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Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics

Key Points

  • Nonsense-mediated mRNA decay (NMD) is a translation-dependent mechanism of RNA decay that probably evolved to eliminate abnormal transcripts that are a consequence of routine abnormalities in gene expression. However, NMD also targets naturally occurring transcripts, such as certain alternatively spliced RNAs and some selenoprotein mRNAs.

  • Generally, premature termination codons (PTCs) that are located within mRNA at a position that is more than 50–55 nucleotides (nt) upstream of a splicing-generated exon–exon junction elicit NMD. However, there are exceptions to the rule. For example, edited apolipoprotein B mRNA is immune to NMD. Furthermore, PTCs within the 5′ end of exon 1 of triosephosphate isomerase mRNA fail to elicit NMD because translation reinitiates at an AUG in the middle of exon 1. Also, PTCs within the 3′ end of T-cell receptor-β mRNA elicit NMD, despite the absence of an exon–exon junction located more than 50–55 nt downstream.

  • The role of a splicing-generated exon–exon junction complex in NMD reflects the splicing-dependent deposition of an exon junction complex (EJC) 20–24 nt upstream of an exon–exon junction. The EJC recruits up-frameshift (UPF) proteins that are required for NMD.

  • NMD, which is restricted to newly synthesized mRNA, targets mRNA bound by the mostly nuclear cap-binding proteins CBP80 and CBP20 during a pioneer round of translation. After the pioneer round of translation, CBP80–CBP20 is replaced by eukaryotic initiation factor eIF4E, which is mostly cytoplasmic but also nuclear. By the time eIF4E binds to the mRNA cap, the EJC and associated UPF proteins have been removed so that eIF4E-bound mRNA is immune to NMD.

  • Most mRNAs are subject to NMD at a point when they co-purify with nuclei. Nucleus-associated NMD has been proposed to involve translation by nuclear ribosomes or, alternatively, translation by cytoplasmic ribosomes either during the process of mRNA export to the cytoplasm or in a mechanism that feeds back to nuclei. Other mRNAs are subject to NMD in the cytoplasm.

  • NMD is mediated by four UPF proteins (UPF1, UPF2, UPF3 and UPF3X), and four SMG proteins (SMG1, SMG5, SMG6 and SMG7). UPF2, UPF3 and UPF3X are mRNP proteins, whereas UPF1 is not. Evidence indicates that SMG proteins function to phosphorylate or dephosphorylate UPF1.

  • NMD degrades mRNA from both ends and involves decapping, deadenylating and exonucleolytic activities.

Abstract

Studies of nonsense-mediated mRNA decay in mammalian cells have proffered unforeseen insights into changes in mRNA–protein interactions throughout the lifetime of an mRNA. Remarkably, mRNA acquires a complex of proteins at each exon–exon junction during pre-mRNA splicing that influences the subsequent steps of mRNA translation and nonsense-mediated mRNA decay. Complex-loaded mRNA is thought to undergo a pioneer round of translation when still bound by cap-binding proteins CBP80 and CBP20 and poly(A)-binding protein 2. The acquisition and loss of mRNA-associated proteins accompanies the transition from the pioneer round to subsequent rounds of translation, and from translational competence to substrate for nonsense-mediated mRNA decay.

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Figure 1: NMD and the 'position-of-an-exon–exon-junction' rule.
Figure 2: Pre-mRNA splicing, the pioneer round of translation and steady-state translation.
Figure 3: NMD degrades mRNAs from both ends.

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References

  1. Maquat, L. E. & Carmichael, G. G. Quality control of mRNA function. Cell 104, 173–176 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. 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 

  3. Maquat, L. E. in Translational Control of Gene Expression (eds. Sonenberg, N., Hershey, J. W. B. & Mathews, M. B.) 849–868 (Cold Spring Harbor Press, New York, 2000).

    Google Scholar 

  4. Arraiano, C. M. & Maquat, L. E. Post-transcriptional control of gene expression: effectors of mRNA decay. Mol. Microbiol. 49 267–276 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Peltz, S. W. & Jacobson, A. in Translational Control of Gene Expression (eds. Sonenberg, N., Hershey, J. W. B. & Mathews, M. B.) 827–847 (Cold Spring Harbor Press, New York, 2000).

    Google Scholar 

  6. Li, S. & Wilkinson, M. F. Nonsense surveillance in lymphocytes? Immunity 8,135–141 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Frischmeyer, P. A. & Dietz, H. C. Nonsense-mediated mRNA decay in health and disease. Hum. Mol. Genet. 8, 1893–1900 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Hentze, M. W. & Kulozik, A. E. A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96, 307–310 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Hilleren, P. & Parker, R. Mechanisms of mRNA surveillance in eukaryotes. Annu. Rev. Genet. 33, 229–260 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Wagner, E. & Lykke-Andersen, J. mRNA surveillance: the perfect persist. J. Cell. Sci. 115, 3033–3038 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Culbertson, M. R. & Leeds, P. F. Looking at mRNA decay pathways through the window of molecular evolution. Curr. Opin. Genet. Dev. 13, 207–214 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Maquat, L. E., Kinniburgh, A. J., Rachmilewitz, E. A. & Ross, J. Unstable β-globin mRNA in mRNA-deficient βo-thalassemia. Cell 27, 543–553 (1981).

    Article  CAS  PubMed  Google Scholar 

  13. Kinniburgh, A. J., Maquat, L. E., Schedl, T., Rachmilewitz, E. & Ross, J. mRNA-deficient βo-thalassemia results from a single nucleotide deletion. Nucleic Acids Res. 10, 5421–5427 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kan, Z., Rouchka, E. C., Gish, W. R. & States, D. J. Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. Genome Res. 11, 889–900 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Morrison, M., Harris, K. S. & Roth, M. B. smg mutants affect the expression of alternatively spliced SR protein mRNAs in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 94, 9782–9785 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Moriarty, P. M., Reddy, C. C. & Maquat, L. E. Selenium deficiency reduces the abundance of mRNA for Se-dependent glutathione peroxidase 1 by a UGA-dependent mechanism likely to be nonsense codon-mediated decay of cytoplasmic mRNA. Mol. Cell. Biol. 18, 2932–2939 (1998). Describes a natural target for cytoplasmic NMD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sun, X. et al. Nonsense-mediated decay of mRNA for the selenoprotein phospholipid hydroperoxide glutathione peroxidase is detectable in cultured cells but masked or inhibited in rat tissues. Mol. Biol. Cell 12, 1009–1017 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lewis, B. P., Green, R. E. & Brenner, S. E. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc. Natl Acad. Sci. USA 100, 189–192 (2003). Provides evidence for widespread use of NMD as a means of regulating gene expression.

    Article  CAS  PubMed  Google Scholar 

  19. 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 

  20. Qian, L. et al. T cell receptor-β mRNA splicing: regulation of unusual splicing intermediates. Mol. Cell. Biol. 13, 1686–1696 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Menon, K. P. & Neufeld, E. F. Evidence for degradation of mRNA encoding α-L-iduronidase in Hurler fibroblasts with premature termination alleles. Cell. Mol. Biol. 40, 999–1005 (1994).

    CAS  PubMed  Google Scholar 

  22. Carter, M. S. et al. A regulatory mechanism that detects premature nonsense codons in T-cell receptor transcripts in vivo is reversed by protein synthesis inhibitors in vitro. J. Biol. Chem. 270, 28995–29003 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Gradi, A., Svitkin, Y. V., Imataka, H. & Sonenberg, N. Proteolysis of human eukaryotic translation initiation factor eIF4GII, but not eIF4GI, coincides with the shutoff of host protein synthesis after poliovirus infection. Proc. Natl Acad. Sci. USA 95, 11089–11094 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kuyumcu-Martinez, N. M., Joachims, M. & Lloyd, R. E. Efficient cleavage of ribosome-associated poly(A)-binding protein by enterovirus 3C protease. J. Virol. 76, 2062–2074 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

  27. Li, S., Leonard, D. & Wilkinson, M. F. T cell receptor (TCR) mini-gene mRNA expression regulated by nonsense codons: a nuclear-associated translation-like mechanism. J. Exp. Med. 185, 985–992 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 

  29. Cheng, J., Belgrader, P., Zhou, X. & Maquat, L. E. Introns are cis effectors of the nonsense-codon-mediated reduction in nuclear mRNA abundance. Mol. Cell. Biol. 14, 6317–6325 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Carter, M. S., Li, S. & 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 

  31. Zhang, J., Sun, X., Qian, Y., 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 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sun, X., Moriarty, P. M. & Maquat, L. E. Nonsense-mediated decay of glutathione peroxidase 1 mRNA in the cytoplasm depends on intron position. EMBO J. 19, 4734–4744 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cheng, J. & Maquat, L. E. Nonsense codons can reduce the abundance of nuclear mRNA without affecting the abundance of pre-mRNA or the half-life of cytoplasmic mRNA. Mol. Cell. Biol. 13, 1892–1902 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Belgrader, P., Cheng, J., Zhou, X., Stephenson, L. S. & Maquat, L. E. Mammalian nonsense codons can be cis effectors of nuclear mRNA half-life. Mol. Cell. Biol. 14, 8219–8228 (1994). Shows that nucleus-associated NMD targets newly synthesized mRNA.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 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). Characterizes the exon junction complex that is formed in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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). Establishes a rule for which PTCs elicit NMD.

    Article  CAS  PubMed  Google Scholar 

  38. 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 

  39. 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 

  40. Wang, J., Gudikote, J. P., Olivas, O. R. & Wilkinson, M. F. Boundary-independent polar nonsense-mediated decay. EMBO Rep. 3, 274–279 (2002). Illustrates an example of an mRNA that breaks the 50–55-nt rule.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. 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 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Danckwardt, S. et al. Abnormally spliced β-globin mRNAs: a single point mutation generates transcripts sensitive and insensitive to nonsense-mediated mRNA decay. Blood 99, 1811–1816 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. 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 

  46. Chester, A. et al. The apolipoprotein B mRNA editing complex performs a multifunctional cycle and suppresses nonsense-mediated decay. EMBO J. 22, 3971–3982 (2003). Describes the mechanism by which edited apoB mRNA is immune to NMD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Homanics, G. E. et al. Targeted modification of the apolipoprotein B gene results in hypobetalipoproteinemia and developmental abnormalities in mice. Proc. Natl Acad. Sci. USA 90, 2389–2393 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim, E., Ambroziak, P., Veniant, M. M., Hamilton, R. L. & Young, S. G. A gene-targeted mouse model for familial hypobetalipoproteinemia. Low levels of apolipoprotein B mRNA in association with a nonsense mutation in exon 26 of the apolipoprotein B gene. J. Biol. Chem. 273, 33977–33984 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Blencowe, B. J., Issner, R., Nickerson, J. A. & Sharp, P. A. A coactivator of pre-mRNA splicing. Genes Dev. 12, 996–1009 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mayeda, A. et al. Purification and characterization of human RNPS1: a general activator of pre-mRNA splicing. EMBO J. 18, 4560–4570 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kataoka, N. et al. Pre-mRNA splicing imprints mRNA in the nucleus with a novel RNA-binding protein that persists in the cytoplasm. Mol. Cell 6, 673–682 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Kataoka, N., Diem, M. D., Kim, V. N., Yong, J. & Dreyfuss, G. Magoh, a human homolog of Drosophila mago nashi protein, is a component of the splicing-dependent exon–exon junction complex. EMBO J. 20, 6424–6433 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Le Hir, H., Gatfield, D., Braun, I. C., Forler, D. & Izaurralde, E. The protein Mago provides a link between splicing and mRNA localization. EMBO Rep. 2, 1119–1124 (2001). Provides an initial characterization of components of the exon junction complex formed in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. McGarvey, T. et al. The acute myeloid leukemia-associated protein, DEK, forms a splicing-dependent interaction with exon-product complexes. J. Cell Biol. 150, 309–320 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhou, Z. et al. The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407, 401–405 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Gatfield, D. et al. The DExH/D box protein HEL/UAP56 is essential for mRNA nuclear export in Drosophila. Curr. Biol. 11, 1716–1721 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Luo, M. L. et al. Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413, 644–647 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Reichert, V. L., Le Hir, H., Jurica, M. S. & Moore, M. J. 5′ exon interactions within the human spliceosome establish a framework for exon junction complex structure and assembly. Genes Dev. 16, 2778–2791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kim, V. N. et al. The Y14 protein communicates to the cytoplasm the position of exon–exon junctions. EMBO J. 20, 2062–2068 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 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). Shows that NMD targets CBP80-bound mRNA during a pioneer round of translation.

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  Google Scholar 

  64. Dostie, J. & Dreyfuss, G. Translation is required to remove Y14 from mRNAs in the cytoplasm. Curr. Biol. 12, 1060–1067 (2002). Provides evidence that translating ribosomes remove a component of the exon junction complex.

    Article  CAS  PubMed  Google Scholar 

  65. Luo, M. J. & Reed, R. Splicing is required for rapid and efficient mRNA export in metazoans. Proc. Natl Acad. Sci. USA 96, 14937–14942 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Katahira, J. et al. The Mex67p-mediated nuclear mRNA export pathway is conserved from yeast to human. EMBO J. 18, 2593–2609 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bachi, A. et al. The C-terminal domain of TAP interacts with the nuclear pore complex and promotes export of specific CTE-bearing RNA substrates. RNA 6, 136–158 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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 

  69. Rodrigues, J. P. et al. REF proteins mediate the export of spliced and unspliced mRNAs from the nucleus. Proc. Natl Acad. Sci. USA 98, 1030–1035 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Strasser, K. & Hurt, E. Yra1p, a conserved nuclear RNA-binding protein, interacts directly with Mex67p and is required for mRNA export. EMBO J. 19, 410–420 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lau, C. K., Diem, M. D., Dreyfuss, G. & Van Duyne, G. D. Structure of the y14–magoh core of the exon junction complex. Curr. Biol. 13, 933–941 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Shi, H. & Xu, R. M. Crystal structure of the Drosophila Mago nashi–Y14 complex. Genes Dev. 17, 971–976 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fribourg, S., Gatfield, D., Izaurralde, E. & Conti, E. A novel mode of RBD-protein recognition in the Y14–Mago complex. Nature Struct. Biol. 10, 433–439 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Hachet, O. & Ephrussi, A. Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Curr. Biol. 11, 1666–1674 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Mohr, S. E., Dillon, S. T. & Boswell, R. E. The RNA-binding protein Tsunagi interacts with Mago Nashi to establish polarity and localize oskar mRNA during Drosophila oogenesis. Genes Dev. 15, 2886–2899 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Reed, R. & Hurt, E. A conserved mRNA export machinery coupled to pre-mRNA splicing. Cell 108, 523–531 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Gatfield, D. & Izaurralde, E. REF1/Aly and the additional exon junction complex proteins are dispensable for nuclear mRNA export. J. Cell Biol. 159, 579–588 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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 

  79. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Huang, Y. & Steitz, J. A. Splicing factors SRp20 and 9G8 promote the nucleocytoplasmic export of mRNA. Mol. Cell 7, 899–905 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Huang, Y., Gattoni, R., Stevenin, J. & Steitz, J. A. SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol. Cell 11, 837–843 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Lykke-Andersen, J., Shu, M. D. & Steitz, J. A. Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon. Cell 103, 1121–1131 (2000). Demonstrates that tethering any one of the UPF proteins downstream of a normal termination codon is sufficient to elicit NMD.

    Article  CAS  PubMed  Google Scholar 

  83. Gehring, N. H., Neu-Yilik, G., Schell, T., Hentze, M. W. & Kulozik, A. E. Y14 and hUpf3b form an NMD-activating complex. Mol. Cell 11, 939–949 (2003). Illustrates a functional difference between UPF3 (UPF3A) and UPF3X (UPF3B) as well as the importance of Y14 to NMD.

    Article  CAS  PubMed  Google Scholar 

  84. 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). Provides an initial characterization of the enzymology of NMD in mammalian cells.

    Article  CAS  PubMed  Google Scholar 

  85. Izaurralde, E. et al. A nuclear cap binding protein complex involved in pre-mRNA splicing. Cell 78, 657–668 (1994).

    Article  CAS  PubMed  Google Scholar 

  86. Lewis, J. D. & Izaurralde, E. The role of the cap structure in RNA processing and nuclear export. Eur. J. Biochem. 247, 461–469 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Visa, N., Izaurralde, E., Ferreira, J., Daneholt, B. & Mattaj, I. W. A nuclear cap-binding complex binds Balbiani ring pre-mRNA cotranscriptionally and accompanies the ribonucleoprotein particle during nuclear export. J. Cell Biol. 133, 5–14 (1996).

    Article  CAS  PubMed  Google Scholar 

  88. Shen, E. C., Stage-Zimmermann, T., Chui, P. & Silver, P. A. The yeast mRNA-binding protein Npl3p interacts with the cap-binding complex. J. Biol. Chem. 275, 23718–23724 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Lejbkowicz, F. et al. A fraction of the mRNA 5′ cap-binding protein, eukaryotic initiation factor 4E, localizes to the nucleus. Proc. Natl Acad. Sci. USA 89, 9612–9616 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gingras, A. C., Raught, B. & Sonenberg, N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68, 913–963 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Dostie, J., Lejbkowicz, F. & Sonenberg, N. Nuclear eukaryotic initiation factor 4E (eIF4E) colocalizes with splicing factors in speckles. J. Cell Biol. 148, 239–247 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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 

  93. Wang, J., Chang, Y. F., Hamilton, J. I. & Wilkinson, M. F. Nonsense-associated altered splicing: a frame-dependent response distinct from nonsense-mediated decay. Mol. Cell 10, 951–957 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Dahlberg, J. E., Lund, E. & Goodwin, E. B. Nuclear translation: what is the evidence? RNA 9, 1–8 (2003). Evaluates the possibility of translation within nuclei, which was re-established with the discovery of NMD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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 

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

    Article  CAS  PubMed  Google Scholar 

  97. Buhler, M., Wilkinson, M. F. & Muhlemann, O. Intranuclear degradation of nonsense codon-containing mRNA. EMBO Rep. 3, 646–651 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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 

  99. Bohnsack, M. T. et al. Exp5 exports eEF1A via tRNA from nuclei and synergizes with other transport pathways to confine translation to the cytoplasm. EMBO J. 21, 6205–6215 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Calado, A., Treichel, N., Muller, E. C., Otto, A. & Kutay, U. Exportin-5-mediated nuclear export of eukaryotic elongation factor 1A and tRNA. EMBO J. 21, 6216–6224 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, J., Hamilton, J. I., Carter, M. S., Li, S. & Wilkinson, M. F. Alternatively spliced TCR mRNA induced by disruption of reading frame. Science 297, 108–110 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Nathanson, L., Xia, T. & Deutscher, M. P. Nuclear protein synthesis: a re-evaluation. RNA 9, 9–13 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Cosson, B. & Philippe, M. Looking for nuclear translation using Xenopus oocytes. Biol. Cell 95, 321–325 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Trotta, C. R., Lund, E., Kahan, L., Johnson, A. W. & Dahlberg, J. E. Coordinated nuclear export of 60S ribosomal subunits and NMD3 in vertebrates. EMBO J. 22, 2841–2851 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Visa, N. et al. A pre-mRNA-binding protein accompanies the RNA from the gene through the nuclear pores and into polysomes. Cell 84, 253–264 (1996).

    Article  CAS  PubMed  Google Scholar 

  106. Mendell, J. T., Ap Rhys, C. M. & Dietz, H. C. Separable roles for rent1/hUpf1 in altered splicing and decay of nonsense transcripts. Science 298, 419–422 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Sun, X., Perlick, H. A., Dietz, H. C. & Maquat, L. E. A mutated human homologue to yeast Upf1 protein has a dominant-negative effect on the decay of nonsense-containing mRNAs in mammalian cells. Proc. Natl Acad. Sci. USA 95, 10009–10014 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Pal, M., Ishigaki, Y., Nagy, E. & Maquat, L. E. Evidence that phosphorylation of human Upfl protein varies with intracellular location and is mediated by a wortmannin-sensitive and rapamycin-sensitive PI 3-kinase-related kinase signaling pathway. RNA 7, 5–15 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Applequist, S. E., Selg, M., Raman, C. & Jack, H. M. Cloning and characterization of HUPF1, a human homolog of the Saccharomyces cerevisiae nonsense mRNA-reducing UPF1 protein. Nucleic Acids Res. 25, 814–821 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 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). Characterizes the function of SMG in NMD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 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).

    Article  CAS  PubMed  Google Scholar 

  116. Yamashita, A., Ohnishi, T., Kashima, I., Taya, Y. & Ohno, S. Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev. 15, 2215–2228 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 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 

  119. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bidou, L. et al. Nonsense-mediated decay mutants do not affect programmed-1 frameshifting. RNA 6, 952–961 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Schell, T. et al. Complexes between the nonsense-mediated mRNA decay pathway factor human upf1 (up-frameshift protein 1) and essential nonsense-mediated mRNA decay factors in HeLa cells. Biochem. J. 373, 775–783 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Maquat, L. E. & Serin, G. Nonsense-mediated mRNA decay: insights into mechanism from the cellular abundance of human Upf1, Upf2, Upf3, and Upf3X proteins. Cold Spring Harb. Symp. Quant. Biol. 66, 313–320 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Gudikote, J. P. & Wilkinson, M. F. T-cell receptor sequences that elicit strong down-regulation of premature termination codon-bearing transcripts. EMBO J. 21, 125–134 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Carastro, L. M. et al. Identification of δ-helicase as the bovine homolog of HUPF1: demonstration of an interaction with the third subunit of DNA polymerase δ. Nucleic Acids Res. 30, 2232–2243 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Li, X., Tan, C. K., So, A. G. & Downey, K. M. Purification and characterization of δ-helicase from fetal calf thymus. Biochemistry 31, 3507–3513 (1992).

    Article  CAS  PubMed  Google Scholar 

  127. Domeier, M. E. et al. A link between RNA interference and nonsense-mediated decay in Caenorhabditis elegans. Science 289, 1928–1931 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Reichenbach, P. et al. A human homolog of yeast est1 associates with telomerase and uncaps chromosome ends when overexpressed. Curr. Biol. 13, 568–574 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Dahlseid, J. N. et al. mRNAs encoding telomerase components and regulators are controlled by UPF genes in Saccharomyces cerevisiae. Eukaryot. Cell 2, 134–142 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Muhlrad, D. & Parker, R. Premature translational termination triggers mRNA decapping. Nature 370, 578–581 (1994).

    Article  CAS  PubMed  Google Scholar 

  132. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ingelfinger, D., Arndt-Jovin, D. J., Luhrmann, R. & Achsel, T. The human LSm1–7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci. RNA 8, 1489–1501 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Van Dijk, E. et al. Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures. EMBO J. 21, 6915–6924 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lim, S., Mullins, J. J., Chen, C. M., Gross, K. W. & Maquat, L. E. Novel metabolism of several βo-thalassemic β-globin mRNAs in the erythroid tissues of transgenic mice. EMBO J. 8, 2613–2619 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lim, S. K. & Maquat, L. E. Human β-globin mRNAs that harbor a nonsense codon are degraded in murine erythroid tissues to intermediates lacking regions of exon I or exons I and II that have a cap-like structure at the 5′ termini. EMBO J. 11, 3271–3278 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lim, S. K., Sigmund, C. D., Gross, K. W. & Maquat, L. E. Nonsense codons in human β-globin mRNA result in the production of mRNA degradation products. Mol. Cell. Biol. 12, 1149–1161 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Stevens, A. et al. β-globin mRNA decay in erythroid cells: UG site-preferred endonucleolytic cleavage that is augmented by a premature termination codon. Proc. Natl Acad. Sci. USA 99, 12741–12746 (2002). Characterizes an endonuclease that degrades β-globin mRNA with a PTC in erythroid cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Bremer, K. A., Stevens, A. & Schoenberg, D. R. An endonuclease activity similar to Xenopus PMR1 catalyzes the degradation of normal and nonsense-containing human β-globin mRNA in erythroid cells. RNA 9, 1157–1167 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Li, Q. et al. Eukaryotic translation initiation factor 4AIII (eIF4AIII) is functionally distinct from eIF4AI and eIF4AII. Mol. Cell. Biol. 19, 7336–7346 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 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). Provides initial characterization of a factor that is required for NMD.

    Article  CAS  PubMed  Google Scholar 

  145. 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 

  146. 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 

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

    Article  CAS  PubMed  Google Scholar 

  148. 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 

  149. Wang, Z., Jiao, X., Carr-Schmid, A. & Kiledjian, M. From the cover: the hDcp2 protein is a mammalian mRNA decapping enzyme. Proc. Natl Acad. Sci. USA 99, 12663–12668 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Piccirillo, C., Khanna, R. & Kiledjian, M. Functional characterization of the mammalian mRNA decapping enzyme hDcp2. RNA 9, 1138–1147 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Decker, C. J. & Parker, R. mRNA decay enzymes: decappers conserved between yeast and mammals. Proc. Natl Acad. Sci. USA 99, 12512–12514 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Bashkirov, V. I., Scherthan, H., Solinger, J. A., Buerstedde, J. M. & Heyer, W. D. A mouse cytoplasmic exoribonuclease (mXRN1p) with preference for G4 tetraplex substrates. J. Cell Biol. 136, 761–773 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Zhang, M. et al. Cloning and mapping of the XRN2 gene to human chromosome 20p11.1–p11.2. Genomics 59, 252–254 (1999).

    Article  CAS  PubMed  Google Scholar 

  154. Dehlin, E., Wormington, M., Korner, C. G. & Wahle, E. Cap-dependent deadenylation of mRNA. EMBO J. 19, 1079–1086 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Korner, C. G. & Wahle, E. Poly(A) tail shortening by a mammalian poly(A)-specific 3′-exoribonuclease. J. Biol. Chem. 272, 10448–10456 (1997).

    Article  CAS  PubMed  Google Scholar 

  156. Allmang, C. et al. The yeast exosome and human PM-Scl are related complexes of 3′→5′ exonucleases. Genes Dev. 13, 2148–2158 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Chen, C. Y. et al. AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell 107, 451–464 (2001).

    Article  CAS  PubMed  Google Scholar 

  158. Hanson, M. N. & Schoenberg, D. R. Identification of in vivo mRNA decay intermediates corresponding to sites of in vitro cleavage by polysomal ribonuclease 1. J. Biol. Chem. 276, 12331–12337 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  160. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    Article  CAS  PubMed  Google Scholar 

  161. 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).

    Article  CAS  PubMed  Google Scholar 

  162. Maquat, L. E. Nonsense-mediated mRNA decay: a comporative analysis of different species. Curr. Genomics (in the press).

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Acknowledgements

I thank B. Lehner, J. Lykke-Andersen, J. Mendell and N. Sonenberg for communicating unpublished data, F. Lejeune for generating figures, and members of the Maquat laboratory for their comments on the manuscript. This work was supported by Public Health Service Grants from the National Institutes of Health.

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DATABASES

Swiss-Prot

CBP20

CBP80

DCP2

eIF4E

MAGOH

NXF1/TAP

PABP2

PARN

PM/SCL100

REF

RNPS1

SMG1

SMG5

SMG7

SRm160

UPF1

UPF2

UPF3

UPF3X

Y14

FURTHER INFORMATION

Lynne E. Maquat's laboratory

Glossary

PREMATURE TERMINATION CODON

(PTC). A UAA, UAG or UGA codon that is located within an mRNA upstream of the normal site of translation termination. The PTC directs the premature termination of translation.

SELENOPROTEIN mRNA

An mRNA that has one or more UGA codons and that, together with a cis-residing selenocysteine insertion element, competes with the process of translation termination to direct the incorporation of the amino acid selenocysteine into the growing polypeptide chain.

mRNA RIBONUCLEOPROTEIN PARTICLE

(mRNP). The composite of mRNA and associated proteins. mRNPs can affect mRNA localization, mRNA translation or mRNA half-life.

NONSENSE CODON RECOGNITION

The process by which UAA, UAG or UGA codons direct translation termination, which is mediated by eukaryotic release factors eRF1 and eRF3.

EXON JUNCTION COMPLEX

(EJC). A complex of proteins that is deposited as a consequence of pre-mRNA splicing 20–24 nucleotides upstream of splicing-generated exon–exon junctions of newly synthesized mRNA.

C-TO-U EDITING

A post-transcriptional process that involves the deamination of a cytidine (C) nucleotide to a uridine (U) nucleotide within pre-mRNA that, in the case of apolipoprotein B transcripts, converts a glutamine codon (CAA) to a termination codon (UAA).

APOBEC1–ACF

Apolipoprotein B mRNA editing catalytic polypeptide 1 (APOBEC1) in complex with the RNA-binding protein APOBEC1 complementation factor (ACF). APOBEC1–ACF is required for the C-to-U editing of apoliproprotein B transcripts.

CYTIDINE DEAMINASES

A family of enzymes, one member of which is the 27-kDa apolipoprotein B mRNA editing catalytic polypeptide 1 (APOBEC1), that catalyse the C-to-U editing of apolipoprotein pre-mRNA.

BALBIANI RING mRNA

A 35–40-kilobase mRNA in the insect Chironomus tentans that, as shown by electron-microscopy studies, is exported from nuclei to the cytoplasm 5′-end first, and becomes associated with cytoplasmic ribosomes before nuclear export is complete.

EUKARYOTIC RELEASE FACTOR

(eRF). eRF1 and eRF3 function in translation termination at the A site of the 80S ribosome: eRF1 recognizes all three termination codons, and eRF3 functions as a ribosome-dependent GTPase that helps eRF1 to release the newly synthesized polypeptide.

EXOSOME

A complex of at least 11 3′-to-5′ exonucleases that functions in nuclei and the cytoplasm in several different RNA-processing and RNA-degradation pathways.

DEADENYLASE

An enzyme that functions to remove the 3′ poly(A) tail from RNA in a 3′-to-5′ direction.

SM-LIKE LSM PROTEIN

A subunit of a heptameric complex that functions in RNA metabolism. LSM2–8 functions in pre-mRNA splicing in nuclei, and LSM1–7 functions in mRNA decay in the cytoplasm.

PH DOMAIN

A protein domain that is characteristic of the RNase PH family of bacterial phosphate-dependent ribonucleases.

S1 DOMAIN

An RNA-binding domain that is characteristic of the small ribosomal subunit protein S1.

KH DOMAIN

An RNA-binding domain that typifies hnRNP K (hnRNP K homology).

RNASE D DOMAIN

A protein domain that is characteristic of bacterial RNase D.

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Maquat, L. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 5, 89–99 (2004). https://doi.org/10.1038/nrm1310

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