signals. EMBO J. 15, 5965–5975 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Thermann, R. et al. Binary specification of nonsense codons by splicing and cytoplasmic translation. EMBO J. 17, 3484–3494 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Le Hir, H., Izaurralde, E., Maquat, L. E. & Moore, M. J. The spliceosome deposits multiple proteins 20–24 nucleotides upstream of mRNA exon–exon junctions. EMBO J. 19, 6860–6869 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Schoenberg, D. R. & Maquat, L. E. Regulation of cytoplasmic mRNA decay. Nature Rev. Genet. 13, 246–259 (2012).

    CAS  PubMed  Google Scholar 

  116. Okada-Katsuhata, Y. et al. N- and C-terminal Upf1 phosphorylations create binding platforms for SMG-6 and SMG-5:SMG-7 during NMD. Nucleic Acids Res. 40, 1251–1266 (2012).

    CAS  PubMed  Google Scholar 

  117. Wen, J. & Brogna, S. Splicing-dependent NMD does not require the EJC in Schizosaccharomyces pombe. EMBO J. 29, 1537–1551 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Zhang, J., Sun, X., Qian, Y. & Maquat, L. E. Intron function in the nonsense-mediated decay of β-globin mRNA: indications that pre-mRNA splicing in the nucleus can influence mRNA translation in the cytoplasm. RNA 4, 801–815 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Rajavel, K. S. & Neufeld, E. F. Nonsense-mediated decay of human HEXA mRNA. Mol. Cell. Biol. 21, 5512–5519 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. LeBlanc, J. J. & Beemon, K. L. Unspliced Rous sarcoma virus genomic RNAs are translated and subjected to nonsense-mediated mRNA decay before packaging. J. Virol. 78, 5139–5146 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Wang, J., Gudikote, J. P., Olivas, O. R. & Wilkinson, M. F. Boundary-independent polar nonsense-mediated decay. EMBO Rep. 3, 274–279 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Johns, L., Grimson, A., Kuchma, S. L., Newman, C. L. & Anderson, P. Caenorhabditis elegans SMG-2 selectively marks mRNAs containing premature translation termination codons. Mol. Cell. Biol. 27, 5630–5638 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Peltz, S. W., Brown, A.H., & Jacobson, A. mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor. Genes Dev. 7, 1737–1754 (1993).

    CAS  PubMed  Google Scholar 

  124. Hagan, K. W., Ruiz-Echevarria, M. J., Quan, Y. & Peltz, S. W. Characterization of cis-acting sequences and decay intermediates involved in nonsense-mediated mRNA turnover. Mol. Cell. Biol. 15, 809–823 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Eberle, A. B., Stalder, L., Mathys, H., Orozco, R. Z. & Muhlemann, O. Posttranscriptional gene regulation by spatial rearrangement of the 3′ untranslated region. PLoS Biol. 6, e92 (2008). References 52, 101 and 125 provide evidence that the distance between a premature termination event and PABPC1 influences NMD activation in mammalian cells and could reflect competition between PABPC1 and UPF1 for binding to eRF3.

    PubMed  PubMed Central  Google Scholar 

  126. Longman, D., Plasterk, R. H., Johnstone, I. L. & Caceres, J. F. Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway. Genes Dev. 21, 1075–1085 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Pulak, R. & Anderson, P. mRNA surveillance by the Caenorhabditis elegans smg genes. Genes Dev. 7, 1885–1897 (1993).

    CAS  PubMed  Google Scholar 

  128. Das, B., Guo, Z., Russo, P., Chartrand, P. & Sherman, F. The role of nuclear cap binding protein Cbc1p of yeast in mRNA termination and degradation. Mol. Cell. Biol. 20, 2827–2838 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Muhlrad, D. & Parker, R. Recognition of yeast mRNAs as “nonsense containing” leads to both inhibition of mRNA translation and mRNA degradation: implications for the control of mRNA decapping. Mol. Biol. Cell. 10, 3971–3978 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Behm-Ansmant, I., Gatfield, D., Rehwinkel, J., Hilgers, V. & Izaurralde, E. A conserved role for cytoplasmic poly(A)-binding protein 1 (PABPC1) in nonsense-mediated mRNA decay. EMBO J. 26, 1591–1601 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Kertesz, S. et al. Both introns and long 3′-UTRs operate as cis-acting elements to trigger nonsense-mediated decay in plants. Nucleic Acids Res. 34, 6147–6157 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Kerenyi, Z. et al. Inter-kingdom conservation of mechanism of nonsense-mediated mRNA decay. EMBO J. 27, 1585–1595 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Deliz-Aguirre, R., Atkin, A. L. & Kebaara, B. W. Copper tolerance of Saccharomyces cerevisiae nonsense-mediated mRNA decay mutants. Curr. Genet. 57, 421–430 (2011).

    CAS  PubMed  Google Scholar 

  134. Buhler, M., Steiner, S., Mohn, F., Paillusson, A. & Muhlemann, O. EJC-independent degradation of nonsense immunoglobulin-mRNA depends on 3′-UTR length. Nature Struct. Mol. Biol. 13, 462–464 (2006).

    Google Scholar 

  135. Amrani, N. et al. Aberrant termination triggers nonsense-mediated mRNA decay. Biochem. Soc. Trans. 34 (part 1), 39–42 (2006).

    CAS  PubMed  Google Scholar 

  136. Meaux, S., van Hoof, A. & Baker, K. E. Nonsense-mediated mRNA decay in yeast does not require PAB1 or a poly(A) tail. Mol. Cell 29, 134–140 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Kervestin, S., Li, C., Buckingham, R. & Jacobson, A. Testing the faux-UTR model for NMD: analysis of Upf1p and Pab1p competition for binding to eRF3/Sup35p. Biochimie 94, 1560–1571 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Hogg, J. R. & Goff, S. P. Upf1 senses 3′ UTR length to potentiate mRNA decay. Cell 143, 379–389 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Wiegand, H. L., Lu, S. & Cullen, B. R. Exon junction complexes mediate the enhancing effect of splicing on mRNA expression. Proc. Natl Acad. Sci. USA 100, 11327–11332 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Gudikote, J. P., Imam, J. S., Garcia, R. F. & Wilkinson, M. F. RNA splicing promotes translation and RNA surveillance. Nature Struct. Mol. Biol. 12, 801–819 (2005).

    CAS  Google Scholar 

  141. Nott, A., Le Hir, H. & Moore, M. J. Splicing enhances translation in mammalian cells: an additional function of the exon junction complex. Genes Dev. 18, 210–222 (2004). References 140 and 141 show that components of the EJC have important roles in determining mRNA translational efficiency.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Sheth, U. & Parker, R. Targeting of aberrant mRNAs to cytoplasmic processing bodies. Cell 125, 1095–1109 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Stalder, L. & Muhlemann, O. Processing bodies are not required for mammalian nonsense-mediated mRNA decay. RNA 15, 1265–1273 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Lejeune, F., Li, X. & Maquat, L. E. Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activities. Mol. Cell 12, 675–687 (2003).

    CAS  PubMed  Google Scholar 

  145. Mitchell, P. & Tollervey, D. An NMD pathway in yeast involving accelerated deadenylation and exosome-mediated 3′ --> 5′ degradation. Mol. Cell 11, 1405–1413 (2003).

    CAS  PubMed  Google Scholar 

  146. Cao, D. & Parker, R. Computational modeling and experimental analysis of nonsense-mediated decay in yeast. Cell 113, 533–545 (2003).

    CAS  PubMed  Google Scholar 

  147. Lykke-Andersen, J. Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay. Mol. Cell. Biol. 22, 8114–8121 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Cho, H., Kim, K. M. & Kim, Y. K. Human proline-rich nuclear receptor coregulatory protein 2 mediates an interaction between mRNA surveillance machinery and decapping complex. Mol. Cell 33, 75–86 (2009).

    CAS  PubMed  Google Scholar 

  149. Swisher, K. D. & Parker, R. Interactions between Upf1 and the decapping factors Edc3 and Pat1 in Saccharomyces cerevisiae. PLoS ONE 6, e26547 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Peltz, S. W., He, F., Welch, E. & Jacobson, A. Nonsense-mediated mRNA decay in yeast. Prog. Nucleic Acid. Res. Mol. Biol. 47, 271–298 (1994).

    CAS  PubMed  Google Scholar 

  151. Eberle, A. B., Lykke-Andersen, S., Muhlemann, O. & Jensen, T. H. SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells. Nature Struct. Mol. Biol. 16, 49–55 (2009).

    CAS  Google Scholar 

  152. Huntzinger, E., Kashima, I., Fauser, M., Sauliere, J. & Izaurralde, E. SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan. RNA 14, 2609–2617 (2008). References 151 and 152 demonstrate that SMG6 is the endonucleolytic enzyme in NMD in humans and D. melanogaster.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Gatfield, D. & Izaurralde, E. Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in Drosophila. Nature 429, 575–578 (2004). Shows that NMD in D. melanogaster is initiated by endonucleolytic cleavage. This is the first demonstration that NMD could trigger endonucleolytic cleavage of the target mRNA.

    CAS  PubMed  Google Scholar 

  154. Fukuhara, N. et al. SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway. Mol. Cell 17, 537–547 (2005).

    CAS  PubMed  Google Scholar 

  155. Unterholzner, L. & Izaurralde, E. SMG7 acts as a molecular link between mRNA surveillance and mRNA decay. Mol. Cell 16, 587–596 (2004).

    CAS  PubMed  Google Scholar 

  156. Glavan, F., Behm-Ansmant, I., Izaurralde, E. & Conti, E. Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex. EMBO J. 25, 5117–5125 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Muhlemann, O. & Lykke-Andersen, J. How and where are nonsense mRNAs degraded in mammalian cells? RNA Biol. 7, 28–32 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Gatfield, D., Unterholzner, L., Ciccarelli, F. D., Bork, P. & Izaurralde, E. Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways. EMBO J. 22, 3960–3970 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Frizzell, K. A., Rynearson, S. G. & Metzstein, M. M. Drosophila mutants show NMD pathway activity is reduced, but not eliminated, in the absence of Smg6. RNA 18, 1475–1486 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Takahashi, S. et al. Upf1 potentially serves as a RING-related E3 ubiquitin ligase via its association with Upf3 in yeast. RNA 14, 1950–1958 (2008). References 14 and 160 reveal that yeast Upf1 targets the polypeptide resulting from premature termination for degradation by the proteasome.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Ito-Harashima, S., Kuroha, K., Tatematsu, T. & Inada, T. Translation of the poly(A) tail plays crucial roles in nonstop mRNA surveillance via translation repression and protein destabilization by proteasome in yeast. Genes Dev. 21, 519–524 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Moore, S. D. & Sauer, R. T. The tmRNA system for translational surveillance and ribosome rescue. Ann. Rev. Biochem. 76, 101–124 (2007).

    CAS  PubMed  Google Scholar 

  163. Muhlemann, O. et al. Precursor RNAs harboring nonsense codons accumulate near the site of transcription. Mol. Cell 8, 33–43 (2001).

    CAS  PubMed  Google Scholar 

  164. de Turris, V., Nicholson, P., Orozco, R. Z., Singer, R. H. & Muhlemann, O. Cotranscriptional effect of a premature termination codon revealed by live-cell imaging. RNA 17, 2094–2107 (2011). Uses an in situ hybridization approach to show that PTC-containing transcripts are specifically retained at the site of transcription.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Buhler, M., Mohn, F., Stalder, L. & Muhlemann, O. Transcriptional silencing of nonsense codon-containing immunoglobulin minigenes. Mol. Cell 18, 307–317 (2005).

    PubMed  Google Scholar 

  166. Hilleren, P., McCarthy, T., Rosbash, M., Parker, R. & Jensen, T. H. Quality control of mRNA 3′-end processing is linked to the nuclear exosome. Nature 413, 538–542 (2001).

    CAS  PubMed  Google Scholar 

  167. Assenholt, J. et al. Implication of Ccr4–Not complex function in mRNA quality control in Saccharomyces cerevisiae. RNA 17, 1788–1794 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Chen, C. Y. & Shyu, A. B. Rapid deadenylation triggered by a nonsense codon precedes decay of the RNA body in a mammalian cytoplasmic nonsense-mediated decay pathway. Mol. Cell. Biol. 23, 4805–4813 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Trcek, T., Larson, D. R., Moldon, A., Query, C. C. & Singer, R. H. Single-molecule mRNA decay measurements reveal promoter-regulated mRNA stability in yeast. Cell 147, 1484–1497 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Harel-Sharvit, L. et al. RNA polymerase II subunits link transcription and mRNA decay to translation. Cell 143, 552–563 (2010).

    CAS  PubMed  Google Scholar 

  171. Bregman, A. et al. Promoter elements regulate cytoplasmic mRNA decay. Cell 147, 1473–1483 (2011).

    CAS  PubMed  Google Scholar 

  172. Keeling, K. M. & Bedwell, D. M. Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases. Wiley Interdiscip. Rev. RNA 2, 837–852 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Ohnishi, T. et al. Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7. Mol. Cell 12, 1187–1200 (2003).

    CAS  PubMed  Google Scholar 

  174. Grimson, A., O'Connor, S., Newman, C. L. & Anderson, P. SMG-1 is a phosphatidylinositol kinase-related protein kinase required for nonsense-mediated mRNA decay in Caenorhabditis elegans. Mol. Cell. Biol. 24, 7483–7490 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Pal, M., Ishigaki, Y., Nagy, E. & Maquat, L. E. Evidence that phosphorylation of human Upf1 protein varies with intracellular location and is mediated by a wortmannin-sensitive and rapamycin-sensitive PI3-kinase-related kinase signaling pathway. RNA 7, 5–15 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Page, M. F., Carr, B., Anders, K. R., Grimson, A. & Anderson, P. SMG-2 is a phosphorylated protein required for mRNA surveillance in Caenorhabditis elegans and related to Upf1p of yeast. Mol. Cell. Biol. 19, 5943–5951 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Denning, G., Jamieson, L., Maquat, L. E., Thompson, E. A. & Fields, A. P. Cloning of a novel phosphatidylinositol kinase-related kinase: characterization of the human SMG-1 RNA surveillance protein. J. Biol. Chem. 276, 22709–22714 (2001).

    CAS  PubMed  Google Scholar 

  178. Arias-Palomo, E. et al. The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. Genes Dev. 25, 153–164 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Anders, K. R., Grimson, A. & Anderson, P. SMG-5, required for C.elegans nonsense-mediated mRNA decay, associates with SMG-2 and protein phosphatase 2A. EMBO J. 22, 641–650 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Cali, B. M., Kuchma, S.L., Latham, J. & Anderson, P. smg-7 is required for mRNA surveillance in Caenorhabditis elegans. Genetics 151, 605–616 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Chiu, S. Y., Serin, G., Ohara, O. & Maquat, L. E. Characterization of human Smg5/7a: a protein with similarities to Caenorhabditis elegans SMG5 and SMG7 that functions in the dephosphorylation of Upf1. RNA 9, 77–87 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Andersen, C. B. et al. Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA. Science 313, 1968–1972 (2006).

    CAS  PubMed  Google Scholar 

  183. Bono, F., Ebert, J., Lorentzen, E. & Conti, E. The crystal structure of the exon junction complex reveals how it maintains a stable grip on mRNA. Cell 126, 713–725 (2006).

    CAS  PubMed  Google Scholar 

  184. Tange, T. O., Nott, A. & Moore, M. J. The ever-increasing complexities of the exon junction complex. Curr. Opin. Cell Biol. 16, 279–284 (2004).

    CAS  PubMed  Google Scholar 

  185. Isken, O. et al. Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay. Cell 133, 314–327 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Eulalio, A., Behm-Ansmant, I. & Izaurralde, E. P bodies: at the crossroads of post-transcriptional pathways. Nature Rev. Mol. Cell Biol. 8, 9–22 (2007).

    CAS  Google Scholar 

  187. Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell 25, 635–646 (2007).

    CAS  PubMed  Google Scholar 

  188. Hu, W., Sweet, T. J., Chamnongpol, S., Baker, K. E. & Coller, J. Co-translational mRNA decay in Saccharomyces cerevisiae. Nature 461, 225–229 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Decker, C. J., Teixeira, D. & Parker, R. Edc3p and a glutamine/asparagine-rich domain of Lsm4p function in processing body assembly in Saccharomyces cerevisiae. J. Cell. Biol. 179, 437–449 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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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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  1. Centre National de la Recherche Scientifique UPR9073, Université Paris Diderot Sorbonne Paris Cité, Institut de Biologie Physico-chimique, 13 rue Pierre et Marie Curie, Paris, 75005, France

    Stephanie Kervestin

  2. Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, 01655-00122, Massachusetts, USA

    Allan Jacobson

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Correspondence to Allan Jacobson.

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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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