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Cited by 267RNA and protein synthesis mechanismsRNA Research and SplicingRNA modifications and cancer

Before It Gets Started: Regulating Translation at the 5′ UTR

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Araujo, Patricia R., Yoon, Kihoon, Ko, Daijin, Smith, Andrew D., Qiao, Mei, Suresh, Uthra, Burns, Suzanne C., Penalva, Luiz O. F.·2012·Comparative and Functional Genomics
DOI 10.1155/2012/475731PMC PMC3368165
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Abstract

Translation regulation plays important roles in both normal physiological conditions and diseases states. This regulation requires cis-regulatory elements located mostly in 5′ and 3′ UTRs and trans-regulatory factors (e.g., RNA binding proteins (RBPs)) which recognize specific RNA features and interact with the translation machinery to modulate its activity. In this paper, we discuss important aspects of 5′ UTR-mediated regulation by providing an overview of the characteristics and the function of the main elements present in this region, like uORF (upstream open reading frame), secondary structures, and RBPs binding motifs and different mechanisms of translation regulation and the impact they have on gene expression and human health when deregulated.

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  1. [1]Vogel C de Sousa Abreu R Ko DJ Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line Molecular Systems Biology 2010 6, article 400 PMC2947365 20739923
  2. [2]Jackson RJ Hellen CUT Pestova TV The mechanism of eukaryotic translation initiation and principles of its regulation Nature Reviews Molecular Cell Biology 2010 11 2 113 127 20094052 PMC4461372
  3. [3]Sonenberg N Hinnebusch AG Regulation of translation initiation in eukaryotes: mechanisms and biological targets Cell 2009 136 4 731 745 19239892 PMC3610329
  4. [4]Gebauer F Hentze MW Molecular mechanisms of translational control Nature Reviews Molecular Cell Biology 2004 5 10 827 835 15459663 PMC7097087
  5. [5]Pesole G Mignone F Gissi C Grillo G Licciulli F Liuni S Structural and functional features of eukaryotic mRNA untranslated regions Gene 2001 276 1-2 73 81 11591473
  6. [6]Davuluri RV Suzuki Y Sugano S Zhang MQ CART classification of human 5′ UTR sequences Genome Research 2000 10 11 1807 1816 11076865 PMC310970
  7. [7]Babendure JR Babendure JL Ding JH Tsien RY Control of mammalian translation by mRNA structure near caps RNA 2006 12 5 851 861 16540693 PMC1440912
  8. [8]Ryabova LA Pooggin MM Hohn T Viral strategies of translation initiation: ribosomal shunt and reinitiation Progress in Nucleic Acid Research and Molecular Biology 2002 72 1 39 12206450 PMC7133299
  9. [9]Yueh A Schneider RJ Translation by ribosome shunting on adenovirus and hsp70 mRNAs facilitated by complementarity to 18S rRNA Genes and Development 2000 14 4 414 421 10691734 PMC316380
  10. [10]Chappell SA Dresios J Edelman GM Mauro VP Ribosomal shunting mediated by a translational enhancer element that base pairs to 18S rRNA Proceedings of the National Academy of Sciences of the United States of America 2006 103 25 9488 9493 16769881 PMC1480434
  11. [11]Trinklein ND Aldred SJF Saldanha AJ Myers RM Identification and functional analysis of human transcriptional promoters Genome Research 2003 13 2 308 312 12566409 PMC420378
  12. [12]Zhang T Haws P Wu Q Multiple variable first exons: a mechanism for cell—and tissue—specific gene regulation Genome Research 2004 14 1 79 89 14672974 PMC314283
  13. [13]Carninci P Kasukawa T Katayama S The transcriptional landscape of the mammalian genome Science 2005 309 5740 1559 1563 16141072
  14. [14]Sobczak K Krzyzosiak WJ Structural determinants of BRCA1 translational regulation The Journal of Biological Chemistry 2002 277 19 17349 17358 11877386
  15. [15]Arrick BA Lee AL Grendell RL Derynck R Inhibition of translation of transforming growth factor-β3 mRNA by its 5′ untranslated region Molecular and Cellular Biology 1991 11 9 4306 4313 1875922 PMC361291
  16. [16]Arrick BA Grendell RL Griffin LA Enhanced translational efficiency of a novel transforming growth factor β3 mRNA in human breast cancer cells Molecular and Cellular Biology 1994 14 1 619 628 8264630 PMC358411
  17. [17]Gray NK Hentze MW Regulation of protein synthesis by mRNA structure Molecular Biology Reports 1994 19 3 195 200 7969107
  18. [18]Pickering BM Willis AE The implications of structured 5′ untranslated regions on translation and disease Seminars in Cell and Developmental Biology 2005 16 1 39 47 15659338
  19. [19]Rozen F Edery I Meerovitch K Dever TE Merrick WC Sonenberg N Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F Molecular and Cellular Biology 1990 10 3 1134 1144 2304461 PMC360981
  20. [20]Robert F Pelletier J Translation initiation: a critical signalling node in cancer Expert Opinion on Therapeutic Targets 2009 13 11 1279 1293 19705976
  21. [21]Kim SJ Park K Koeller D Post-transcriptional regulation of the human transforming growth factor-β1 gene The Journal of Biological Chemistry 1992 267 19 13702 13707 1618868
  22. [22]Romeo DS Park K Roberts AB Sporn MB Kim SJ An element of the transforming growth factor-β1 5′-untranslated region represses translation and specifically binds a cytosolic factor Molecular Endocrinology 1993 7 6 759 766 8361501
  23. [23]Fraser DJ Phillips AO Zhang X Y-box protein-1 controls transforming growth factor-β1 translation in proximal tubular cells Kidney International 2008 73 6 724 732 18075498
  24. [24]Jenkins RH Bennagi R Martin J Phillips AO Redman JE Fraser DJ A conserved stem loop motif in the 59untranslated region regulates transforming growth factor-β1 translation PLoS one 2010 5 8 Article ID e12283. PMC2928724 20865036
  25. [25]Abaza I Gebauer F Functional domains of Drosophila UNR in translational control RNA 2008 14 3 482 490 18203923 PMC2248260
  26. [26]Goss DJ Theil EC Iron responsive mRNAs: a family of Fe2+ sensitive riboregulators Accounts of Chemical Research 2011 44 12 1320 1328 22026512 PMC3243817
  27. [27]Zhang DL Hughes RM Ollivierre-Wilson H Ghosh MC Rouault TA A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression Cell Metabolism 2009 9 5 461 473 19416716 PMC2685206
  28. [29]Girelli D Corrocher R Bisceglia L Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene Blood 1997 90 5 2084 2088 9292547
  29. [30]Merendino L Guth S Bilbao D Martínez C Valcárcel J Inhibition of msl-2 splicing by Sex-lethal reveals interaction between U2AF35 and the 3′ splice site AG Nature 1999 402 6763 838 841 10617208
  30. [31]Forch P Merendino L Martinez C Valcarcel J Modulation of msl-2 5′ splice site recognition by Sex-lethal RNA 2001 7 9 1185 1191 11565743 PMC1370165
  31. [32]Beckmann K Grskovic M Gebauer F Hentze MW A dual inhibitory mechanism restricts msl-2 mRNA translation for dosage compensation in drosophila Cell 2005 122 4 529 540 16122421
  32. [33]Duncan K Grskovic M Strein C Sex-lethal imparts a sex-specific function to UNR by recruiting it to the msl-2 mRNA 3′ UTR: translational repression for dosage compensation Genes & Development 2006 20 3 368 379 16452508 PMC1361707
  33. [34]Abaza I Coll O Patalano S Gebauer F Drosophila UNR is required for translational repression of male-specific lethal 2 mRNA during regulation of X-chromosome dosage compensation Genes & Development 2006 20 3 380 389 16452509 PMC1361708
  34. [35]Duncan KE Strein C Hentze MW The SXL-UNR corepressor complex uses a PABP-mediated mechanism to inhibit ribosome recruitment to msl-2 mRNA Molecular Cell 2009 36 4 571 582 19941818
  35. [36]Medenbach J Seiler M Hentze MW Translational control via protein-regulated upstream open reading frames Cell 2011 145 6 902 913 21663794
  36. [37]Iakova P Wang GL Timchenko L Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate The EMBO Journal 2004 23 2 406 417 14726956 PMC1271759
  37. [38]Calvo SE Pagliarini DJ Mootha VK Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans Proceedings of the National Academy of Sciences of the United States of America 2009 106 18 7507 7512 19372376 PMC2669787
  38. [39]Iacono M Mignone F Pesole G UAUG and uORFs in human and rodent 5′ untranslated mRNAs Gene 2005 349 97 105 15777708
  39. [40]Lawless C Pearson RD Selley JN Upstream sequence elements direct post-transcriptional regulation of gene expression under stress conditions in yeast BMC Genomics 2009 10, article 7 PMC2649001 19128476
  40. [41]Matsui M Yachie N Okada Y Saito R Tomita M Bioinformatic analysis of post-transcriptional regulation by uORF in human and mouse The FEBS Letters 2007 581 22 4184 4188 17692847
  41. [42]Kozak M Constraints on reinitiation of translation in mammals Nucleic Acids Research 2001 29 24 5226 5232 11812856 PMC97554
  42. [43]Morris DR Geballe AP Upstream open reading frames as regulators of mRNA translation Molecular and Cellular Biology 2000 20 23 8635 8642 11073965 PMC86464
  43. [44]Oyama M Itagaki C Hata H Analysis of small human proteins reveals the translation of upstream open reading frames of mRNAs Genome Research 2004 14 10 2048 2052 15489325 PMC528919
  44. [45]Wang Z Gaba A Sachs MS A highly conserved mechanism of regulated ribosome stalling mediated by fungal arginine attenuator peptides that appears independent of the charging status of arginyl-tRNAs The Journal of Biological Chemistry 1999 274 53 37565 37574 10608810
  45. [46]Gaba A Wang Z Krishnamoorthy T Hinnebusch AG Sachs MS Physical evidence for distinct mechanisms of translational control by upstream open reading frames The EMBO Journal 2001 20 22 6453 6463 11707416 PMC125715
  46. [47]Wu C Wei J Lin PJ Arginine changes the conformation of the arginine attenuator peptide relative to the ribosome tunnel Journal of Molecular Biology 2012 416 4 518 533 22244852 PMC3568992
  47. [48]Fang P Spevak CC Wu C Sachs MS A nascent polypeptide domain that can regulate translation elongation Proceedings of the National Academy of Sciences of the United States of America 2004 101 12 4059 4064 15020769 PMC384695
  48. [49]Mueller PP Hinnebusch AG Multiple upstream AUG codons mediate translational control of GCN4 Cell 1986 45 2 201 207 3516411
  49. [50]Hinnebusch AG Translational regulation of GCN4 and the general amino acid control of yeast Annual Review of Microbiology 2005 59 1 407 450 16153175
  50. [51]Lohse I Reilly P Zaugg K The CPT1C 5′UTR contains a repressing upstream open reading frame that is regulated by cellular energy availability and AMPK PLoS one 2011 6 9 PMC3178533 21961029
  51. [52]Oliveira CC McCarthy JEG The relationship between eukaryotic translation and mRNA stability. A short upstream open reading frame strongly inhibits translational initiation and greatly accelerates mRNA degradation in the yeast Saccharomyces cerevisiae The Journal of Biological Chemistry 1995 270 15 8936 8943 7721802
  52. [53]Wethmar K Smink JJ Leutz A Upstream open reading frames: molecular switches in (patho)physiology Bioessays 2010 32 10 885 893 20726009 PMC3045505
  53. [54]Liu L Dilworth D Gao LZ Mutation of the CDKN2A 5′ UTR creates an aberrant initiation codon and predisposes to melanoma Nature Genetics 1999 21 1 128 132 9916806
  54. [55]Wiestner A Schlemper RJ van der Maas APC Skoda RC An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia Nature Genetics 1998 18 1 49 52 9425899
  55. [56]Wen YR Liu Y Xu YM Erratum: ‘loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis (Nature Genetics (2009) 41 (228-233))’ Nature Genetics 2009 41 6 p. 762 19122663
  56. [57]Beffagna G Occhi G Nava A Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1 Cardiovascular Research 2005 65 2 366 373 15639475
  57. [58]Calvo SE Pagliarini DJ Mootha VK Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans Proceedings of the National Academy of Sciences of the United States of America 2009 106 18 7507 7512 19372376 PMC2669787
  58. [59]Poulat F Desclozeaux M Tuffery S Jay P Boizet B Berta P Mutation in the 5′ noncoding region of the SRY gene in an XY sex-reversed patient Human Mutation 1998 10 1 S192 S194 9452083
  59. [60]Kondo S Schutte BC Richardson RJ Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes Nature Genetics 2002 32 2 285 289 12219090 PMC3169431
  60. [61]Groussin L Kirschner LS Vincent-Dejean C Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD American Journal of Human Genetics 2002 71 6 1433 1442 12424709 PMC378588
  61. [62]Witt H Luck W Hennies HC Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis Nature Genetics 2000 25 2 213 216 10835640
  62. [63]Oner R Agarwal S Dimovski AJ The G→A mutation at position +22 3′ to the cap site of the β-globin gene as a possible cause for a β-thalassemia Hemoglobin 1991 15 1-2 67 76 1717406
  63. [64]Konig J Zarnack K Rot G ICLIP—transcriptome-wide mapping of protein-RNA interactions with individual nucleotide resolution Journal of Visualized Experiments 2011 50, article 2638 PMC3169244 21559008
  64. [65]Morris DR Geballe AP Upstream open reading frames as regulators of mRNA translation Molecular and Cellular Biology 2000 20 23 8635 8642 11073965 PMC86464
  65. [66]Matys V Kel-Margoulis OV Fricke E TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes Nucleic Acids Research 2006 34 D108 D110 16381825 PMC1347505
  66. [67]Keyser RJ van der Merwe L Venter M Identification of a novel functional deletion variant in the 5′-UTR of the DJ-1 gene BMC Medical Genetics 2009 10, article 105 PMC2767350 19825160

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Authors
Araujo, P. R., Yoon, K., Ko, D., Smith, A. D., Qiao, M., Suresh, U., Burns, S. C., & Penalva, L. O. F.
Affiliations
  • Greehey Children's Cancer Research Institute, UTHSCSA, San Antonio, TX 78229-3900, USA
  • The University of Texas at San Antonio Health Science Center (US)
  • The University of Texas at San Antonio (US)
  • University of Southern California (US)
Corresponding author
Penalva, Luiz O. F.
ORCID
Venue
Comparative and Functional Genomics
Publisher
Wiley
Published
2012
Volume
2012
Pages
1-8
ISSN
  • 1531-6912 (ISSN-L)
  • 1532-6268
DOI
10.1155/2012/475731
PMC
PMC3368165
OpenAlex
W2062299199
Cited by
267
References
1
Citations by year
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FWCI
5.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Comparative and Functional Genomics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Children's Brain Tumor Foundation
  • National Institutes of Health (5r21hg004664-02)
  • National Human Genome Research Institute (R01HG006015, R21 HG004664)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
translational regulation, 5' untranslated region, upstream open reading frames, RNA secondary structure, RNA-binding proteins, cis-regulatory elements, gene expression, human disease

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