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Nonsense-mediated mRNA decay (NMD) mechanisms

Nature Structural & Molecular Biology volume 16, pages 107–113 (2009)Cite this article

Abstract

Nonsense-mediated mRNA decay (NMD) is a translation-coupled mechanism that eliminates mRNAs containing premature translation-termination codons (PTCs). In mammalian cells, NMD is also linked to pre-mRNA splicing, as in many instances strong mRNA reduction occurs only when the PTC is located upstream of an intron. It is proposed that in these systems, the exon junction complex (EJC) mediates the link between splicing and NMD. Recent studies have questioned the role of splicing and the EJC in initiating NMD. Instead, they put forward a general and evolutionarily conserved mechanism in which the main regulator of NMD is the distance between a PTC and the poly(A) tail of an mRNA. Here we discuss the limitations of the new NMD model and the EJC concept; we argue that neither satisfactorily accounts for all of the available data and offer a new model to test in future studies.

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Figure 1: Current NMD models.
Figure 2: The proposed ribosome release NMD model.

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References

  1. Maquat, L.E. When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. RNA 1, 453–465 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Peltz, S.W., Brown, A.H. & Jacobson, A. Messenger RNA destabilization triggered by premature translational termination depends on at least 3 cis-acting sequence elements and one trans-acting factor. Genes Dev. 7, 1737–1754 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Morse, D.E. & Yanofsky, C. Polarity and the degradation of mRNA. Nature 224, 329–331 (1969).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Maquat, L.E. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat. Rev. Mol. Cell Biol. 5, 89–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Culbertson, M.R., Underbrink, K.M. & Fink, G.R. Frameshift suppression in Saccharomyces cerevisiae II. Genetic properties of group II suppressors. Genetics 95, 833–853 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Cui, Y., Gonzalez, C.I., Kinzy, T.G., Dinman, J.D. & Peltz, S.W. Mutations in the MOF2/SUI1 gene affect both translation and nonsense-mediated mRNA decay. RNA 5, 794–804 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sayani, S., Janis, M., Lee, C.Y., Toesca, I. & Chanfreau, G.F. Widespread impact of nonsense-mediated mRNA decay on the yeast intronome. Mol. Cell 31, 360–370 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jaillon, O. et al. Translational control of intron splicing in eukaryotes. Nature 451, 359–362 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. McGlincy, N.J. & Smith, C.W. Alternative splicing resulting in nonsense-mediated mRNA decay: what is the meaning of nonsense? Trends Biochem. Sci. 33, 385–393 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Medghalchi, S.M. et al. Rent1, a trans-effector of nonsense-mediated mRNA decay, is essential for mammalian embryonic viability. Hum. Mol. Genet. 10, 99–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Metzstein, M.M. & Krasnow, M.A. Functions of the nonsense-mediated mRNA decay pathway in Drosophila development. PLoS Genet. 2, e180 (2006).

  23. Yoine, M., Nishii, T. & Nakamura, K. Arabidopsis UPF1 RNA helicase for nonsense-mediated mRNA decay is involved in seed size control and is essential for growth. Plant Cell Physiol. 47, 572–580 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Weischenfeldt, J. et al. NMD is essential for hematopoietic stem and progenitor cells and for eliminating by-products of programmed DNA rearrangements. Genes Dev. 22, 1381–1396 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ajamian, L. et al. Unexpected roles for UPF1 in HIV-1 RNA metabolism and translation. RNA 14, 914–927 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Azzalin, C.M. & Lingner, J. The human RNA surveillance factor UPF1 is required for S phase progression and genome stability. Curr. Biol. 16, 433–439 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Azzalin, C.M., Reichenbach, P., Khoriauli, L., Giulotto, E. & Lingner, J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318, 798–801 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Brumbaugh, K.M. et al. The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells. Mol. Cell 14, 585–598 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Zhang, S, Ruizechevarria, M.J., Quan, Y. & Peltz, S.W. Identification and characterization of a sequence motif involved in nonsense-mediated messenger RNA decay. Mol. Cell. Biol. 15, 2231–2244 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gonzalez, 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).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Amrani, N. et al. A faux 3′-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature 432, 112–118 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang, J., Sun, X.L., Qian, Y.M., LaDuca, J.P. & Maquat, L.E. At least one intron is required for the nonsense-mediated decay of triosephosphate isomerase mRNA: a possible link between nuclear splicing and cytoplasmic translation. Mol. Cell. Biol. 18, 5272–5283 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brocke, K.S., Neu-Yilik, G., Gehring, N.H., Hentze, M.W. & Kulozik, A.E. The human intronless melanocortin 4-receptor gene is NMD insensitive. Hum. Mol. Genet. 11, 331–335 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Maquat, L.E. & Li, X. Mammalian heat shock p70 and histone H4 transcripts, which derive from naturally intronless genes, are immune to nonsense-mediated decay. RNA 7, 445–456 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nagy, E. & Maquat, L.E. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem. Sci. 23, 198–199 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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. Nat. Struct. Mol. Biol. 15, 85–93 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Ishigaki, Y., Li, X., Serin, G. & Maquat, L.E. Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell 106, 607–617 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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).

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Buhler, M., Paillusson, A. & Muhlemann, O. Efficient downregulation of immunoglobulin μ mRNA with premature translation-termination codons requires the 5′-half of the VDJ exon. Nucleic Acids Res. 32, 3304–3315 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Silva, A.L., Ribeiro, P., Inacio, A., Liebhaber, S.A. & Romao, L. Proximity of the poly(A)-binding protein to a premature termination codon inhibits mammalian nonsense-mediated mRNA decay. RNA 14, 563–576 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. 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).

  58. 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).

  59. Mangus, D.A., Evans, M.C. & Jacobson, A. Poly(A)-binding proteins: multifunctional scaffolds for the post-transcriptional control of gene expression. Genome Biol. 4, 223 (2003).

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Brogna, S. Nonsense mutations in the alcohol dehydrogenase gene of Drosophila melanogaster correlate with an abnormal 3′ end processing of the corresponding pre-mRNA. RNA 5, 562–573 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yun, D.F. & Sherman, F. Initiation of translation can occur only in a restricted region of the CYC1 mRNA of Saccharomyces cerevisiae. Mol. Cell. Biol. 15, 1021–1033 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sachs, A. Physical and functional interactions between the mRNA cap structure and the poly(A) tail. in Translational Control of Gene Expression. (eds. Sonenberg, N., Hershey, J.W.B. & Mathews, M.B.) 447–465 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2000).

    Google Scholar 

  64. Amrani, N., Ghosh, S., Mangus, D.A. & Jacobson, A. Translation factors promote the formation of two states of the closed-loop mRNP. Nature 453, 1276–1280 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Imataka, H., Gradi, A. & Sonenberg, N. A newly identified N-terminal amino acid sequence of human eIF4G binds poly(A)-binding protein and functions in poly(A)-dependent translation. EMBO J. 17, 7480–7489 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Le, H. et al. Translation initiation factors eIF-iso4G and eIF-4B interact with the poly(A)-binding protein and increase its RNA binding activity. J. Biol. Chem. 272, 16247–16255 (1997).

    Article  CAS  PubMed  Google Scholar 

  67. Christensen, A.K. & Bourne, C.M. Shape of large bound polysomes in cultured fibroblasts and thyroid epithelial cells. Anat. Rec. 255, 116–129 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Kuperwasser, N., Brogna, S., Dower, K. & Rosbash, M. Nonsense-mediated decay does not occur within the yeast nucleus. RNA 10, 1907–1915 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Romao, L. et al. Nonsense mutations in the human β-globin gene lead to unexpected levels of cytoplasmic mRNA accumulation. Blood 96, 2895–2901 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Belgrader, P., Cheng, J., Zhou, X.B., Stephenson, L.S. & Maquat, L.E. Mammalian nonsense codons can be cis effectors of nuclear messenger RNA half life. Mol. Cell. Biol. 14, 8219–8228 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang, J. & Maquat, L.E. Evidence that translation reinitiation abrogates nonsense-mediated mRNA decay in mammalian cells. EMBO J. 16, 826–833 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Inacio, A. et al. Nonsense mutations in close proximity to the initiation codon fail to trigger full nonsense-mediated mRNA decay. J. Biol. Chem. 279, 32170–32180 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Poyry, T.A., Kaminski, A. & Jackson, R.J. What determines whether mammalian ribosomes resume scanning after translation of a short upstream open reading frame? Genes Dev. 18, 62–75 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Szamecz, B. et al. eIF3a cooperates with sequences 5′ of uORF1 to promote resumption of scanning by post-termination ribosomes for reinitiation on GCN4 mRNA. Genes Dev. 22, 2414–2425 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kahvejian, A., Svitkin, Y.V., Sukarieh, R., M'Boutchou, M.N. & Sonenberg, N. Mammalian poly(A)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms. Genes Dev. 19, 104–113 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gilbert, W.V., Zhou, K., Butler, T.K. & Doudna, J.A. Cap-independent translation is required for starvation-induced differentiation in yeast. Science 317, 1224–1227 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Coller, J.M., Gray, N.K. & Wickens, M.P. mRNA stabilization by poly(A) binding protein is independent of poly(A) and requires translation. Genes Dev. 12, 3226–3235 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Simon, E. & Seraphin, B. A specific role for the C-terminal region of the poly(A)-binding protein in mRNA decay. Nucleic Acids Res. 35, 6017–6028 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Neu-Yilik, G. et al. Splicing and 3′ end formation in the definition of nonsense-mediated decay-competent human β-globin mRNPs. EMBO J. 20, 532–540 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ling, J., Morley, S.J., Pain, V.M., Marzluff, W.F. & Gallie, D.R. The histone 3′-terminal stem-loop-binding protein enhances translation through a functional and physical interaction with eukaryotic initiation factor 4G (eIF4G) and eIF3. Mol. Cell. Biol. 22, 7853–7867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kaygun, H. & Marzluff, W.F. Regulated degradation of replication-dependent histone mRNAs requires both ATR and Upf1. Nat. Struct. Mol. Biol. 12, 794–800 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Morris, C., Wittmann, J., Jack, H.M. & Jalinot, P. Human INT6/eIF3e is required for nonsense-mediated mRNA decay. EMBO Rep. 8, 596–602 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. Gatfield, D. & Izaurralde, E. Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in Drosophila. Nature 429, 575–578 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kopeina, G.S. et al. Step-wise formation of eukaryotic double-row polyribosomes and circular translation of polysomal mRNA. Nucleic Acids Res. 36, 2476–2488 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Uchida, N., Hoshino, S., Imataka, H., Sonenberg, N. & Katada, T. A novel role of the mammalian GSPT/eRF3 associating with poly(A)-binding protein in cap/poly(A)-dependent translation. J. Biol. Chem. 277, 50286–50292 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Matsuda, D., Hosoda, N., Kim, Y.K. & Maquat, L.E. Failsafe nonsense-mediated mRNA decay does not detectably target eIF4E-bound mRNA. Nat. Struct. Mol. Biol. 14, 974–979 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Nott, A., Meislin, S.H. & Moore, M.J. A quantitative analysis of intron effects on mammalian gene expression. RNA 9, 607–617 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ma, X.M., Yoon, S.O., Richardson, C.J., Julich, K. & Blenis, J. SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell 133, 303–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Brogna, S., Sato, T.A. & Rosbash, M. Ribosome components are associated with sites of transcription. Mol. Cell 10, 93–104 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Iborra, F.J., Jackson, D.A. & Cook, P.R. Coupled transcription and translation within nuclei of mammalian cells. Science 293, 1139–1142 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Maquat, L.E. NASty effects on fibrillin pre-mRNA splicing: another case of ESE does it, but proposals for translation-dependent splice site choice live on. Genes Dev. 16, 1743–1753 (2002).

    Article  CAS  PubMed  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank B. Michell for critically reading the manuscript. S.B. is supported by a Royal Society URF fellowship and J.W. by a Darwin Trust PhD Scholarship.

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  1. Saverio Brogna and Jikai Wen are at the University of Birmingham, School of Biosciences, Edgbaston, Birmingham B15 2TT, UK. s.brogna@bham.ac.uk,

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Brogna, S., Wen, J. Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol 16, 107–113 (2009). https://doi.org/10.1038/nsmb.1550

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