Skip to main content

Advertisement

Log in

Physiological and pathophysiological role of nonsense-mediated mRNA decay

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a quality control mechanism that degrades irregular or faulty mRNAs. NMD mainly degrades mRNAs, which contain a premature termination codon (PTC) and therefore encode a truncated protein. Furthermore, NMD alters the expression of different types of cellular mRNAs, the so-called endogenous NMD substrates. In this review, we focus on the impact of NMD on cellular and molecular physiology. We specify key classes of NMD substrates and provide a detailed overview of the physiological function of gene regulation by NMD. We also describe different mechanisms of NMD substrate degradation and how the regulation of the NMD machinery affects cellular physiology. Finally, we outline the physiological functions of central NMD factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Abernathy E, Glaunsinger B (2015) Emerging roles for RNA degradation in viral replication and antiviral defense. Virology 479–480:600–608. doi:10.1016/j.virol.2015.02.007

    Article  PubMed  CAS  Google Scholar 

  2. Addington AM, Gauthier J, Piton A, Hamdan FF, Raymond A, Gogtay N, Miller R, Tossell J, Bakalar J, Inoff-Germain G, Gochman P, Long R, Rapoport JL, Rouleau GA (2011) A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Mol Psychiatry 16:238–239. doi:10.1038/mp.2010.59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ahlquist P (2006) Parallels among positive-strand RNA viruses, reverse-transcribing viruses and double-stranded RNA viruses. Nat Rev Microbiol 4:371–382. doi:10.1038/nrmicro1389

    Article  CAS  PubMed  Google Scholar 

  4. Ajamian L, Abrahamyan L, Milev M, Ivanov PV, Kulozik AE, Gehring NH, Mouland AJ (2008) Unexpected roles for UPF1 in HIV-1 RNA metabolism and translation. RNA 14:914–927. doi:10.1261/rna.829208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ameri K, Lewis CE, Raida M, Sowter H, Hai T, Harris AL (2004) Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells. Blood 103:1876–1882. doi:10.1182/blood-2003-06-1859

    Article  CAS  PubMed  Google Scholar 

  6. Anko ML, Neugebauer KM (2012) RNA-protein interactions in vivo: global gets specific. Trends Biochem Sci 37:255–262. doi:10.1016/j.tibs.2012.02.005

    Article  PubMed  CAS  Google Scholar 

  7. Applequist SE, Selg M, Raman C, Jack HM (1997) Cloning and characterization of HUPF1, a human homolog of the Saccharomyces cerevisiae nonsense mRNA-reducing UPF1 protein. Nucleic Acids Res 25:814–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Azzalin CM, Lingner J (2006) The human RNA surveillance factor UPF1 is required for S phase progression and genome stability. Curr Biol 16:433–439. doi:10.1016/j.cub.2006.01.018

    Article  CAS  PubMed  Google Scholar 

  9. Bak M, Silahtaroglu A, Moller M, Christensen M, Rath MF, Skryabin B, Tommerup N, Kauppinen S (2008) MicroRNA expression in the adult mouse central nervous system. RNA 14:432–444. doi:10.1261/rna.783108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Balistreri G, Horvath P, Schweingruber C, Zund D, McInerney G, Merits A, Muhlemann O, Azzalin C, Helenius A (2014) The host nonsense-mediated mRNA decay pathway restricts Mammalian RNA virus replication. Cell Host Microbe 16:403–411. doi:10.1016/j.chom.2014.08.007

    Article  CAS  PubMed  Google Scholar 

  11. Barker GF, Beemon K (1994) Rous sarcoma virus RNA stability requires an open reading frame in the gag gene and sequences downstream of the gag-pol junction. Mol Cell Biol 14:1986–1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C (2005) ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 24:3470–3481. doi:10.1038/sj.emboj.7600777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336. doi:10.1146/annurev.biochem.72.121801.161720

    Article  CAS  PubMed  Google Scholar 

  14. Blais JD, Filipenko V, Bi M, Harding HP, Ron D, Koumenis C, Wouters BG, Bell JC (2004) Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol 24:7469–7482. doi:10.1128/MCB.24.17.7469-7482.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boehm V, Haberman N, Ottens F, Ule J, Gehring NH (2014) 3′ UTR length and messenger ribonucleoprotein composition determine endocleavage efficiencies at termination codons. Cell Rep 9:555–568. doi:10.1016/j.celrep.2014.09.012

    Article  CAS  PubMed  Google Scholar 

  16. Boutz PL, Stoilov P, Li Q, Lin CH, Chawla G, Ostrow K, Shiue L, Ares M Jr, Black DL (2007) A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev 21:1636–1652. doi:10.1101/gad.1558107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Brumbaugh KM, Otterness DM, Geisen C, Oliveira V, Brognard J, Li X, Lejeune F, Tibbetts RS, Maquat LE, Abraham RT (2004) The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells. Mol Cell 14:585–598. doi:10.1016/j.molcel.2004.05.005

    Article  CAS  PubMed  Google Scholar 

  18. Bruno IG, Karam R, Huang L, Bhardwaj A, Lou CH, Shum EY, Song HW, Corbett MA, Gifford WD, Gecz J, Pfaff SL, Wilkinson MF (2011) Identification of a microRNA that activates gene expression by repressing nonsense-mediated RNA decay. Mol Cell 42:500–510. doi:10.1016/j.molcel.2011.04.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Buchwald G, Ebert J, Basquin C, Sauliere J, Jayachandran U, Bono F, Le Hir H, Conti E (2010) Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex. Proc Natl Acad Sci U S A 107:10050–10055. doi:10.1073/pnas.1000993107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Carter MS, Doskow J, Morris P, Li S, Nhim RP, Sandstedt S, Wilkinson MF (1995) 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

    Article  CAS  PubMed  Google Scholar 

  21. Cases S, Novak S, Zheng YW, Myers HM, Lear SR, Sande E, Welch CB, Lusis AJ, Spencer TA, Krause BR, Erickson SK, Farese RV Jr (1998) ACAT-2, a second mammalian acyl-CoA:cholesterol acyltransferase. Its cloning, expression, and characterization. J Biol Chem 273:26755–26764

    Article  CAS  PubMed  Google Scholar 

  22. Chan WK, Bhalla AD, Le Hir H, Nguyen LS, Huang L, Gecz J, Wilkinson MF (2009) A UPF3-mediated regulatory switch that maintains RNA surveillance. Nat Struct Mol Biol 16:747–753. doi:10.1038/nsmb.1612

    Article  CAS  PubMed  Google Scholar 

  23. Chen Z, Gore BB, Long H, Ma L, Tessier-Lavigne M (2008) Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion. Neuron 58:325–332. doi:10.1016/j.neuron.2008.02.016

    Article  CAS  PubMed  Google Scholar 

  24. Clerici M, Deniaud A, Boehm V, Gehring NH, Schaffitzel C, Cusack S (2014) Structural and functional analysis of the three MIF4G domains of nonsense-mediated decay factor UPF2. Nucleic Acids Res 42:2673–2686. doi:10.1093/nar/gkt1197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Clerici M, Mourao A, Gutsche I, Gehring NH, Hentze MW, Kulozik A, Kadlec J, Sattler M, Cusack S (2009) Unusual bipartite mode of interaction between the nonsense-mediated decay factors, UPF1 and UPF2. EMBO J 28:2293–2306. doi:10.1038/emboj.2009.175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Colak D, Ji SJ, Porse BT, Jaffrey SR (2013) Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay. Cell 153:1252–1265. doi:10.1016/j.cell.2013.04.056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Desbois C, Rousset R, Bantignies F, Jalinot P (1996) Exclusion of Int-6 from PML nuclear bodies by binding to the HTLV-I Tax oncoprotein. Science 273:951–953

    Article  CAS  PubMed  Google Scholar 

  28. Donnelly N, Gorman AM, Gupta S, Samali A (2013) The eIF2alpha kinases: their structures and functions. Cell Mol Life Sci 70:3493–3511. doi:10.1007/s00018-012-1252-6

    Article  CAS  PubMed  Google Scholar 

  29. Eberle AB, Lykke-Andersen S, Muhlemann O, Jensen TH (2009) SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells. Nat Struct Mol Biol 16:49–55. doi:10.1038/nsmb.1530

    Article  CAS  PubMed  Google Scholar 

  30. Garcia D, Garcia S, Voinnet O (2014) Nonsense-mediated decay serves as a general viral restriction mechanism in plants. Cell Host Microbe 16:391–402. doi:10.1016/j.chom.2014.08.001

    Article  CAS  PubMed  Google Scholar 

  31. Gardner LB (2008) Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response. Mol Cell Biol 28:3729–3741. doi:10.1128/MCB.02284-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gehring NH, Lamprinaki S, Kulozik AE, Hentze MW (2009) Disassembly of exon junction complexes by PYM. Cell 137:536–548. doi:10.1016/j.cell.2009.02.042

    Article  CAS  PubMed  Google Scholar 

  33. Gerondopoulos A, Langemeyer L, Liang JR, Linford A, Barr FA (2012) BLOC-3 mutated in Hermansky-Pudlak syndrome is a Rab32/38 guanine nucleotide exchange factor. Curr Biol 22:2135–2139. doi:10.1016/j.cub.2012.09.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ghigna C, Giordano S, Shen H, Benvenuto F, Castiglioni F, Comoglio PM, Green MR, Riva S, Biamonti G (2005) Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell 20:881–890. doi:10.1016/j.molcel.2005.10.026

    Article  CAS  PubMed  Google Scholar 

  35. Graveley BR (2000) Sorting out the complexity of SR protein functions. RNA 6:1197–1211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hamid FM, Makeyev EV (2014) Regulation of mRNA abundance by polypyrimidine tract-binding protein-controlled alternate 5′ splice site choice. PLoS Genet 10, e1004771. doi:10.1371/journal.pgen.1004771

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Harding CL, Lloyd DR, McFarlane CM, Al-Rubeai M (2000) Using the Microcyte flow cytometer to monitor cell number, viability, and apoptosis in mammalian cell culture. Biotechnol Prog 16:800–802. doi:10.1021/bp0000813

    Article  CAS  PubMed  Google Scholar 

  38. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633

    Article  CAS  PubMed  Google Scholar 

  39. Hirschfeld M, zur Hausen A, Bettendorf H, Jager M, Stickeler E (2009) Alternative splicing of Cyr61 is regulated by hypoxia and significantly changed in breast cancer. Cancer Res 69:2082–2090. doi:10.1158/0008-5472.CAN-08-1997

    Article  CAS  PubMed  Google Scholar 

  40. Huntzinger E, Kashima I, Fauser M, Sauliere J, Izaurralde E (2008) SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan. RNA 14:2609–2617. doi:10.1261/rna.1386208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ivanov PV, Gehring NH, Kunz JB, Hentze MW, Kulozik AE (2008) Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways. EMBO J 27:736–747. doi:10.1038/emboj.2008.17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kadlec J, Izaurralde E, Cusack S (2004) The structural basis for the interaction between nonsense-mediated mRNA decay factors UPF2 and UPF3. Nat Struct Mol Biol 11:330–337. doi:10.1038/nsmb741

    Article  CAS  PubMed  Google Scholar 

  43. Karam R, Lou CH, Kroeger H, Huang L, Lin JH, Wilkinson MF (2015) The unfolded protein response is shaped by the NMD pathway. EMBO Rep 16:599–609. doi:10.15252/embr.201439696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kashima I, Yamashita A, Izumi N, Kataoka N, Morishita R, Hoshino S, Ohno M, Dreyfuss G, Ohno S (2006) 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. doi:10.1101/gad.1389006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Keppetipola N, Sharma S, Li Q, Black DL (2012) Neuronal regulation of pre-mRNA splicing by polypyrimidine tract binding proteins, PTBP1 and PTBP2. Crit Rev Biochem Mol Biol 47:360–378. doi:10.3109/10409238.2012.691456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Keren H, Lev-Maor G, Ast G (2010) Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 11:345–355. doi:10.1038/nrg2776

    Article  CAS  PubMed  Google Scholar 

  47. Kunz JB, Neu-Yilik G, Hentze MW, Kulozik AE, Gehring NH (2006) Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation. RNA 12:1015–1022. doi:10.1261/rna.12506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lareau LF, Inada M, Green RE, Wengrod JC, Brenner SE (2007) Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 446:926–929. doi:10.1038/nature05676

    Article  CAS  PubMed  Google Scholar 

  49. Laumonnier F, Shoubridge C, Antar C, Nguyen LS, Van Esch H, Kleefstra T, Briault S, Fryns JP, Hamel B, Chelly J, Ropers HH, Ronce N, Blesson S, Moraine C, Gecz J, Raynaud M (2010) 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. doi:10.1038/mp.2009.14

    Article  CAS  PubMed  Google Scholar 

  50. Le Hir H, Gatfield D, Izaurralde E, Moore MJ (2001) 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. doi:10.1093/emboj/20.17.4987

    Article  PubMed  PubMed Central  Google Scholar 

  51. Le Hir H, Izaurralde E, Maquat LE, Moore MJ (2000) The spliceosome deposits multiple proteins 20–24 nucleotides upstream of mRNA exon-exon junctions. EMBO J 19:6860–6869. doi:10.1093/emboj/19.24.6860

    Article  PubMed  PubMed Central  Google Scholar 

  52. Lewis BP, Green RE, Brenner SE (2003) Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc Natl Acad Sci U S A 100:189–192. doi:10.1073/pnas.0136770100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li T, Shi Y, Wang P, Guachalla LM, Sun B, Joerss T, Chen YS, Groth M, Krueger A, Platzer M, Yang YG, Rudolph KL, Wang ZQ (2015) Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay. EMBO J. doi:10.15252/embj.201489947

    Google Scholar 

  54. Li Z, Nagy PD (2011) Diverse roles of host RNA binding proteins in RNA virus replication. RNA Biol 8:305–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu C, Karam R, Zhou Y, Su F, Ji Y, Li G, Xu G, Lu L, Wang C, Song M, Zhu J, Wang Y, Zhao Y, Foo WC, Zuo M, Valasek MA, Javle M, Wilkinson MF, Lu Y (2014) The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma. Nat Med 20:596–598. doi:10.1038/nm.3548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Loh B, Jonas S, Izaurralde E (2013) 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. doi:10.1101/gad.226951.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Long H, Sabatier C, Ma L, Plump A, Yuan W, Ornitz DM, Tamada A, Murakami F, Goodman CS, Tessier-Lavigne M (2004) Conserved roles for Slit and Robo proteins in midline commissural axon guidance. Neuron 42:213–223

    Article  CAS  PubMed  Google Scholar 

  58. Lou CH, Shao A, Shum EY, Espinoza JL, Huang L, Karam R, Wilkinson MF (2014) Posttranscriptional control of the stem cell and neurogenic programs by the nonsense-mediated RNA decay pathway. Cell Rep 6:748–764. doi:10.1016/j.celrep.2014.01.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lykke-Andersen J, Shu MD, Steitz JA (2000) Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon. Cell 103:1121–1131

    Article  CAS  PubMed  Google Scholar 

  60. Lykke-Andersen S, Chen Y, Ardal BR, Lilje B, Waage J, Sandelin A, Jensen TH (2014) Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes. Genes Dev 28:2498–2517. doi:10.1101/gad.246538.114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Lynch SA, Nguyen LS, Ng LY, Waldron M, McDonald D, Gecz J (2012) 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. doi:10.1016/j.ejmg.2012.03.010

    Article  PubMed  Google Scholar 

  62. Makeyev EV, Zhang J, Carrasco MA, Maniatis T (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27:435–448. doi:10.1016/j.molcel.2007.07.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Matlin AJ, Clark F, Smith CW (2005) Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 6:386–398. doi:10.1038/nrm1645

    Article  CAS  PubMed  Google Scholar 

  64. McIlwain DR, Pan Q, Reilly PT, Elia AJ, McCracken S, Wakeham AC, Itie-Youten A, Blencowe BJ, Mak TW (2010) Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay. Proc Natl Acad Sci U S A 107:12186–12191. doi:10.1073/pnas.1007336107

    Article  PubMed  PubMed Central  Google Scholar 

  65. Medghalchi SM, Frischmeyer PA, Mendell JT, Kelly AG, Lawler AM, Dietz HC (2001) Rent1, a trans-effector of nonsense-mediated mRNA decay, is essential for mammalian embryonic viability. Hum Mol Genet 10:99–105

    Article  CAS  PubMed  Google Scholar 

  66. Mendell JT, Medghalchi SM, Lake RG, Noensie EN, Dietz HC (2000) Novel Upf2p orthologues suggest a functional link between translation initiation and nonsense surveillance complexes. Mol Cell Biol 20:8944–8957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mendell JT, Sharifi NA, Meyers JL, Martinez-Murillo F, Dietz HC (2004) Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet 36:1073–1078. doi:10.1038/ng1429

    Article  CAS  PubMed  Google Scholar 

  68. Menendez JA, Mehmi I, Griggs DW, Lupu R (2003) The angiogenic factor CYR61 in breast cancer: molecular pathology and therapeutic perspectives. Endocr Relat Cancer 10:141–152

    Article  CAS  PubMed  Google Scholar 

  69. Mocquet V, Neusiedler J, Rende F, Cluet D, Robin JP, Terme JM, Duc Dodon M, Wittmann J, Morris C, Le Hir H, Ciminale V, Jalinot P (2012) The human T-lymphotropic virus type 1 tax protein inhibits nonsense-mediated mRNA decay by interacting with INT6/EIF3E and UPF1. J Virol 86:7530–7543. doi:10.1128/JVI.07021-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Morris-Desbois C, Bochard V, Reynaud C, Jalinot P (1999) Interaction between the Ret finger protein and the Int-6 gene product and co-localisation into nuclear bodies. J Cell Sci 112(Pt 19):3331–3342

    CAS  PubMed  Google Scholar 

  71. Morrison M, Harris KS, Roth MB (1997) smg mutants affect the expression of alternatively spliced SR protein mRNAs in Caenorhabditis elegans. Proc Natl Acad Sci U S A 94:9782–9785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mort M, Ivanov D, Cooper DN, Chuzhanova NA (2008) A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat 29:1037–1047. doi:10.1002/humu.20763

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  75. Nakano K, Ando T, Yamagishi M, Yokoyama K, Ishida T, Ohsugi T, Tanaka Y, Brighty DW, Watanabe T (2013) Viral interference with host mRNA surveillance, the nonsense-mediated mRNA decay (NMD) pathway, through a new function of HTLV-1 Rex: implications for retroviral replication. Microbes Infect 15:491–505. doi:10.1016/j.micinf.2013.03.006

    Article  CAS  PubMed  Google Scholar 

  76. Narayanan K, Makino S (2013) Interplay between viruses and host mRNA degradation. Biochim Biophys Acta 1829:732–741. doi:10.1016/j.bbagrm.2012.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ni JZ, Grate L, Donohue JP, Preston C, Nobida N, O’Brien G, Shiue L, Clark TA, Blume JE, Ares M Jr (2007) Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev 21:708–718. doi:10.1101/gad.1525507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. O’Donnell M, Chance RK, Bashaw GJ (2009) Axon growth and guidance: receptor regulation and signal transduction. Annu Rev Neurosci 32:383–412. doi:10.1146/annurev.neuro.051508.135614

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Okada-Katsuhata Y, Yamashita A, Kutsuzawa K, Izumi N, Hirahara F, Ohno S (2012) 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. doi:10.1093/nar/gkr791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Oren YS, McClure ML, Rowe SM, Sorscher EJ, Bester AC, Manor M, Kerem E, Rivlin J, Zahdeh F, Mann M, Geiger T, Kerem B (2014) The unfolded protein response affects readthrough of premature termination codons. EMBO Mol Med 6:685–701. doi:10.1002/emmm.201303347

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 40:1413–1415. doi:10.1038/ng.259

    Article  CAS  PubMed  Google Scholar 

  82. Pan Y, Chen H, Siu F, Kilberg MS (2003) Amino acid deprivation and endoplasmic reticulum stress induce expression of multiple activating transcription factor-3 mRNA species that, when overexpressed in HepG2 cells, modulate transcription by the human asparagine synthetase promoter. J Biol Chem 278:38402–38412. doi:10.1074/jbc.M304574200

    Article  CAS  PubMed  Google Scholar 

  83. Perlick HA, Medghalchi SM, Spencer FA, Kendzior RJ Jr, Dietz HC (1996) Mammalian orthologues of a yeast regulator of nonsense transcript stability. Proc Natl Acad Sci U S A 93:10928–10932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pinol-Roma S, Choi YD, Matunis MJ, Dreyfuss G (1988) Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins. Genes Dev 2:215–227

    Article  CAS  PubMed  Google Scholar 

  85. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273. doi:10.1038/nrc2620

    Article  CAS  PubMed  Google Scholar 

  86. Rahman L, Bliskovski V, Kaye FJ, Zajac-Kaye M (2004) Evolutionary conservation of a 2-kb intronic sequence flanking a tissue-specific alternative exon in the PTBP2 gene. Genomics 83:76–84

    Article  CAS  PubMed  Google Scholar 

  87. Ramage HR, Kumar GR, Verschueren E, Johnson JR, Von Dollen J, Johnson T, Newton B, Shah P, Horner J, Krogan NJ, Ott M (2015) A combined proteomics/genomics approach links hepatitis C virus infection with nonsense-mediated mRNA decay. Mol Cell 57:329–340. doi:10.1016/j.molcel.2014.12.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rigby RE, Rehwinkel J (2015) RNA degradation in antiviral immunity and autoimmunity. Trends Immunol 36:179–188. doi:10.1016/j.it.2015.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel AJ, Koritzinsky M, Wouters BG (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 120:127–141. doi:10.1172/JCI40027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Saltzman AL, Kim YK, Pan Q, Fagnani MM, Maquat LE, Blencowe BJ (2008) Regulation of multiple core spliceosomal proteins by alternative splicing-coupled nonsense-mediated mRNA decay. Mol Cell Biol 28:4320–4330. doi:10.1128/MCB.00361-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Schmidt SA, Foley PL, Jeong DH, Rymarquis LA, Doyle F, Tenenbaum SA, Belasco JG, Green PJ (2015) Identification of SMG6 cleavage sites and a preferred RNA cleavage motif by global analysis of endogenous NMD targets in human cells. Nucleic Acids Res 43:309–323. doi:10.1093/nar/gku1258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V (2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 5:R13. doi:10.1186/gb-2004-5-3-r13

    Article  PubMed  PubMed Central  Google Scholar 

  93. Serafini T, Kennedy TE, Galko MJ, Mirzayan C, Jessell TM, Tessier-Lavigne M (1994) The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 78:409–424

    Article  CAS  PubMed  Google Scholar 

  94. Serin G, Gersappe A, Black JD, Aronoff R, Maquat LE (2001) Identification and characterization of human orthologues to Saccharomyces cerevisiae Upf2 protein and Upf3 protein (Caenorhabditis elegans SMG-4). Mol Cell Biol 21:209–223. doi:10.1128/MCB.21.1.209-223.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Seward SL Jr, Gahl WA (2013) Hermansky-Pudlak syndrome: health care throughout life. Pediatrics 132:153–160. doi:10.1542/peds.2012-4003

    Article  PubMed  Google Scholar 

  96. Shepard PJ, Hertel KJ (2009) The SR protein family. Genome Biol 10:242. doi:10.1186/gb-2009-10-10-242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Sheth U, Parker R (2006) Targeting of aberrant mRNAs to cytoplasmic processing bodies. Cell 125:1095–1109. doi:10.1016/j.cell.2006.04.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Shum EY, Jones SH, Shao A, Dumdie J, Krause MD, Chan WK, Lou CH, Espinoza JL, Song HW, Phan MH, Ramaiah M, Huang L, McCarrey JR, Peterson KJ, De Rooij DG, Cook-Andersen H, Wilkinson MF (2016) The antagonistic gene paralogs Upf3a and Upf3b govern nonsense-mediated RNA decay. Cell. doi:10.1016/j.cell.2016.02.046

    PubMed  Google Scholar 

  99. Silvain J, Collet JP, Nagaswami C, Beygui F, Edmondson KE, Bellemain-Appaix A, Cayla G, Pena A, Brugier D, Barthelemy O, Montalescot G, Weisel JW (2011) Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 57:1359–1367. doi:10.1016/j.jacc.2010.09.077

    Article  PubMed  PubMed Central  Google Scholar 

  100. Simons-Evelyn M, Young HA, Anderson SK (1997) Characterization of the mouse Nktr gene and promoter. Genomics 40:94–100. doi:10.1006/geno.1996.4562

    Article  CAS  PubMed  Google Scholar 

  101. Singh G, Kucukural A, Cenik C, Leszyk JD, Shaffer SA, Weng Z, Moore MJ (2012) The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 151:750–764. doi:10.1016/j.cell.2012.10.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Singh G, Rebbapragada I, Lykke-Andersen J (2008) A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay. PLoS Biol 6, e111. doi:10.1371/journal.pbio.0060111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Smirnova L, Grafe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG (2005) Regulation of miRNA expression during neural cell specification. Eur J Neurosci 21:1469–1477. doi:10.1111/j.1460-9568.2005.03978.x

    Article  PubMed  Google Scholar 

  104. Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136:731–745. doi:10.1016/j.cell.2009.01.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Spellman R, Llorian M, Smith CW (2007) Crossregulation and functional redundancy between the splicing regulator PTB and its paralogs nPTB and ROD1. Mol Cell 27:420–434. doi:10.1016/j.molcel.2007.06.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Stockklausner C, Breit S, Neu-Yilik G, Echner N, Hentze MW, Kulozik AE, Gehring NH (2006) The uORF-containing thrombopoietin mRNA escapes nonsense-mediated decay (NMD). Nucleic Acids Res 34:2355–2363. doi:10.1093/nar/gkl277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sureau A, Gattoni R, Dooghe Y, Stevenin J, Soret J (2001) SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs. EMBO J 20:1785–1796. doi:10.1093/emboj/20.7.1785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Susova O, Gurtsevich VE (2003) The role of region pX in the life cycle of HTLV-I and in carcinogenesis. Mol Biol 37:392–403

    Article  Google Scholar 

  109. Talloczy Z, Jiang W, Virgin HW, Leib DA, Scheuner D, Kaufman RJ, Eskelinen EL, Levine B (2002) Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc Natl Acad Sci U S A 99:190–195. doi:10.1073/pnas.012485299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tani H, Imamachi N, Salam KA, Mizutani R, Ijiri K, Irie T, Yada T, Suzuki Y, Akimitsu N (2012) Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability. RNA Biol 9:1370–1379. doi:10.4161/rna.22360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tarpey PS, Raymond FL, Nguyen LS, Rodriguez J, Hackett A, Vandeleur L, Smith R, Shoubridge C, Edkins S, Stevens C, O’Meara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Hills K, Jones D, Mironenko T, Perry J, Varian J, West S, Widaa S, Teague J, Dicks E, Butler A, Menzies A, Richardson D, Jenkinson A, Shepherd R, Raine K, Moon J, Luo Y, Parnau J, Bhat SS, Gardner A, Corbett M, Brooks D, Thomas P, Parkinson-Lawrence E, Porteous ME, Warner JP, Sanderson T, Pearson P, Simensen RJ, Skinner C, Hoganson G, Superneau D, Wooster R, Bobrow M, Turner G, Stevenson RE, Schwartz CE, Futreal PA, Srivastava AK, Stratton MR, Gecz J (2007) Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat Genet 39:1127–1133. doi:10.1038/ng2100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142. doi:10.1038/nrm1835

    Article  CAS  PubMed  Google Scholar 

  113. Trusolino L, Comoglio PM (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2:289–300. doi:10.1038/nrc779

    Article  CAS  PubMed  Google Scholar 

  114. Valacca C, Bonomi S, Buratti E, Pedrotti S, Baralle FE, Sette C, Ghigna C, Biamonti G (2010) Sam68 regulates EMT through alternative splicing-activated nonsense-mediated mRNA decay of the SF2/ASF proto-oncogene. J Cell Biol 191:87–99. doi:10.1083/jcb.201001073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Vattem KM, Wek RC (2004) Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A 101:11269–11274. doi:10.1073/pnas.0400541101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Viegas MH, Gehring NH, Breit S, Hentze MW, Kulozik AE (2007) 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. doi:10.1093/nar/gkm461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086. doi:10.1126/science.1209038

    Article  CAS  PubMed  Google Scholar 

  118. Wang D, Zavadil J, Martin L, Parisi F, Friedman E, Levy D, Harding H, Ron D, Gardner LB (2011) Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis. Mol Cell Biol 31:3670–3680. doi:10.1128/MCB.05704-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wei ML (2006) Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res 19:19–42. doi:10.1111/j.1600-0749.2005.00289.x

    Article  CAS  PubMed  Google Scholar 

  120. Weil JE, Beemon KL (2006) A 3′ UTR sequence stabilizes termination codons in the unspliced RNA of Rous sarcoma virus. RNA 12:102–110. doi:10.1261/rna.2129806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Weischenfeldt J, Damgaard I, Bryder D, Theilgaard-Monch K, Thoren LA, Nielsen FC, Jacobsen SE, Nerlov C, Porse BT (2008) NMD is essential for hematopoietic stem and progenitor cells and for eliminating by-products of programmed DNA rearrangements. Genes Dev 22:1381–1396. doi:10.1101/gad.468808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Weischenfeldt J, Waage J, Tian G, Zhao J, Damgaard I, Jakobsen JS, Kristiansen K, Krogh A, Wang J, Porse BT (2012) Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns. Genome Biol 13:R35. doi:10.1186/gb-2012-13-5-r35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wek RC, Cavener DR (2007) Translational control and the unfolded protein response. Antioxid Redox Signal 9:2357–2371. doi:10.1089/ars.2007.1764

    Article  CAS  PubMed  Google Scholar 

  124. Wengrod J, Martin L, Wang D, Frischmeyer-Guerrerio P, Dietz HC, Gardner LB (2013) Inhibition of nonsense-mediated RNA decay activates autophagy. Mol Cell Biol 33:2128–2135. doi:10.1128/MCB.00174-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Withers JB, Beemon KL (2010) Structural features in the Rous sarcoma virus RNA stability element are necessary for sensing the correct termination codon. Retrovirology 7:65. doi:10.1186/1742-4690-7-65

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Wittmann J, Hol EM, Jack HM (2006) hUPF2 silencing identifies physiologic substrates of mammalian nonsense-mediated mRNA decay. Mol Cell Biol 26:1272–1287. doi:10.1128/MCB.26.4.1272-1287.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wollerton MC, Gooding C, Wagner EJ, Garcia-Blanco MA, Smith CW (2004) Autoregulation of polypyrimidine tract binding protein by alternative splicing leading to nonsense-mediated decay. Mol Cell 13:91–100

    Article  CAS  PubMed  Google Scholar 

  128. Xu X, Zhang L, Tong P, Xun G, Su W, Xiong Z, Zhu T, Zheng Y, Luo S, Pan Y, Xia K, Hu Z (2013) Exome sequencing identifies UPF3B as the causative gene for a Chinese non-syndrome mental retardation pedigree. Clin Genet 83:560–564. doi:10.1111/cge.12014

    Article  CAS  PubMed  Google Scholar 

  129. Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN, Bobrovnikova-Marjon E, Diehl JA, Ron D, Koumenis C (2010) The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J 29:2082–2096. doi:10.1038/emboj.2010.81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Yepiskoposyan H, Aeschimann F, Nilsson D, Okoniewski M, Muhlemann O (2011) Autoregulation of the nonsense-mediated mRNA decay pathway in human cells. RNA 17:2108–2118. doi:10.1261/rna.030247.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Younis I, Green PL (2005) The human T-cell leukemia virus Rex protein. Front Biosci 10:431–445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zahler AM, Lane WS, Stolk JA, Roth MB (1992) SR proteins: a conserved family of pre-mRNA splicing factors. Genes Dev 6:837–847

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was funded by a grant from the Deutsche Forschungsgemeinschaft (GE2014/4-1) to N.H.G.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Niels H. Gehring.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ottens, F., Gehring, N.H. Physiological and pathophysiological role of nonsense-mediated mRNA decay. Pflugers Arch - Eur J Physiol 468, 1013–1028 (2016). https://doi.org/10.1007/s00424-016-1826-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-016-1826-5

Keywords

Navigation