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.
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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Maquat, L. E. & Carmichael, G. G. Quality control of mRNA function. Cell 104, 173–176 (2001).
Maquat, L. E. When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. RNA 1, 453–465 (1995).
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).
Arraiano, C. M. & Maquat, L. E. Post-transcriptional control of gene expression: effectors of mRNA decay. Mol. Microbiol. 49 267–276 (2003).
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).
Li, S. & Wilkinson, M. F. Nonsense surveillance in lymphocytes? Immunity 8,135–141 (1998).
Frischmeyer, P. A. & Dietz, H. C. Nonsense-mediated mRNA decay in health and disease. Hum. Mol. Genet. 8, 1893–1900 (1999).
Hentze, M. W. & Kulozik, A. E. A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96, 307–310 (1999).
Hilleren, P. & Parker, R. Mechanisms of mRNA surveillance in eukaryotes. Annu. Rev. Genet. 33, 229–260 (1999).
Wagner, E. & Lykke-Andersen, J. mRNA surveillance: the perfect persist. J. Cell. Sci. 115, 3033–3038 (2002).
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).
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).
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).
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).
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).
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.
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).
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.
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).
Qian, L. et al. T cell receptor-β mRNA splicing: regulation of unusual splicing intermediates. Mol. Cell. Biol. 13, 1686–1696 (1993).
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).
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).
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).
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).
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).
Thermann, R. et al. Binary specification of nonsense codons by splicing and cytoplasmic translation. EMBO J. 17, 3484–3494 (1998).
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).
Zhang, J. & Maquat, L. E. Evidence that translation reinitiation abrogates nonsense-mediated mRNA decay in mammalian cells. EMBO J. 16, 826–833 (1997).
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).
Carter, M. S., Li, S. & Wilkinson, M. F. A splicing-dependent regulatory mechanism that detects translation signals. EMBO J. 15, 5965–5975 (1996).
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).
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).
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).
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).
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.
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.
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.
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).
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).
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.
Cao, D. & Parker, R. Computational modeling and experimental analysis of nonsense-mediated decay in yeast. Cell 113, 533–545 (2003).
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).
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).
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).
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).
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.
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).
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).
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).
Blencowe, B. J., Issner, R., Nickerson, J. A. & Sharp, P. A. A coactivator of pre-mRNA splicing. Genes Dev. 12, 996–1009 (1998).
Mayeda, A. et al. Purification and characterization of human RNPS1: a general activator of pre-mRNA splicing. EMBO J. 18, 4560–4570 (1999).
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).
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).
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).
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.
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).
Zhou, Z. et al. The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407, 401–405 (2000).
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).
Luo, M. L. et al. Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413, 644–647 (2001).
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).
Kim, V. N. et al. The Y14 protein communicates to the cytoplasm the position of exon–exon junctions. EMBO J. 20, 2062–2068 (2001).
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.
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).
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.
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).
Katahira, J. et al. The Mex67p-mediated nuclear mRNA export pathway is conserved from yeast to human. EMBO J. 18, 2593–2609 (1999).
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).
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).
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).
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).
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).
Shi, H. & Xu, R. M. Crystal structure of the Drosophila Mago nashi–Y14 complex. Genes Dev. 17, 971–976 (2003).
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).
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).
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).
Reed, R. & Hurt, E. A conserved mRNA export machinery coupled to pre-mRNA splicing. Cell 108, 523–531 (2002).
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).
Nott, A., Meislin, S. H. & Moore, M. J. A quantitative analysis of intron effects on mammalian gene expression. RNA 9, 607–617 (2003).
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).
Huang, Y. & Steitz, J. A. Splicing factors SRp20 and 9G8 promote the nucleocytoplasmic export of mRNA. Mol. Cell 7, 899–905 (2001).
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).
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.
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.
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.
Izaurralde, E. et al. A nuclear cap binding protein complex involved in pre-mRNA splicing. Cell 78, 657–668 (1994).
Lewis, J. D. & Izaurralde, E. The role of the cap structure in RNA processing and nuclear export. Eur. J. Biochem. 247, 461–469 (1997).
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).
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).
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).
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).
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).
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).
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).
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.
Iborra, F. J., Jackson, D. A. & Cook, P. R. Coupled transcription and translation within nuclei of mammalian cells. Science 293, 1139–1142 (2001).
Muhlemann, O. et al. Precursor RNAs harboring nonsense codons accumulate near the site of transcription. Mol. Cell 8, 33–43 (2001).
Buhler, M., Wilkinson, M. F. & Muhlemann, O. Intranuclear degradation of nonsense codon-containing mRNA. EMBO Rep. 3, 646–651 (2002).
Brogna, S., Sato, T. A. & Rosbash, M. Ribosome components are associated with sites of transcription. Mol. Cell 10, 93–104 (2002).
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).
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).
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).
Nathanson, L., Xia, T. & Deutscher, M. P. Nuclear protein synthesis: a re-evaluation. RNA 9, 9–13 (2003).
Cosson, B. & Philippe, M. Looking for nuclear translation using Xenopus oocytes. Biol. Cell 95, 321–325 (2003).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
Bidou, L. et al. Nonsense-mediated decay mutants do not affect programmed-1 frameshifting. RNA 6, 952–961 (2000).
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).
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).
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).
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).
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).
Domeier, M. E. et al. A link between RNA interference and nonsense-mediated decay in Caenorhabditis elegans. Science 289, 1928–1931 (2000).
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).
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).
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).
Muhlrad, D. & Parker, R. Premature translational termination triggers mRNA decapping. Nature 370, 578–581 (1994).
Muhlrad, D. & Parker, R. Aberrant mRNAs with extended 3′ UTRs are substrates for rapid degradation by mRNA surveillance. RNA 5, 1299–1307 (1999).
Mitchell, P. & Tollervey, D. An NMD pathway in yeast involving accelerated deadenylation and exosome-mediated 3′→5′ degradation. Mol. Cell 11, 1405–1413 (2003).
Lykke-Andersen, J. Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay. Mol. Cell. Biol. 22, 8114–8121 (2002).
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).
Van Dijk, E. et al. Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures. EMBO J. 21, 6915–6924 (2002).
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).
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).
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).
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).
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.
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).
Li, Q. et al. Eukaryotic translation initiation factor 4AIII (eIF4AIII) is functionally distinct from eIF4AI and eIF4AII. Mol. Cell. Biol. 19, 7336–7346 (1999).
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.
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).
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).
Pulak, R. & Anderson, P. mRNA surveillance by the Caenorhabditis elegans smg genes. Genes Dev. 7, 1885–1897 (1993).
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).
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).
Piccirillo, C., Khanna, R. & Kiledjian, M. Functional characterization of the mammalian mRNA decapping enzyme hDcp2. RNA 9, 1138–1147 (2003).
Decker, C. J. & Parker, R. mRNA decay enzymes: decappers conserved between yeast and mammals. Proc. Natl Acad. Sci. USA 99, 12512–12514 (2002).
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).
Zhang, M. et al. Cloning and mapping of the XRN2 gene to human chromosome 20p11.1–p11.2. Genomics 59, 252–254 (1999).
Dehlin, E., Wormington, M., Korner, C. G. & Wahle, E. Cap-dependent deadenylation of mRNA. EMBO J. 19, 1079–1086 (2000).
Korner, C. G. & Wahle, E. Poly(A) tail shortening by a mammalian poly(A)-specific 3′-exoribonuclease. J. Biol. Chem. 272, 10448–10456 (1997).
Allmang, C. et al. The yeast exosome and human PM-Scl are related complexes of 3′→5′ exonucleases. Genes Dev. 13, 2148–2158 (1999).
Chen, C. Y. et al. AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell 107, 451–464 (2001).
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).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).
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).
Maquat, L. E. Nonsense-mediated mRNA decay: a comporative analysis of different species. Curr. Genomics (in the press).
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.
The author declares no competing financial interests.
- 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).
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.
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.
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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