Review Article | Published:

Quality and quantity control of gene expression by nonsense-mediated mRNA decay

Abstract

Nonsense-mediated mRNA decay (NMD) is one of the best characterized and most evolutionarily conserved cellular quality control mechanisms. Although NMD was first found to target one-third of mutated, disease-causing mRNAs, it is now known to also target ~10% of unmutated mammalian mRNAs to facilitate appropriate cellular responses — adaptation, differentiation or death — to environmental changes. Mutations in NMD genes in humans are associated with intellectual disability and cancer. In this Review, we discuss how NMD serves multiple purposes in human cells by degrading both mutated mRNAs to protect the integrity of the transcriptome and normal mRNAs to control the quantities of unmutated transcripts.

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Change history

  • 26 April 2019

    The HTML version of the article displayed the wrong Figure 3 (while the PDF version was correct); the HTML has now been corrected and we apologize for any confusion it may have created.

References

  1. 1.

    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).

  2. 2.

    Atkin, A. L., Altamura, N., Leeds, P. & Culbertson, M. R. The majority of yeast UPF1 co-localizes with polyribosomes in the cytoplasm. Mol. Biol. Cell 6, 611–625 (1995).

  3. 3.

    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).

  4. 4.

    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).

  5. 5.

    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).

  6. 6.

    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).

  7. 7.

    Kurosaki, T. & Maquat, L. E. Rules that govern UPF1 binding to mRNA 3′ UTRs. Proc. Natl Acad. Sci. USA 110, 3357–3362 (2013).

  8. 8.

    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).

  9. 9.

    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).

  10. 10.

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

  11. 11.

    Hurt, J. A., Robertson, A. D. & Burge, C. B. Global analyses of UPF1 binding and function reveal expanded scope of nonsense-mediated mRNA decay. Genome Res. 23, 1636–1650 (2013).

  12. 12.

    Kurosaki, T. et al. A post-translational regulatory switch on UPF1 controls targeted mRNA degradation. Genes Dev. 28, 1900–1916 (2014).

  13. 13.

    Lee, S. R., Pratt, G. A., Martinez, F. J., Yeo, G. W. & Lykke-Andersen, J. Target discrimination in nonsense-mediated mRNA decay requires Upf1 ATPase activity. Mol. Cell 59, 413–425 (2015).

  14. 14.

    Zund, D., Gruber, A. R., Zavolan, M. & Mühlemann, O. Translation-dependent displacement of UPF1 from coding sequences causes its enrichment in 3′ UTRs. Nat. Struct. Mol. Biol. 20, 936–943 (2013).

  15. 15.

    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).

  16. 16.

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

  17. 17.

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

  18. 18.

    Fiorini, F., Bagchi, D., Le Hir, H. & Croquette, V. Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities. Nat. Commun. 6, 7581 (2015).

  19. 19.

    Franks, T. M., Singh, G. & Lykke-Andersen, J. Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense-mediated mRNA decay. Cell 143, 938–950 (2010).

  20. 20.

    Shigeoka, T., Kato, S., Kawaichi, M. & Ishida, Y. Evidence that the Upf1-related molecular motor scans the 3′-UTR to ensure mRNA integrity. Nucleic Acids Res. 40, 6887–6897 (2012).

  21. 21.

    Chakrabarti, S. et al. Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2. Mol. Cell 41, 693–703 (2011).

  22. 22.

    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).

  23. 23.

    Kanaan, J. et al. UPF1-like helicase grip on nucleic acids dictates processivity. Nat. Commun. 9, 3752 (2018).

  24. 24.

    Fiorini, F., Boudvillain, M. & Le Hir, H. Tight intramolecular regulation of the human Upf1 helicase by its N- and C-terminal domains. Nucleic Acids Res. 41, 2404–2415 (2013).

  25. 25.

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

  26. 26.

    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).

  27. 27.

    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).

  28. 28.

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

  29. 29.

    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).

  30. 30.

    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).

  31. 31.

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

  32. 32.

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

  33. 33.

    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).

  34. 34.

    Chan, W. K. et al. A UPF3-mediated regulatory switch that maintains RNA surveillance. Nat. Struct. Mol. Biol. 16, 747–753 (2009).

  35. 35.

    Kunz, J. B., Neu-Yilik, G., Hentze, M. W., Kulozik, A. E. & Gehring, N. H. Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation. RNA 12, 1015–1022 (2006).

  36. 36.

    Lou, C. H., Shum, E. Y. & Wilkinson, M. F. RNA degradation drives stem cell differentiation. EMBO J. 34, 1606–1608 (2015).

  37. 37.

    Shum, E. Y. et al. The antagonistic gene paralogs Upf3a and Upf3b govern nonsense-mediated RNA decay. Cell 165, 382–395 (2016).

  38. 38.

    Aznarez, I. et al. Mechanism of nonsense-mediated mRNA decay stimulation by splicing factor SRSF1. Cell Rep. 23, 2186–2198 (2018).

  39. 39.

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

  40. 40.

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

  41. 41.

    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).

  42. 42.

    Gregersen, L. H. et al. MOV10 Is a 5′ to 3′ RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3′ UTRs. Mol. Cell 54, 573–585 (2014).

  43. 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).

  44. 44.

    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).

  45. 45.

    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).

  46. 46.

    Singh, G. et al. The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 151, 915–916 (2012).

  47. 47.

    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).

  48. 48.

    Pan, Q. et al. Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression. Genes Dev. 20, 153–158 (2006).

  49. 49.

    Weischenfeldt, J. et al. Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns. Genome Biol. 13, R35 (2012).

  50. 50.

    Calvo, S. E., Pagliarini, D. J. & Mootha, V. K. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc. Natl Acad. Sci. USA 106, 7507–7512 (2009).

  51. 51.

    Skarshewski, A. et al. uPEPperoni: an online tool for upstream open reading frame location and analysis of transcript conservation. BMC Bioinformatics 15, 36 (2014).

  52. 52.

    Mabin, J. W. et al. The exon junction complex undergoes a compositional switch that alters mRNP structure and nonsense-mediated mRNA decay activity. Cell Rep. 25, 2431–2446 (2018).

  53. 53.

    Ashton-Beaucage, D. et al. The exon junction complex controls the splicing of MAPK and other long intron-containing transcripts in Drosophila. Cell 143, 251–262 (2010).

  54. 54.

    Roignant, J. Y. & Treisman, J. E. Exon junction complex subunits are required to splice Drosophila MAP kinase, a large heterochromatic gene. Cell 143, 238–250 (2010).

  55. 55.

    Wang, Z., Murigneux, V. & Le Hir, H. Transcriptome-wide modulation of splicing by the exon junction complex. Genome Biol. 15, 551 (2014).

  56. 56.

    Schmidt, U., Richter, K., Berger, A. B. & Lichter, P. In vivo BiFC analysis of Y14 and NXF1 mRNA export complexes: preferential localization within and around SC35 domains. J. Cell Biol. 172, 373–381 (2006).

  57. 57.

    Chazal, P. E. et al. EJC core component MLN51 interacts with eIF3 and activates translation. Proc. Natl Acad. Sci. USA 110, 5903–5908 (2013).

  58. 58.

    Diem, M. D., Chan, C. C., Younis, I. & Dreyfuss, G. PYM binds the cytoplasmic exon-junction complex and ribosomes to enhance translation of spliced mRNAs. Nat. Struct. Mol. Biol. 14, 1173–1179 (2007).

  59. 59.

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

  60. 60.

    Hosoda, N., Kim, Y. K., Lejeune, F. & Maquat, L. E. CBP80 promotes interaction of Upf1 with Upf2 during nonsense-mediated mRNA decay in mammalian cells. Nat. Struct. Mol. Biol. 12, 893–901 (2005).

  61. 61.

    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).

  62. 62.

    Dostie, J. & Dreyfuss, G. Translation is required to remove Y14 from mRNAs in the cytoplasm. Curr. Biol. 12, 1060–1067 (2002).

  63. 63.

    Sato, H. & Maquat, L. E. Remodeling of the pioneer translation initiation complex involves translation and the karyopherin importin beta. Genes Dev. 23, 2537–2550 (2009).

  64. 64.

    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).

  65. 65.

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

  66. 66.

    Buchwald, G. et al. Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex. Proc. Natl Acad. Sci. USA 107, 10050–10055 (2010).

  67. 67.

    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).

  68. 68.

    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).

  69. 69.

    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).

  70. 70.

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

  71. 71.

    Sato, H., Hosoda, N. & Maquat, L. E. Efficiency of the pioneer round of translation affects the cellular site of nonsense-mediated mRNA decay. Mol. Cell 29, 255–262 (2008).

  72. 72.

    Zhang, Z. & Krainer, A. R. Involvement of SR proteins in mRNA surveillance. Mol. Cell 16, 597–607 (2004).

  73. 73.

    Alexandrov, A., Colognori, D., Shu, M. D. & Steitz, J. A. Human spliceosomal protein CWC22 plays a role in coupling splicing to exon junction complex deposition and nonsense-mediated decay. Proc. Natl Acad. Sci. USA 109, 21313–21318 (2012).

  74. 74.

    Barbosa, I. et al. Human CWC22 escorts the helicase eIF4AIII to spliceosomes and promotes exon junction complex assembly. Nat. Struct. Mol. Biol. 19, 983–990 (2012).

  75. 75.

    Steckelberg, A. L., Altmueller, J., Dieterich, C. & Gehring, N. H. CWC22-dependent pre-mRNA splicing and eIF4A3 binding enables global deposition of exon junction complexes. Nucleic Acids Res. 43, 4687–4700 (2015).

  76. 76.

    Baird, T. D. et al. ICE1 promotes the link between splicing and nonsense-mediated mRNA decay. eLife 7, e33178 (2018).

  77. 77.

    Chakrabarti, S., Bonneau, F., Schussler, S., Eppinger, E. & Conti, E. Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6. Nucleic Acids Res. 42, 9447–9460 (2014).

  78. 78.

    Durand, S., Franks, T. M. & Lykke-Andersen, J. Hyperphosphorylation amplifies UPF1 activity to resolve stalls in nonsense-mediated mRNA decay. Nat. Commun. 7, 12434 (2016).

  79. 79.

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

  80. 80.

    Deniaud, A. et al. A network of SMG-8, SMG-9 and SMG-1 C-terminal insertion domain regulates UPF1 substrate recruitment and phosphorylation. Nucleic Acids Res. 43, 7600–7611 (2015).

  81. 81.

    Melero, R. et al. The RNA helicase DHX34 functions as a scaffold for SMG1-mediated UPF1 phosphorylation. Nat. Commun. 7, 10585 (2016).

  82. 82.

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

  83. 83.

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

  84. 84.

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

  85. 85.

    Hug, N. & Cáceres, J. F. The RNA helicase DHX34 activates NMD by promoting a transition from the surveillance to the decay-inducing complex. Cell Rep. 8, 1845–1856 (2014).

  86. 86.

    Neu-Yilik, G. et al. Dual function of UPF3B in early and late translation termination. EMBO J. 36, 2968–2986 (2017).

  87. 87.

    He, F. & Jacobson, A. Nonsense-mediated mRNA decay: degradation of defective transcripts is only part of the story. Annu. Rev. Genet. 49, 339–366 (2015).

  88. 88.

    Gao, Z. & Wilkinson, M. An RNA decay factor wears a new coat: UPF3B modulates translation termination. F1000Res. 6, 2159 (2017).

  89. 89.

    Schuller, A. P., Zinshteyn, B., Enam, S. U. & Green, R. Directed hydroxyl radical probing reveals Upf1 binding to the 80S ribosomal E site rRNA at the L1 stalk. Nucleic Acids Res. 46, 2060–2073 (2018).

  90. 90.

    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).

  91. 91.

    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).

  92. 92.

    Kugler, W., Enssle, J., Hentze, M. W. & Kulozik, A. E. Nuclear degradation of nonsense mutated beta-globin mRNA: a post-transcriptional mechanism to protect heterozygotes from severe clinical manifestations of beta-thalassemia? Nucleic Acids Res. 23, 413–418 (1995).

  93. 93.

    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).

  94. 94.

    Halstead, J. M. et al. Translation. An RNA biosensor for imaging the first round of translation from single cells to living animals. Science 347, 1367–1671 (2015).

  95. 95.

    Popp, M. W. & Maquat, L. E. A TRICK’n way to see the pioneer round of translation. Science 347, 1316–1317 (2015).

  96. 96.

    Trcek, T., Sato, H., Singer, R. H. & Maquat, L. E. Temporal and spatial characterization of nonsense-mediated mRNA decay. Genes Dev. 27, 541–551 (2013).

  97. 97.

    Maquat, L. E., Tarn, W. Y. & Isken, O. The pioneer round of translation: features and functions. Cell 142, 368–374 (2010).

  98. 98.

    Chiu, S. Y., Lejeune, F., Ranganathan, A. C. & Maquat, L. E. The pioneer translation initiation complex is functionally distinct from but structurally overlaps with the steady-state translation initiation complex. Genes Dev. 18, 745–754 (2004).

  99. 99.

    Hwang, J., Sato, H., Tang, Y., Matsuda, D. & Maquat, L. E. UPF1 association with the cap-binding protein, CBP80, promotes nonsense-mediated mRNA decay at two distinct steps. Mol. Cell 39, 396–409 (2010).

  100. 100.

    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).

  101. 101.

    Durand, S. & Lykke-Andersen, J. Nonsense-mediated mRNA decay occurs during eIF4F-dependent translation in human cells. Nat. Struct. Mol. Biol. 20, 702–709 (2013).

  102. 102.

    Rufener, S. C. & Mühlemann, O. eIF4E-bound mRNPs are substrates for nonsense-mediated mRNA decay in mammalian cells. Nat. Struct. Mol. Biol. 20, 710–717 (2013).

  103. 103.

    Gao, Q., Das, B., Sherman, F. & Maquat, L. E. Cap-binding protein 1-mediated and eukaryotic translation initiation factor 4E-mediated pioneer rounds of translation in yeast. Proc. Natl Acad. Sci. USA 102, 4258–4263 (2005).

  104. 104.

    Lopez, P. J. & Seraphin, B. Genomic-scale quantitative analysis of yeast pre-mRNA splicing: implications for splice-site recognition. RNA 5, 1135–1137 (1999).

  105. 105.

    Spingola, M., Grate, L., Haussler, D. & Ares, M. Jr. Genome-wide bioinformatic and molecular analysis of introns in Saccharomyces cerevisiae. RNA 5, 221–234 (1999).

  106. 106.

    Malabat, C., Feuerbach, F., Ma, L., Saveanu, C. & Jacquier, A. Quality control of transcription start site selection by nonsense-mediated-mRNA decay. eLife 4, e06722 (2015).

  107. 107.

    Celik, A., He, F. & Jacobson, A. NMD monitors translational fidelity 24/7. Curr. Genet. 63, 1007–1010 (2017).

  108. 108.

    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).

  109. 109.

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

  110. 110.

    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).

  111. 111.

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

  112. 112.

    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).

  113. 113.

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

  114. 114.

    Hosoda, N., Lejeune, F. & Maquat, L. E. Evidence that poly(A) binding protein C1 binds nuclear pre-mRNA poly(A) tails. Mol. Cell. Biol. 26, 3085–3097 (2006).

  115. 115.

    Ivanov, A. et al. PABP enhances release factor recruitment and stop codon recognition during translation termination. Nucleic Acids Res. 44, 7766–7776 (2016).

  116. 116.

    Fatscher, T., Boehm, V., Weiche, B. & Gehring, N. H. The interaction of cytoplasmic poly(A)-binding protein with eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay. RNA 20, 1579–1592 (2014).

  117. 117.

    Joncourt, R., Eberle, A. B., Rufener, S. C. & Mühlemann, O. Eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay by two genetically separable mechanisms. PLOS ONE 9, e104391 (2014).

  118. 118.

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

  119. 119.

    Silva, A. L., Ribeiro, P., Inácio, 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).

  120. 120.

    Lejeune, F., Ranganathan, A. C. & Maquat, L. E. eIF4G is required for the pioneer round of translation in mammalian cells. Nat. Struct. Mol. Biol. 11, 992–1000 (2004).

  121. 121.

    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).

  122. 122.

    Peixeiro, I. et al. Interaction of PABPC1 with the translation initiation complex is critical to the NMD resistance of AUG-proximal nonsense mutations. Nucleic Acids Res. 40, 1160–1173 (2012).

  123. 123.

    Neu-Yilik, G. et al. Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon. RNA 17, 843–854 (2011).

  124. 124.

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

  125. 125.

    Baker, K. E. & Parker, R. Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr. Opin. Cell Biol. 16, 293–299 (2004).

  126. 126.

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

  127. 127.

    Tani, H. et al. Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability. RNA Biol. 9, 1370–1379 (2012).

  128. 128.

    Toma, K. G., Rebbapragada, I., Durand, S. & Lykke-Andersen, J. Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay. RNA 21, 887–897 (2015).

  129. 129.

    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).

  130. 130.

    Ge, Z., Quek, B. L., Beemon, K. L. & Hogg, J. R. Polypyrimidine tract binding protein 1 protects mRNAs from recognition by the nonsense-mediated mRNA decay pathway. eLife 5, e11155 (2016).

  131. 131.

    Kishor, A., Ge, Z. & Hogg, J. R. hnRNP L-dependent protection of normal mRNAs from NMD subverts quality control in B cell lymphoma. EMBO J. 38, e99128 (2019).

  132. 132.

    Imamachi, N., Salam, K. A., Suzuki, Y. & Akimitsu, N. A. GC-rich sequence feature in the 3′ UTR directs UPF1-dependent mRNA decay in mammalian cells. Genome Res. 27, 407–418 (2017).

  133. 133.

    Park, E. & Maquat, L. E. Staufen-mediated mRNA decay. Wiley Interdiscip. Rev. RNA 4, 423–435 (2013).

  134. 134.

    Marzluff, W. F. & Koreski, K. P. Birth and death of histone mRNAs. Trends Genet. 33, 745–759 (2017).

  135. 135.

    Kim, Y. K., Furic, L., Desgroseillers, L. & Maquat, L. E. Mammalian Staufen1 recruits Upf1 to specific mRNA 3′UTRs so as to elicit mRNA decay. Cell 120, 195–208 (2005).

  136. 136.

    Choe, J., Ahn, S. H. & Kim, Y. K. The mRNP remodeling mediated by UPF1 promotes rapid degradation of replication-dependent histone mRNA. Nucleic Acids Res. 42, 9334–9349 (2014).

  137. 137.

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

  138. 138.

    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).

  139. 139.

    Lykke-Andersen, S. et al. Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes. Genes Dev. 28, 2498–2517 (2014).

  140. 140.

    Schmid, M. & Jensen, T. H. The exosome: a multipurpose RNA-decay machine. Trends Biochem. Sci. 33, 501–510 (2008).

  141. 141.

    Kurosaki, T., Miyoshi, K., Myers, J. R. & Maquat, L. E. NMD-degradome sequencing reveals ribosome-bound intermediates with 3′-end non-templated nucleotides. Nat. Struct. Mol. Biol. 25, 940–950 (2018).

  142. 142.

    Malecki, M. et al. The exoribonuclease Dis3L2 defines a novel eukaryotic RNA degradation pathway. EMBO J. 32, 1842–1854 (2013).

  143. 143.

    Loh, B., Jonas, S. & Izaurralde, E. The SMG5-SMG7 heterodimer directly recruits the CCR4-NOT deadenylase complex to mRNAs containing nonsense codons via interaction with POP2. Genes Dev. 27, 2125–2138 (2013).

  144. 144.

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

  145. 145.

    Yamashita, A. et al. Concerted action of poly(A) nucleases and decapping enzyme in mammalian mRNA turnover. Nat. Struct. Mol. Biol. 12, 1054–1063 (2005).

  146. 146.

    Cho, H. et al. SMG5-PNRC2 is functionally dominant compared with SMG5-SMG7 in mammalian nonsense-mediated mRNA decay. Nucleic Acids Res. 41, 1319–1328 (2013).

  147. 147.

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

  148. 148.

    Lai, T. et al. Structural basis of the PNRC2-mediated link between mrna surveillance and decapping. Structure 20, 2025–2037 (2012).

  149. 149.

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

  150. 150.

    Dehecq, M. et al. Nonsense-mediated mRNA decay involves two distinct Upf1-bound complexes. EMBO J. 37, e99278 (2018).

  151. 151.

    Arribere, J. A. & Fire, A. Z. Nonsense mRNA suppression via nonstop decay. eLife 7, e33292 (2018).

  152. 152.

    Colombo, M., Karousis, E. D., Bourquin, J., Bruggmann, R. & Mühlemann, O. Transcriptome-wide identification of NMD-targeted human mRNAs reveals extensive redundancy between SMG6- and SMG7-mediated degradation pathways. RNA 23, 189–201 (2017).

  153. 153.

    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).

  154. 154.

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

  155. 155.

    Fillman, C. & Lykke-Andersen, J. RNA decapping inside and outside of processing bodies. Curr. Opin. Cell Biol. 17, 326–331 (2005).

  156. 156.

    Eulalio, A., Behm-Ansmant, I., Schweizer, D. & Izaurralde, E. P-Body formation is a consequence, not the cause, of RNA-mediated gene silencing. Mol. Cell. Biol. 27, 3970–3981 (2007).

  157. 157.

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

  158. 158.

    Hu, W., Petzold, C., Coller, J. & Baker, K. E. Nonsense-mediated mRNA decapping occurs on polyribosomes in Saccharomyces cerevisiae. Nat. Struct. Mol. Biol. 17, 244–247 (2010).

  159. 159.

    Green, R. E. et al. Widespread predicted nonsense-mediated mRNA decay of alternatively-spliced transcripts of human normal and disease genes. Bioinformatics 19 (Suppl. 1), i118–i121 (2003).

  160. 160.

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

  161. 161.

    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).

  162. 162.

    Wengrod, J. et al. Inhibition of nonsense-mediated RNA decay activates autophagy. Mol. Cell. Biol. 33, 2128–2135 (2013).

  163. 163.

    Gardner, L. B. Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response. Mol. Cell. Biol. 28, 3729–3741 (2008).

  164. 164.

    Wang, D., Wengrod, J. & Gardner, L. B. Overexpression of the c-myc oncogene inhibits nonsense-mediated RNA decay in B lymphocytes. J. Biol. Chem. 286, 40038–40043 (2011).

  165. 165.

    Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).

  166. 166.

    Goetz, A. E. & Wilkinson, M. Stress and the nonsense-mediated RNA decay pathway. Cell. Mol. Life Sci. 74, 3509–3531 (2017).

  167. 167.

    Karam, R. et al. The unfolded protein response is shaped by the NMD pathway. EMBO Rep. 16, 599–609 (2015).

  168. 168.

    Jia, J. et al. Caspases shutdown nonsense-mediated mRNA decay during apoptosis. Cell Death Differ. 22, 1754–1763 (2015).

  169. 169.

    Popp, M. W. & Maquat, L. E. Attenuation of nonsense-mediated mRNA decay facilitates the response to chemotherapeutics. Nat. Commun. 6, 6632 (2015).

  170. 170.

    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).

  171. 171.

    McIlwain, D. R. et al. Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay. Proc. Natl Acad. Sci. USA 107, 12186–12191 (2010).

  172. 172.

    Li, T. et al. Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay. EMBO J. 34, 1630–1647 (2015).

  173. 173.

    Nelson, J. O., Moore, K. A., Chapin, A., Hollien, J. & Metzstein, M. M. Degradation of Gadd45 mRNA by nonsense-mediated decay is essential for viability. eLife 5, e12876 (2016).

  174. 174.

    Lou, C. H. et al. Nonsense-mediated RNA decay influences human embryonic stem cell fate. Stem Cell Rep. 6, 844–857 (2016).

  175. 175.

    Bruno, I. G. et al. Identification of a microRNA that activates gene expression by repressing nonsense-mediated RNA decay. Mol. Cell 42, 500–510 (2011).

  176. 176.

    Lou, C. H. et al. Posttranscriptional control of the stem cell and neurogenic programs by the nonsense-mediated RNA decay pathway. Cell Rep. 6, 748–764 (2014).

  177. 177.

    Wong, J. J. et al. Orchestrated intron retention regulates normal granulocyte differentiation. Cell 154, 583–595 (2013).

  178. 178.

    Colak, D., Ji, S. J., Porse, B. T. & Jaffrey, S. R. Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay. Cell 153, 1252–1265 (2013).

  179. 179.

    Belew, A. T. et al. Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway. Nature 512, 265–269 (2014).

  180. 180.

    Inoue, K. et al. Translation of SOX10 3′ untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain. Hum. Mol. Genet. 16, 3037–3046 (2007).

  181. 181.

    Bhuvanagiri, M. et al. 5-Azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion. EMBO Mol. Med. 6, 1593–1609 (2014).

  182. 182.

    Miller, J. N. & Pearce, D. A. Nonsense-mediated decay in genetic disease: friend or foe? Mutat. Res. Rev. Mutat. Res. 762, 52–64 (2014).

  183. 183.

    Kerr, T. P., Sewry, C. A., Robb, S. A. & Roberts, R. G. Long mutant dystrophins and variable phenotypes: evasion of nonsense-mediated decay? Hum. Genet. 109, 402–407 (2001).

  184. 184.

    Tarpey, P. S. et al. Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat. Genet. 39, 1127–1133 (2007).

  185. 185.

    Jaffrey, S. R. & Wilkinson, M. F. Nonsense-mediated RNA decay in the brain: emerging modulator of neural development and disease. Nat. Rev. Neurosci. 19, 715–728 (2018).

  186. 186.

    Fryns, J. P. & Buttiens, M. X-Linked mental retardation with marfanoid habitus. Am. J. Med. Genet. 28, 267–274 (1987).

  187. 187.

    Opitz, J. M. & Kaveggia, E. G. Studies of malformation syndromes of man 33: the FG syndrome. An X-linked recessive syndrome of multiple congenital anomalies and mental retardation. Z. Kinderheilkd. 117, 1–18 (1974).

  188. 188.

    Addington, A. M. et al. A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Mol. Psychiatry 16, 238–239 (2011).

  189. 189.

    Laumonnier, F. et al. Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism. Mol. Psychiatry 15, 767–776 (2010).

  190. 190.

    Lynch, S. A. et al. Broadening the phenotype associated with mutations in UPF3B: two further cases with renal dysplasia and variable developmental delay. Eur. J. Med. Genet. 55, 476–479 (2012).

  191. 191.

    Xu, X. et al. Exome sequencing identifies UPF3B as the causative gene for a Chinese non-syndrome mental retardation pedigree. Clin. Genet. 83, 560–564 (2013).

  192. 192.

    Nguyen, L. S. et al. Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders. Hum. Mol. Genet. 22, 1816–1825 (2013).

  193. 193.

    Brunetti-Pierri, N. et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat. Genet. 40, 1466–1471 (2008).

  194. 194.

    Huang, L. et al. A Upf3b-mutant mouse model with behavioral and neurogenesis defects. Mol. Psychiatry 23, 1773–1786 (2018).

  195. 195.

    Mao, H. et al. Rbm8a haploinsufficiency disrupts embryonic cortical development resulting in microcephaly. J. Neurosci. 35, 7003–7018 (2015).

  196. 196.

    Alrahbeni, T. et al. Full UPF3B function is critical for neuronal differentiation of neural stem cells. Mol. Brain 8, 33 (2015).

  197. 197.

    Jolly, L. A., Homan, C. C., Jacob, R., Barry, S. & Gecz, J. The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth. Hum. Mol. Genet. 22, 4673–4687 (2013).

  198. 198.

    Long, A. A. et al. The nonsense-mediated decay pathway maintains synapse architecture and synaptic vesicle cycle efficacy. J. Cell Sci. 123, 3303–3315 (2010).

  199. 199.

    Nguyen, L. S. et al. Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability. Mol. Psychiatry 17, 1103–1115 (2012).

  200. 200.

    Perrin-Vidoz, L., Sinilnikova, O. M., Stoppa-Lyonnet, D., Lenoir, G. M. & Mazoyer, S. The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons. Hum. Mol. Genet. 11, 2805–2814 (2002).

  201. 201.

    Ware, M. D. et al. Does nonsense-mediated mRNA decay explain the ovarian cancer cluster region of the BRCA2 gene? Oncogene 25, 323–328 (2006).

  202. 202.

    Anczukow, O. et al. Does the nonsense-mediated mRNA decay mechanism prevent the synthesis of truncated BRCA1, CHK2, and p53 proteins? Hum. Mutat. 29, 65–73 (2008).

  203. 203.

    Pinyol, M. et al. Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis. Blood 109, 5422–5429 (2007).

  204. 204.

    Reddy, J. C. et al. WT1-mediated transcriptional activation is inhibited by dominant negative mutant proteins. J. Biol. Chem. 270, 10878–10884 (1995).

  205. 205.

    Mort, M., Ivanov, D., Cooper, D. N. & Chuzhanova, N. A. A meta-analysis of nonsense mutations causing human genetic disease. Hum. Mutat. 29, 1037–1047 (2008).

  206. 206.

    Hu, Z., Yau, C. & Ahmed, A. A. A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay. Nat. Commun. 8, 15943 (2017).

  207. 207.

    Lindeboom, R. G., Supek, F. & Lehner, B. The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat. Genet. 48, 1112–1118 (2016).

  208. 208.

    Liu, C. et al. The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma. Nat. Med. 20, 596–598 (2014).

  209. 209.

    Lu, J. et al. The nonsense-mediated RNA decay pathway is disrupted in inflammatory myofibroblastic tumors. J. Clin. Invest. 126, 3058–3062 (2016).

  210. 210.

    Chang, L. et al. The human RNA surveillance factor UPF1 regulates tumorigenesis by targeting Smad7 in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 35, 8 (2016).

  211. 211.

    Bokhari, A. et al. Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability. Oncogenesis 7, 70 (2018).

  212. 212.

    Pastor, F., Kolonias, D., Giangrande, P. H. & Gilboa, E. Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. Nature 465, 227–230 (2010).

  213. 213.

    Wang, D. et al. Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis. Mol. Cell. Biol. 31, 3670–3680 (2011).

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Acknowledgements

The authors thank X. Rambout and H. Cho for critically reading the manuscript and R. Green for helpful conversations. The authors apologize to colleagues whose work was not referenced owing to space limitations. Work on nonsense-mediated mRNA decay in the Maquat laboratory is supported by the National Institutes of Health R01 grant GM059614. T.K. was partially supported by a Schmitt Program in Integrative Neuroscience from the University of Rochester Medical Center.

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All authors contributed equally to the discussion of the content and to the writing and editing of the manuscript before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Lynne E. Maquat.

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Glossary

Dominant-negative proteins

Mutated proteins that can antagonize the function of the wild-type protein, often because the proteins are part of a macromolecular complex, which is rendered defective by the presence of the mutated protein.

β0-thalassaemia

Thalassaemia is a blood disorder causing anaemia. In the severe form of β0-thalassaemia, no β-globin protein is detectable in peripheral blood.

NMD-activating feature

An mRNA feature that increases the probability of the mRNA undergoing nonsense-mediated mRNA decay. Examples include an exon–exon junction complex deposited as a consequence of splicing more than ~30–35 nucleotides downstream of a termination codon, an unusually long (>1 kb) 3′ untranslated region or a selenocysteine codon that is interpreted as a stop codon.

Upstream open reading frame

(uORF). A short ORF in the 5′ end of mRNA (upstream of the main ORF) that can regulate the translation of the main ORF.

A site

The amino-acyl site on the ribosome is where charged tRNA molecules (with the exception of the translation-initiating charged tRNA) bind during protein synthesis.

Peptidyl-tRNA hydrolysis

A process that occurs during translation when a water molecule attacks the bond between the nascent peptide and the tRNA molecule in the ribosome, thereby releasing the completed polypeptide.

Staufen-mediated mRNA decay

An mRNA decay pathway in which the staufen protein recruits UPF1 to an mRNA 3′ untranslated region, causing translation-dependent destabilization of the mRNA.

Exosome

A large protein complex that degrades mRNAs through its 3′-to-5′ exoribonuclease activities.

Selenocysteine

An amino acid that is inserted into mRNA bearing a selenocysteine insertion sequence that directs its incorporation at UGA codons, which otherwise would be recognized as termination codons.

Intron retention

Occurs when an intron fails to be excised out of a pre-mRNA during alternative splicing, giving rise to a transcript with a premature termination codon.

Programmed ribosomal frameshifts

(PRFs). During translation, incidents of ribosome ‘slippage’ and adoption of a new reading frame.

Pseudoknot

A tertiary RNA structure formed by base pairing between the loop of a stem–loop structure and nearby ribonucleotides. It is extremely difficult for helicases to unwind this structure.

Waardenburg syndrome

A disease manifesting defects in tissues derived from cells in the neural crest lineage (neurocristopathy). Individuals with Waardenburg syndrome have defects in hair, skin and eye pigmentation and may suffer from hearing loss.

Hirschprung disease

A congenital malady in which nerve cells are missing from the end of the bowel, thereby causing problems with passing stool.

Lujan–Fryns syndrome

An X-linked disorder causing mild to moderate intellectual disability, facial dysmorphism and arms and legs that are abnormally long and slender.

FG syndrome

An X-linked disorder characterized by intellectual disability, poor muscle tone and macrocephaly.

Tumour neo-antigens

Peptides absent from normal cells that are produced by tumour-mutated genes that are presented to and activate the immune system.

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Fig. 1: Discriminating between targets and nontargets of nonsense-mediated mRNA decay.
Fig. 2: UPF1 binding to mRNA and activation of nonsense-mediated mRNA decay.
Fig. 3: Degradation of the nonsense-mediated mRNA decay targets.
Fig. 4: Features of cellular mRNAs that activate nonsense-mediated mRNA decay.
Fig. 5: Physiological roles of nonsense-mediated mRNA decay.
Fig. 6: Involvement of nonsense-mediated mRNA decay in disease.