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Upf proteins: highly conserved factors involved in nonsense mRNA mediated decay

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Abstract

Over 10% of genetic diseases are caused by mutations that introduce a premature termination codon in protein-coding mRNA. Nonsense-mediated mRNA decay (NMD) is an essential cellular pathway that degrades these mRNAs to prevent the accumulation of harmful partial protein products. NMD machinery is also increasingly appreciated to play a role in other essential cellular functions, including telomere homeostasis and the regulation of normal mRNA turnover, and is misregulated in numerous cancers. Hence, understanding and designing therapeutics targeting NMD is an important goal in biomedical science. The central regulator of NMD, the Upf1 protein, interacts with translation termination factors and contextual factors to initiate NMD specifically on mRNAs containing PTCs. The molecular details of how these contextual factors affect Upf1 function remain poorly understood. Here, we review plausible models for the NMD pathway and the evidence for the variety of roles NMD machinery may play in different cellular processes.

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References

  1. Frazer KA (2012) Decoding the human genome. Genome Res 22:1599–1601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kurosaki T, Maquat LE (2016) Nonsense-mediated mRNA decay in humans at a glance. J Cell Sci 129:461–467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gandhi R, Manzoor M, Hudak KA (2008) Depurination of Brome mosaic virus RNA3 in vivo results in translation-dependent accelerated degradation of the viral RNA. J Biol Chem 283:32218–32228

    Article  CAS  PubMed  Google Scholar 

  4. Simms CL, Thomas EN, Zaher HS (2017) Ribosome-based quality control of mRNA and nascent peptides. Wiley Interdiscip Rev RNA 8:e1366

    Article  CAS  Google Scholar 

  5. Frischmeyer PA, van Hoof A, O’Donnell K, Guerrerio AL, Parker R, Dietz HC (2002) An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science 295:2258–2261

    Article  CAS  PubMed  Google Scholar 

  6. Stalder L, Mühlemann O (2008) The meaning of nonsense. Trends Cell Biol 18:315–321

    Article  CAS  PubMed  Google Scholar 

  7. He F, Li X, Spatrick P, Casillo R, Dong S, Jacobson A (2003) Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5′ to 3′ mRNA decay pathways in yeast. Mol Cell 12:1439–1452

    Article  CAS  PubMed  Google Scholar 

  8. McGlincy N, Smith CW (2008) Alternative splicing resulting in nonsense-mediated mRNA decay: What is the meaning of nonsense? Trends Biochem Sci 33:385–393

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thompson DM, Parker R (2007) Cytoplasmic decay of intergenic transcripts in Saccharomyces cerevisiae. Mol Cell Biol 27:92–101

    Article  CAS  PubMed  Google Scholar 

  11. Tani H, Torimura M, Akimitsu N (2013) The RNA degradation pathway regulates the function of GAS5 a non-coding RNA in mammalian cells. PLoS ONE 8:e55684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kurihara Y, Matsui A, Hanada K, Kawashima M, Ishida J, Morosawa T, Seki M (2009) Genome-wide suppression of aberrant mRNA-like noncoding RNAs by NMD in Arabidopsis. Proc Natl Acad Sci USA 106:2453–2458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Karousis ED, Nasif S, Mühlemann O (2016) Nonsense-mediated mRNA decay: novel mechanistic insights and biological impact. Wiley Interdiscip Rev RNA 7:661–682

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Thermann R, Neu-Yilik G, Deters A, Frede U, Wehr K, Hagemeier C, Kulozik AE (1998) Binary specification of nonsense codons by splicing and cytoplasmic translation. EMBO J 17:3484–3494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang J, Sun X, Qian Y, Maquat LE (1998) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bhuvanagiri M, Schlitter AM, Hentze MW, Kulozik AE (2010) NMD: RNA biology meets human genetic medicine. Biochem J 430:365–377

    Article  CAS  PubMed  Google Scholar 

  18. Culbertson MR, Underbrink KM, Fink GR (1980) Frameshift suppression in Saccharomyces cerevisiae. II. Genetic properties of group II suppressors. Genetics 95:833–853

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Page MF, Carr B, Anders KR, Grimson A, Anderson P (1999) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chiu SY, Serin G, Ohara O, Maquat LE (2003) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bhattacharya A, Czaplinski K, Trifillis P, He F, Jacobson A, Peltz SW (2000) Characterization of the biochemical properties of the human Upf1 gene product that is involved in nonsense-mediated mRNA decay. RNA 6:1226–1235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Min EE, Roy B, Amrani N, He F, Jacobson A (2013) Yeast Upf1 CH domain interacts with Rps26 of the 40S ribosomal subunit. RNA 19:1105–1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ghosh S, Ganesan R, Amrani N, Jacobson A (2010) Translational competence of ribosomes released from a premature termination codon is modulated by NMD factors. RNA 16:1832–1847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chamieh H, Ballut L, Bonneau F, Le Hir H (2008) 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

    Article  CAS  PubMed  Google Scholar 

  26. Chakrabarti S, Jayachandran U, Bonneau F, Fiorini F, Basquin C, Domcke S, Le Hir H, Conti E (2011) Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2. Mol Cell 41:693–703

    Article  CAS  PubMed  Google Scholar 

  27. Buchwald G, Ebert J, Basquin C, Sauliere J, Jayachandran U et al (2010) Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex. PNAS 107:10050–10055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gehring NH, Neu-Yilik G, Schel T, Hentze MW, Kulozik AE (2003) Y14 and hUpf3b form an NMD-activating complex. Mol Cell 11:939–949

    Article  CAS  PubMed  Google Scholar 

  29. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jolly LA, Homan CC, Jacob R, Barry S, Gecz J (2013) 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

    Article  CAS  PubMed  Google Scholar 

  33. Nguyen LS, Jolly L, Shoubridge C, Chan WK, Huang L et al (2012) Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability. Mol Psychiatry 17:1103–1115

    Article  CAS  PubMed  Google Scholar 

  34. Nguyen LS, Kim H-G, Rosenfeld JA, Shen Y, Gusella JF, Lacassie Y, Layman LC, Shaffer LG, Gécz J (2013) Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders. Hum Mol Genet 22:1816–1825

    Article  CAS  PubMed  Google Scholar 

  35. Tarpey PS, Raymond FL, Nguyen LS, Rodriguez J, Hackett A, Vandeleur L, Smith R, Shoubridge C, Edkins S, Stevens C (2007) Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat Genet 39:1127–1133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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

    Article  PubMed  Google Scholar 

  37. Addington AM, Gauthier J, Piton A, Hamdan FF, Raymond A, Gogtay N, Miller R, Tossell J, Bakalar J, Inoff-Germain G et al (2011) A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Mol Psychiatry 16:238–239

    Article  CAS  PubMed  Google Scholar 

  38. Xu X, Zhang L, Tong P, Xun G, Su W (2013) Exome sequencing identifies UPF3B as the causative gene for a Chinese non-syndrome mental retardation pedigree. Clin Genet 83:560–564

    Article  CAS  PubMed  Google Scholar 

  39. Daar IO, Maquat LE (1988) Premature translation termination mediates triosephosphate isomerase mRNA degradation. Mol Cell Biol 8:802–813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Caputi M, Kendzior RJ, Beemon KL (2002) A nonsense mutation in the fibrillin-1 gene of a Marfan syndrome patient induces NMD and disrupts an exonic splicing enhancer. Genes Dev 16:1754–1759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Leeds P, Peltz SW, Jacobson A, Culbertson MR (1991) 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

    Article  CAS  PubMed  Google Scholar 

  42. Applequist SE, Selg M, Raman C, Jäck 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 

  43. Kadlec J, Guilligay D, Ravelli RB, Cusack S (2006) Crystal structure of the UPF2-interacting domain of nonsense-mediated mRNA decay factor UPF1. RNA 12:1817–1824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  45. 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Nicholson P, Josi C, Kurosawa H, Yamashita A, Mühlemann O (2014) A novel phosphorylation-independent interaction between SMG6 and UPF1 is essential for human NMD. Nucleic Acids Res 42:9217–9235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Imamachi N, Tani H, Akimitsu N (2012) Up-frameshift protein 1 (UPF1): multitalented entertainer in RNA decay. Drug Discov Ther 6:55–61

    CAS  PubMed  Google Scholar 

  50. Cheng Z, Muhlrad D, Lim MK, Parker R, Song H (2007) Structural and functional insights into the human Upf1 helicase core. EMBO J 26:253–264

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Deniaud A, Karuppasamy M, Bock T, Masiulis S, Huard K, Garzoni F et al (2015) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

  54. López-Perrote A, Castaño R, Melero R, Zamarro T, Kurosawa H, Ohnishi T et al (2016) Human nonsense-mediated mRNA decay factor UPF2 interacts directly with eRF3 and the SURF complex. Nucleic Acids Res 44:1909–1923

    Article  PubMed  PubMed Central  Google Scholar 

  55. Tatsuno T, Nakamura Y, Ma S, Tomosugi N, Ishigaki Y (2016) Nonsense-mediated mRNA decay factor Upf2 exists in both the nucleoplasm and the cytoplasm. Mol Med Rep 14:655–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Clerici M, Mourão A, Gutsche I, Gehring NH, Hentze MW, Kulozik A et al (2009) Unusual bipartite mode of interaction between the nonsense-mediated decay factors, UPF1 and UPF2. EMBO J 28:2293–2306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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

    Article  CAS  PubMed  Google Scholar 

  58. 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

    Article  CAS  PubMed  Google Scholar 

  59. LaRonde-LeBlanc N, Santhanam AN, Baker AR, Wlodawer A, Colburn NH (2007) Structural basis for inhibition of translation by the tumor suppressor Pdcd4. Mol Cell Biol 27:147–156

    Article  CAS  PubMed  Google Scholar 

  60. Melero R, Uchiyama A, Castaño R, Kataoka N, Kurosawa H, Ohno S, Yamashita A, Llorca O (2014) Structures of SMG1-UPFs complexes: SMG1 contributes to regulate UPF2-dependent activation of UPF1 in NMD. Structure 22:1105–1119

    Article  CAS  PubMed  Google Scholar 

  61. Fourati Z, Roy B, Millan C, Coureux PD, Kervestin S, van Tilbeurgh H et al (2014) A highly conserved region essential for NMD in the Upf2 N-terminal domain. J Mol Biol 426:3689–3702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang W, Cajigas IJ, Peltz SW, Wilkinson MF, Gonzalez CI (2006) Role for Upf2p phosphorylation in Saccharomyces cerevisiae nonsense-mediated mRNA decay. Mol Cell Biol 26:3390–3400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Weischenfeldt J, Damgaard I, Bryder D, Theilgaard-Mönch 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bao J, Tang C, Yuan S, Porse BT, Yan W (2015) UPF2, a nonsense-mediated mRNA decay factor, is required for prepubertal Sertoli cell development and male fertility by ensuring fidelity of the transcriptome. Development 142:352–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bao J, Vitting-Seerup K, Waage J, Tang C, Ge Y, Porse BT, Yan W (2016) UPF2-dependent nonsense-mediated mRNA decay pathway is essential for spermatogenesis by selectively eliminating longer 3′UTR transcripts. PLoS Genet 12:e1005863

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Thapar R, Denmon AP (2013) Signaling pathways that control mRNA turnover. Cell Signal 25:1699–1710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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 

  68. Melero R, Buchwald G, Castaño R, Raabe M, Gil D, Lázaro M, Urlaub H, Conti E, Llorca O (2012) The cryo-EM structure of the UPF-EJC complex shows UPF1 poised toward the RNA 3′ end. Nat Struct Mol Biol 19:498–505, S1–S2

  69. Alrahbeni T, Sartor F, Anderson J, Miedzybrodzka Z, McCaig C, Müller B (2015) Full UPF3B function is critical for neuronal differentiation of neural stem cells. Mol Brain 8:33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Shum EY, Jones SH, Shao A, Dumdie J, Krause MD, Chan WK, Wilkinson MF (2016) The antagonistic gene paralogs Upf3a and Upf3b govern nonsense-mediated RNA decay. Cell 165:382–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vexler K, Cymerman MA, Berezin I, Fridman A, Golani L, Lasnoy M, Saul H, Shaul O (2016) The Arabidopsis NMD factor UPF3 is feedback-regulated at multiple levels and plays a role in plant response to salt stress. Front Plant Sci 1376: eCollection

  72. de Pinto B, Lippolis R, Castaldo R, Altamura N (2004) Overexpression of Upf1p compensates for mitochondrial splicing deficiency independently of its role in mRNA surveillance. Mol Microbiol 51:1129–1142

    Article  PubMed  CAS  Google Scholar 

  73. Ito K, Ebihara K, Nakamura Y (1998) The stretch of C-terminal acidic amino acids of translational release factor eRF1 is a primary binding site for eRF3 of fission yeast. RNA 4:958–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Czaplinski K, Ruiz-Echevarria MJ, Paushkin SV, Han X, Weng Y, Haley A, Perlick HA, Dietz HC, Ter-Avanesyan MD, Peltz SW (1998) The surveillance complex interacts with the translation release factors to enhance termination and degrade aberrant mRNAs. Genes Dev 12:1665–1677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kashima I, Yamashita A, Izumi N, Kataoka N, Morishita R et al (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Anders KR, Grimson A, Anderson P (2003) SMG-5, required for C. elegans nonsense-mediated mRNA decay, associates with SMG-2 and protein phosphatase 2A. EMBO J 22:641–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ohnishi T, Yamashita A, Kashima I, Schell T, Anders KR, Grimson A, Hachiya T, Hentze MW, Anderson P, Ohno S (2003) Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7. Mol Cell 12:1187–1200

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  79. Yamashita A, Izumi N, Kashima I, Ohnishi T, Saari B (2009) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Shaheen R, Anazi S, Ben-Omran T, Seidahmed MZ, Caddle LB, Palmer K et al (2016) Mutations in SMG9, encoding an essential component of nonsense-mediated decay machinery, cause a multiple congenital anomaly syndrome in humans and mice. Am J Hum Genet 98:643–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Serdar LD, Whiteside DL, Baker KE (2016) ATP hydrolysis by UPF1 is required for efficient translation termination at premature stop codons. Nat Commun 7:14021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Frolova LY, Tsivkovskii RY, Sivolobova GF, Oparina NY, Serpinsky OI, Blinov VM, Tatkov SI, Kisselev LL (1999) Mutations in the highly conserved GGQ motif of class 1 polypeptide release factors abolish ability of human eRF1 to trigger peptidyl-tRNA hydrolysis. RNA 5:1014–1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Song H, Mugnier P, Das AK, Webb HM, Evans DR, Tuite MF, Hemmings BA, Barford D (2000) The crystal structure of human eukaryotic release factor eRF1—mechanism of stop codon recognition and peptidyl-tRNA hydrolysis. Cell 100:311–321

    Article  CAS  PubMed  Google Scholar 

  84. Alkalaeva EZ, Pisarev AV, Frolova LY, Kisselev LL, Pestova TV (2006) In vitro reconstitution of eukaryotic translation reveals cooperativity between release factors eRF1 and eRF3. Cell 125:1125–1136

    Article  CAS  PubMed  Google Scholar 

  85. Eyler DE, Green R (2011) Distinct response of yeast ribosomes to a miscoding event during translation. RNA 17:925–932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shoemaker CJ, Green R (2011) Kinetic analysis reveals the ordered coupling of translation termination and ribosome recycling in yeast. Proc Natl Acad Sci USA 108:1392–1398

    Article  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang W, Czaplinski K, Rao Y, Peltz SW (2001) The role of Upf proteins in modulating the translation read-through of nonsense-containing transcripts. EMBO J 20:880–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Daniel EE, Karen AW, Rachel G (2013) Eukaryotic release factor 3 is required for multiple turnovers of peptide release catalysis by eukaryotic release factor 1. J Biol Chem 288:29530–29538

    Article  CAS  Google Scholar 

  90. Hogg JR, Goff SP (2010) Upf1 senses 3′UTR length to potentiate mRNA decay. Cell 143:379–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hurt JA, Robertson AD, Burge CB (2013) Global analyses of UPF1 binding and function reveal expanded scope of nonsense-mediated mRNA decay. Genome Res 23:1636–1650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Tani H, Imamachi N, Salam KA, Mizutani R, Ijiri K, Irie T, Akimitsu N (2012) Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability. RNA Biol 9:1370–1379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lee SR, Pratt G, Martinez F, Yeo GW, Lykke-Andersen J (2015) Target discrimination in nonsense-mediated mRNA decay requires Upf1 ATPase activity. Mol Cell 59:413–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kurosaki T, Li W, Hoque M, Popp MWL, Ermolenko DN, Tian B, Maquat LE (2014) A post-translational regulatory switch on UPF1 controls targeted mRNA degradation. Genes Dev 28:1900–1916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Amrani N, Ganesan R, Kervestin S, Mangus DA, Ghosh S, Jacobson A (2004) A faux 3′-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature 432:112–118

    Article  CAS  PubMed  Google Scholar 

  97. Kervestin S, Jacobson A (2012) NMD: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol 13:700–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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 

  99. Eberle AB, Stalder L, Mathys H, Orozco RZ, Muhlemann O (2008) Posttranscriptional gene regulation by spatial rearrangement of the 3′ untranslated region. PLoS Biol 6:e92

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Behm-Ansmant I, Gatfield D, Rehwinkel J, Hilgers V, Izaurralde E (2007) A conserved role for cytoplasmic poly(A)-binding protein 1 (PABPC1) in nonsense-mediated mRNA decay. EMBO J 26:1591–1601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zahdeh F, Carmel L (2016) The role of nucleotide composition in premature termination codon recognition. BMC Bioinform 17:519

    Article  Google Scholar 

  103. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gehring NH, Lamprinaki S, Hentze MW, Kulozik AE (2009) The hierarchy of exon-junction complex assembly by the spliceosome explains key features of mammalian nonsense-mediated mRNA decay. PLoS Biol 7:e1000120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Bono F, Gehring NH (2011) Assembly, disassembly and recycling: the dynamics of exon junction complexes. RNA Biol 8:24–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ishigaki Y, Li X, Serin G, Maquat LE (2001) 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

    Article  CAS  PubMed  Google Scholar 

  107. Lejeune F, Ishigaki Y, Li X, Maquat LE (2002) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hug N, Longman D, Cáceres JF (2016) Mechanism and regulation of the nonsense-mediated decay pathway. Nucleic Acids Res 44:1483–1495

    Article  PubMed  PubMed Central  Google Scholar 

  109. Schweingruber C, Rufener SC, Zund D, Yamashita A, Muhlemann O (2013) Nonsense-mediated mRNA decay: mechanisms of substrate mRNA recognition and degradation in mammalian cells. Biochim Biophys Acta 1829:612–623

    Article  CAS  PubMed  Google Scholar 

  110. LeBlanc JJ, Beemon KL (2004) Unspliced Rous sarcoma virus genomic RNAs are translated and subjected to nonsense-mediated mRNA decay before packaging. J Virol 78:5139–5146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wen J, Brogna S (2010) Splicing-dependent NMD does not require the EJC in Schizosaccharomyces pombe. EMBO J 29:1537–1551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wang J, Gudikote JP, Olivas OR, Wilkinson MF (2002) Boundary-independent polar nonsense-mediated decay. EMBO Rep 3:274–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Kuroha K, Tatematsu T, Inada T (2009) Upf1 stimulates degradation of the product derived from aberrant messenger RNA containing a specific nonsense mutation by the proteasome. EMBO Rep 10:1265–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Takahashi S, Araki Y, Ohya Y, Sakuno T, Hoshino S, Kontani K, Nishina H, Katada T (2008) Upf1 potentially serves as a RING-related E3 ubiquitin ligase via its association with Upf3 in yeast. RNA 14:1950–1958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Arias-Palomo E, Yamashita A, Fernández IS, Núñez-Ramírez R, Bamba Y, Izumi N et al (2011) The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. Genes Dev 25:153–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yamashita A (2013) Role of SMG-1-mediated Upf1 phosphorylation in mammalian nonsense-mediated mRNA decay. Genes Cells 18:161–175

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jonas S, Weichenrieder O, Izaurralde E (2013) An unusual arrangement of two 14–3-3-like domains in the SMG5-SMG7 heterodimer is required for efficient nonsense-mediated mRNA decay. Genes Dev 27:211–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  121. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lejeune F, Li X, Maquat LE (2003) Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activities. Mol Cell 12:675–687

    Article  CAS  PubMed  Google Scholar 

  123. Mühlemann O, Lykke-Andersen J (2010) How and where are nonsense mRNAs degraded in mammalian cells? RNA Biol 7:28–32

    Article  PubMed  PubMed Central  Google Scholar 

  124. Huntzinger E, Kashima I, Fauser M, Saulière J, Izaurralde E (2008) SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan. RNA 14:2609–2617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  127. 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. van Dijk E, Cougot N, Meyer S, Babajko S, Wahle E, Séraphin B (2002) Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures. EMBO J 21:6915–6924

    Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Eulalio A, Behm-Ansmant I, Izaurralde E (2007) P bodies: at the crossroads of post-transcriptional pathways. Nat Rev Mol Cell Biol 8:9–22

    Article  CAS  PubMed  Google Scholar 

  131. Sheth U, Parker R (2003) Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. Science 300:805–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Schneider MD, Najand N, Chaker S, Pare JM, Haskins J, Hughes SC, Hobman TC, Locke J, Simmonds AJ (2006) Gawky is a component of cytoplasmic mRNA processing bodies required for early Drosophila development. J Cell Biol 174:349–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ding L, Han M (2007) GW182 family proteins are crucial for microRNA-mediated gene silencing. Trends Cell Biol 17:411–416

    Article  CAS  PubMed  Google Scholar 

  134. Brogna S, Ramanathan P, Wen J (2008) UPF1 P-body localization. Biochem Soc Trans 36:698–700

    Article  CAS  PubMed  Google Scholar 

  135. Fukuhara N, Ebert J, Unterholzner L, Lindner D, Izaurralde E, Conti E (2005) SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway. Mol Cell 17:537–547

    Article  CAS  PubMed  Google Scholar 

  136. Sheth U, Parker R (2006) Targeting of aberrant mRNAs to cytoplasmic processing bodies. Cell 125:1095–1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Varsally W, Brogna S (2012) UPF1 involvement in nuclear functions. Biochem Soc Trans 40:778–784

    Article  CAS  PubMed  Google Scholar 

  138. Kim YK, Furic L, Desgroseillers L, Maquat LE (2005) Mammalian Staufen1 recruits Upf1 to specific mRNA 3′UTRs so as to elicit mRNA decay. Cell 120:195–208

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  140. Ajamian L, Abrahamyan L, Milev M, Ivanov PV, Kulozik AE et al (2008) Unexpected roles for UPF1 in HIV-1 RNA metabolism and translation. RNA 14:914–927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Saul MJ, Stein S, Grez M, Jakobsson PJ, Steinhilber D, Suess B (2016) UPF1 regulates myeloid cell functions and S100A9 expression by the hnRNP E2/miRNA-328 balance. Sci Rep 6:31995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Rehwinkel J, Letunic I, Raes J, Bork P, Izaurralde E (2005) Nonsense-mediated mRNA decay factors act in concert to regulate common mRNA targets. RNA 11:1530–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 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 

  144. 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

    Article  CAS  PubMed  Google Scholar 

  145. 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

    Article  CAS  PubMed  Google Scholar 

  146. Zakian VA (1995) Telomeres: beginning to understand the end. Science 270:1601–1607

    Article  CAS  PubMed  Google Scholar 

  147. Lew JE, Enomoto S, Berman J (1998) Telomere length regulation and telomeric chromatin require the nonsense-mediated mRNA decay pathway. Mol Cell Biol 18:6121–6130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Dahlseid JN, Lew-Smith J, Lelivelt MJ, Enomoto S, Ford A, Desruisseaux M, McClellan M, Lue N, Culbertson MR, Berman J (2003) mRNAs encoding telomerase components and regulators are controlled by UPF genes in Saccharomyces cerevisiae. Eukaryot Cell 2:134–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Reichenbach P, Höss M, Azzalin CM, Nabholz M, Bucher P, Lingner J (2003) A human homolog of yeast Est1 associates with telomerase and uncaps chromosome ends when overexpressed. Curr Biol 13:568–574

    Article  CAS  PubMed  Google Scholar 

  150. Chawla R, Redon S, Raftopoulou C, Wischnewski H, Gagos S, Azzalin CM (2011) Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication. EMBO J 30:4047–4058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9:616–627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42:301–334

    Article  CAS  PubMed  Google Scholar 

  153. Wickham L, Duchaine T, Luo M, Nabi IR, DesGroseillers L (1999) Mammalian staufen is a double-stranded-RNA- and tubulin-binding protein which localizes to the rough endoplasmic reticulum. Mol Cell Biol 19:2220–2230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kiebler MA, Hemraj I, Verkade P, Kohrmann M, Fortes P, Marion RM, Ortin J, Dotti CG (1999) The mammalian staufen protein localizes to the somatodendritic domain of cultured hippocampal neurons: implications for its involvement in mRNA transport. J Neurosci 19:288–297

    CAS  PubMed  Google Scholar 

  155. Kanai Y, Dohmae N, Hirokawa N (2004) Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43:513–525

    Article  CAS  PubMed  Google Scholar 

  156. Bachand F, Triki I, Autexier C (2001) Human telomerase RNA-protein interactions. Nucleic Acids Res 29:3385–3393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Le S, Sternglanz R. Greider CW (2000) Identification of two RNA-binding proteins associated with human telomerase RNA. Mol Biol Cell 11:999–1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Baumbach LL, Stein GS, Stein JL (1987) Regulation of human histone gene expression: transcriptional and posttranscriptional control in the coupling of histone messenger RNA stability with DNA replication. Biochemistry 26:6178–6187

    Article  CAS  PubMed  Google Scholar 

  159. Jaeger S, Barends S, Giegé R, Eriani G, Martin F (2005) Expression of metazoan replication-dependent histone genes. Biochimie 87:827–834

    Article  CAS  PubMed  Google Scholar 

  160. Broderick J, Wang J, Andreadis A (2004) Heterogeneous nuclear ribonucleoprotein E2 binds to tau exon 10 and moderately activates its splicing. Gene 331:107–114

    Article  CAS  PubMed  Google Scholar 

  161. Motta-Mena LB, Smith SA, Mallory MJ, Jackson J, Wang J, Lynch KW (2011) A disease-associated polymorphism alters splicing of the human CD45 phosphatase gene by disrupting combinatorial repression by heterogeneous nuclear ribonucleoproteins (hnRNPs). J Biol Chem 286:20043–20053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Perrotti D, Cesi V, Trotta R, Guerzoni C, Santilli G, Campbell K, Iervolino A, Condorelli F, Gambacorti-Passerini C, Caligiuri MA, Calabretta B (2002) BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Nat Genet 30:48–58

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors express gratitude to Skanda Setty, Magid Abdo, Karthik Dhanireddy, Zhihua Li and Mingye Yan in their support of this project. Moreover, we would like to thank the members of BRAX for their encouragement as well.

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Authors and Affiliations

  1. Harvard College, Harvard University, Cambridge, MA, 02138, USA

    Puneet Gupta

  2. School of Arts and Sciences, St. Bonaventure University, St. Bonaventure, NY, 14778, USA

    Puneet Gupta

  3. Harvard Medical School, Harvard University, Boston, MA, 02115, USA

    Yan-Ruide Li

  4. College of Life Sciences, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, 310058, China

    Yan-Ruide Li

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  1. Puneet Gupta
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Y-RL and PG conceived and authored the manuscript.

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Correspondence to Yan-Ruide Li.

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Gupta, P., Li, YR. Upf proteins: highly conserved factors involved in nonsense mRNA mediated decay. Mol Biol Rep 45, 39–55 (2018). https://doi.org/10.1007/s11033-017-4139-7

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