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Klin Padiatr 2004; 216(6): 304-314
DOI: 10.1055/s-2004-832337
Grundlagenforschung

© Georg Thieme Verlag Stuttgart · New York

mRNA Metabolism and Hereditary Disorders: A Tale of Surveillance and Escape

mRNA-Metabolismus und hereditäre ErkrankungenG. Neu-Yilik1 , 2 , A. E. Kulozik1 , 2
  • 1Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany
  • 2Molecular Medicine Partnership Unit, Heidelberg, Germany
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Publication History

Publication Date:
24 November 2004 (online)

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Abstract

The exploration of the molecular origin of hereditary diseases focused on genes and proteins for many years. Recently, mRNA has gained increasing attention. Most human genes contain introns and a considerable proportion of transcripts are not only alternatively spliced but also regulated posttranscriptionally in manifold ways. mRNA processing as well as a complex network of interactions between the steps of gene expression and associated quality control mechanisms are guided by a multitude of regulative mRNA sequence elements. Therefore it is not surprising that mutations of such elements can cause or modify human disease. The purpose of this review is the illustration of principles of physiological and dysregulated mRNA metabolism as well as a survey of new analytical tools and therapeutic approaches.

Zusammenfassung

Während über viele Jahre die Erforschung der molekularen Ursachen hereditärer Erkrankungen sich auf Gene und auf Proteine als wesentliche Funktionsträger der Zelle konzentrierte, ist die mRNA in jüngerer Zeit mehr in den Blickpunkt gerückt. Die meisten humanen Gene enthalten Introns, und ein erheblicher Anteil der Transkripte werden nicht nur alternativ gespleißt, sondern auf vielfältige Weise posttranskriptionell reguliert. Die Vorgänge der mRNA-Prozessierung, sowie ein komplexes Netzwerk von Interaktionen zwischen den einzelnen Schritten der Genexpression und damit assoziierten Qualitätskontrollmechanismen werden von einer Vielzahl von regulativen Sequenzelementen in der mRNA gesteuert. Daher ist es nicht überraschend, dass Mutationen, die solche Elemente betreffen, humane Erkrankungen verursachen oder modifizieren können. Ziel dieser Übersicht ist, die Prinzipien von physiologischem und pathologischem mRNA-Metabolismus darzustellen und einen Überblick über neue analytische Methoden und therapeutische Ansätze zu geben.

Key words

mRNA - hereditary disorders - NMD - mRNA surveillance - therapy

Schlüsselwörter

mRNA - hereditäre Erkrankungen - NMD - mRNA-Qualitätskontrolle - Therapie

References

  • 1 Bentley D. The mRNA assembly line: transcription and processing machines in the same factory.  Curr Opin Cell Biol. 2002;  14 336-342
    CrossrefPubMedGoogle Scholar
  • 2 Black C. Switching on gene therapy. PharmaGenomics 2003; 48-52
    Google Scholar
  • 3 Bracco L, Kearsey J. The relevance of alternative RNA splicing to pharmacogenomics.  Trends Biotechnol. 2003;  21 346-353
    CrossrefPubMedGoogle Scholar
  • 4 Brais B, Bouchard J P, Xie Y G, Rochefort D L, Chretien N, Tome F M, Lafreniere R G, Rommens J M, Uyama E, Nohira O, Blumen S, Korczyn A D, Heutink P, Mathieu J, Duranceau A, Codere F, Fardeau M, Rouleau G A, Korcyn A D. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy.  Nat Genet. 1998;  18 164-167
    PubMedGoogle Scholar
  • 5 Brinkman B M. Splice variants as cancer biomarkers.  Clin Biochem. 2004;  37 584-594
    PubMedGoogle Scholar
  • 6 Butler J S. The yin and yang of the exosome.  Trends Cell Biol. 2002;  12 90-96
    CrossrefPubMedGoogle Scholar
  • 7 Cartegni L, Chew S L, Krainer A R. Listening to silence and understanding nonsense: exonic mutations that affect splicing.  Nat Rev Genet. 2002;  3 285-298
    CrossrefPubMedGoogle Scholar
  • 8 Cartegni L, Krainer A R. Correction of disease-associated exon skipping by synthetic exon-specific activators.  Nat Struct Biol. 2003;  10 120-125
    CrossrefPubMedGoogle Scholar
  • 9 Cartegni L, Wang J, Zhu Z, Zhang M Q, Krainer A R. ESEfinder: A web resource to identify exonic splicing enhancers.  Nucleic Acids Res. 2003;  31 3568-3571
    CrossrefPubMedGoogle Scholar
  • 10 Casolari J M, Silver P A. Guardian at the gate: preventing unspliced pre-mRNA export.  Trends Cell Biol. 2004;  14 222-225
    CrossrefPubMedGoogle Scholar
  • 11 Celotto A M, Graveley B R. Exon-specific RNAi: a tool for dissecting the functional relevance of alternative splicing.  RNA. 2002;  8 718-724
    CrossrefPubMedGoogle Scholar
  • 12 Chandrasekharan N V, Dai H, Roos K L, Evanson N K, Tomsik J, Elton T S, Simmons D L. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression.  Proc Natl Acad Sci USA. 2002;  99 13926-13931
    CrossrefPubMedGoogle Scholar
  • 13 Cochet O, Heard D, Fehlbaum P, Ducray C, Bracco L. Exploiting human genomic diversity through alternative RNA splicing. PharmaGenomics 2003; 26-36
    Google Scholar
  • 14 Danckwardt S, Gehring N H, Neu-Yilik G, Hundsdoerfer P, Pforsich M, Frede U, Hentze M W, Kulozik A E. The prothrombin 3′ end formation signal reveals a unique architecture that is sensitive to thrombophilic gain-of-function mutations.  Blood. 2004;  104 428-435
    CrossrefPubMedGoogle Scholar
  • 15 Edwalds-Gilbert G, Veraldi K L, Milcarek C. Alternative poly(A) site selection in complex transcription units: means to an end?.  Nucleic Acids Res. 1997;  25 2547-2561
    CrossrefPubMedGoogle Scholar
  • 16 Fairbrother W G, Yeh R F, Sharp P A, Burge C B. Predictive identification of exonic splicing enhancers in human genes.  Science. 2002;  297 1007-1013
    CrossrefPubMedGoogle Scholar
  • 17 Faustino N A, Cooper T A. Pre-mRNA splicing and human disease.  Genes Dev. 2003;  17 419-437
    CrossrefPubMedGoogle Scholar
  • 18 Frischmeyer P A, van Hoof A, O'Donnell K, Guerrerio A L, Parker R, Dietz H C. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons.  Science. 2002;  295 2258-2261
    CrossrefPubMedGoogle Scholar
  • 19 Garcia-Blanco M A, Baraniak A P, Lasda E L. Alternative splicing in disease and therapy.  Nat Biotechnol. 2004;  22 535-546
    PubMedGoogle Scholar
  • 20 Gehring N H, Frede U, Neu-Yilik G, Hundsdoerfer P, Vetter B, Hentze M W, Kulozik A E. Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia.  Nat Genet. 2001;  28 389-392
    PubMedGoogle Scholar
  • 21 Graveley B R. Alternative splicing: increasing diversity in the proteomic world.  Trends Genet. 2001;  17 100-107
    CrossrefPubMedGoogle Scholar
  • 22 Graveley B R. Sorting out the complexity of SR protein functions.  RNA. 2000;  6 1197-1211
    CrossrefPubMedGoogle Scholar
  • 23 Hayes G M, Carpenito C, Davis P D, Dougherty S T, Dirks J F, Dougherty G J. Alternative splicing as a novel of means of regulating the expression of therapeutic genes.  Cancer Gene Ther. 2002;  9 133-141
    CrossrefPubMedGoogle Scholar
  • 24 Heasman J. Morpholino oligos: making sense of antisense?.  Dev Biol. 2002;  243 209-214
    CrossrefPubMedGoogle Scholar
  • 25 Hentze M W, Kulozik A E. A perfect message: RNA surveillance and nonsense-mediated decay.  Cell. 1999;  96 307-310
    CrossrefPubMedGoogle Scholar
  • 26 Holbrook J A, Neu-Yilik G, Hentze M W, Kulozik A E. Nonsense-mediated decay approaches the clinic.  Nature Genetics. 2004;  36 801-808
    CrossrefPubMedGoogle Scholar
  • 27 Jensen T H, Dower K, Libri D, Rosbash M. Early formation of mRNP: license for export or quality control?.  Mol Cell. 2003;  11 1129-1138
    CrossrefPubMedGoogle Scholar
  • 28 Jensen T H, Rosbash M. Co-transcriptional monitoring of mRNP formation.  Nat Struct Biol. 2003;  10 10-12
    CrossrefPubMedGoogle Scholar
  • 29 Johnson J M, Castle J, Garrett-Engele P, Kan Z, Loerch P M, Armour C D, Santos R, Schadt E E, Stoughton R, Shoemaker D D. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays.  Science. 2003;  302 2141-2144
    CrossrefPubMedGoogle Scholar
  • 30 Keene J D, Tenenbaum S A. Eukaryotic mRNPs may represent posttranscriptional operons.  Mol Cell. 2002;  9 1161-1167
    CrossrefPubMedGoogle Scholar
  • 31 Kolev N G, Huber P W. VgRBP71 stimulates cleavage at a polyadenylation signal in Vg1 mRNA, resulting in the removal of a cis-acting element that represses translation.  Mol Cell. 2003;  11 745-755
    CrossrefPubMedGoogle Scholar
  • 32 Krawczak M, Reiss J, Cooper D N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences.  Hum Genet. 1992;  90 41-54
    PubMedGoogle Scholar
  • 33 Ladd A N, Cooper T A. Finding signals that regulate alternative splicing in the post-genomic era.  Genome Biol. 2002;  3 0008.1-0008.16
    PubMedGoogle Scholar
  • 34 Liu H X, Cartegni L, Zhang M Q, Krainer A R. A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes.  Nat Genet. 2001;  27 55-58
    PubMedGoogle Scholar
  • 35 Long M B, Jones J P, Sullenger B A, Byun J. Ribozyme-mediated revision of RNA and DNA.  J Clin Invest. 2003;  112 312-318
    CrossrefPubMedGoogle Scholar
  • 36 Maniatis T, Reed R. An extensive network of coupling among gene expression machines.  Nature. 2002;  416 499-506
    CrossrefPubMedGoogle Scholar
  • 37 Mansfield S G, Chao H, Walsh C E. RNA repair using spliceosome-mediated RNA trans-splicing.  Trends Mol Med. 2004;  10 263-268
    CrossrefPubMedGoogle Scholar
  • 38 Maquat L E. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics.  Nature Reviews Molecular Cell Biology. 2004;  5 89-99
    CrossrefPubMedGoogle Scholar
  • 39 Maquat L E. The power of point mutations.  Nat Genet. 2001;  27 5-6
    PubMedGoogle Scholar
  • 40 Maquat L E, Carmichael G G. Quality control of mRNA function.  Cell. 2001;  104 173-176
    CrossrefPubMedGoogle Scholar
  • 41 Matsumoto K, Wassarman K M, Wolffe A P. Nuclear history of a pre-mRNA determines the translational activity of cytoplasmic mRNA.  EMBO J. 1998;  17 2107-2121
    CrossrefPubMedGoogle Scholar
  • 42 Mercatante D R, Bortner C D, Cidlowski J A, Kole R. Modification of alternative splicing of Bcl-x pre-mRNA in prostate and breast cancer cells. analysis of apoptosis and cell death.  J Biol Chem. 2001;  276 16411-16417
    CrossrefPubMedGoogle Scholar
  • 43 Miyamoto S, Chiorini J A, Urcelay E, Safer B. Regulation of gene expression for translation initiation factor eIF-2 alpha: importance of the 3′ untranslated region.  Biochem J. 1996;  315 791-798
    PubMedGoogle Scholar
  • 44 Modrek B, Lee C. A genomic view of alternative splicing.  Nat Genet. 2002;  30 13-19
    CrossrefPubMedGoogle Scholar
  • 45 Moteki S, Price D. Functional coupling of capping and transcription of mRNA.  Mol Cell. 2002;  10 599-609
    CrossrefPubMedGoogle Scholar
  • 46 Mukherjee D, Gao M, O'Connor J P, Raijmakers R, Pruijn G, Lutz C S, Wilusz J. The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements.  EMBO J. 2002;  21 165-174
    CrossrefPubMedGoogle Scholar
  • 47 Nagy E, Maquat L E. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance.  Trends Biochem Sci. 1998;  23 198-199
    CrossrefPubMedGoogle Scholar
  • 48 Philips A V, Cooper T A. RNA processing and human disease.  Cell Mol Life Sci. 2000;  57 235-249
    PubMedGoogle Scholar
  • 49 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood. 1996;  88 3698-3703
    CrossrefPubMedGoogle Scholar
  • 50 Proudfoot N J, Furger A, Dye M J. Integrating mRNA processing with transcription.  Cell. 2002;  108 501-512
    Google Scholar
  • 51 Rogers C S, Vanoye C G, Sullenger B A, George A L. Functional repair of a mutant chloride channel using a trans-splicing ribozyme.  J Clin Invest. 2002;  110 1783-1789
    CrossrefPubMedGoogle Scholar
  • 52 Scott J. A place in the world for RNA editing.  Cell. 1995;  81 833-836
    CrossrefPubMedGoogle Scholar
  • 53 Simmons D L. Variants of cyclooxygenase-1 and their roles in medicine.  Thromb Res. 2003;  110 265-268
    CrossrefPubMedGoogle Scholar
  • 54 Staege M S, Hattenhorst U E, Neumann U E, Hutter C, Foja S, Burdach S. DNA-microarrays as tools for the identification of tumor specific gene expression profiles: applications in tumor biology, diagnosis and therapy.  Klin Paediatr. 2003;  215 135-139
    PubMedGoogle Scholar
  • 55 Summerton J E. Custom cancer therapies: safe and effective treatments for most or all cancers.  Ann N Y Acad Sci. 2003;  1002 189-196
    CrossrefPubMedGoogle Scholar
  • 56 Thein S L. Genetic insights into the clinical diversity of beta thalassaemia.  Br J Haematol. 2004;  124 264-274
    CrossrefPubMedGoogle Scholar
  • 57 Vacek M, Sazani P, Kole R. Antisense-mediated redirection of mRNA splicing.  Cell Mol Life Sci. 2003;  60 825-833
    PubMedGoogle Scholar
  • 58 van Hoof A, Parker R. The exosome: a proteasome for RNA?.  Cell. 1999;  99 347-350
    CrossrefPubMedGoogle Scholar
  • 59 Vasudevan S, Peltz S W. Nuclear mRNA surveillance.  Curr Opin Cell Biol. 2003;  15 332-337
    CrossrefPubMedGoogle Scholar
  • 60 Vinciguerra P, Stutz F. mRNA export: an assembly line from genes to nuclear pores.  Curr Opin Cell Biol. 2004;  16 285-292
    CrossrefPubMedGoogle Scholar
  • 61 Waggoner S A, Liebhaber S A. Regulation of alpha-globin mRNA stability.  Exp Biol Med. 2003;  228 387-395
    PubMedGoogle Scholar
  • 62 Wagner E, Lykke-Andersen J. mRNA surveillance: the perfect persist.  J Cell Sci. 2002;  115 3033-3038
    PubMedGoogle Scholar
  • 63 Zamaratski E, Pradeepkumar P I, Chattopadhyaya J. A critical survey of the structure-function of the antisense oligo/RNA heteroduplex as substrate for RNase H.  J Biochem Biophys Methods. 2001;  48 189-208
    CrossrefPubMedGoogle Scholar
  • 64 Zhang K, Kaufman R J. Signaling the unfolded protein response from the endoplasmic reticulum.  J Biol Chem. 2004;  279 25935-25938
    CrossrefPubMedGoogle Scholar
  • 65 Zhao J, Hyman L, Moore C. Formation of mRNA 3′ ends in eukaryotes: mechanism, regulation, and interrelationships with other steps in mRNA synthesis.  Microbiol Mol Biol Rev. 1999;  63 405-445
    PubMedGoogle Scholar

Gabriele Neu-Yilik

Phone: 49-62 21-56 45 79

Fax: 49-62 21-56 45 80

Email: gaby.neu-yilik@med.uni-heidelberg.de

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