mRNA Editing

Christopher L Sansam, Vanderbilt University, Nashville, Tennessee, USA
Ronald B Emeson, Vanderbilt University, Nashville, Tennessee, USA

Published online: September 2005

DOI: 10.1038/npg.els.0005041

The editing of messenger RNA transcripts respresents a recently identified processing event by which multiple RNA transcripts can be generated from a single genomic locus to increase the coding potential of the human genome.

Keywords: RNA processing; modification; deamination; receptor; protein diversity

Figure 1. RNA editing by hydrolytic deamination. RNA editing events involving the conversion of cytidine to uridine (C to U) and adenosine to inosine (A to I) occur as a result of hydrolytic deamination at the C4 and C6 positions of the pyrimidine and purine bases, respectively, with the oxygen of water acting as the nucleophile. R: ribose.
Figure 2. Biosynthetic pathway for the tissue-specific production of apoB isoforms through site-specific C-to-U editing. (a) Organization of the APOB gene, with the start (ATG), stop (TAA) and edited glutamine (CAA) codons indicated in exons 1, 26 and 29, respectively; the cytidine residue in the nonedited intestinal transcript and the uridine residue in the edited mRNA, after the C-to-U modification, are underlined. The structures of the apoB-100 and apoB-48 protein isoforms are shown below, with their principal functional domains and corresponding amino acid lengths. (A)n, poly(A) tail. (b) The tripartite sequence motif required for the C-to-U editing of APOB transcripts (efficiency element, spacer, mooring sequence), with the edited cytidine residue indicated in white on black lettering.
Figure 3. RNA editing of 5-HT2CR transcripts. (a) Representation of the amino acid sequence and predicted topology of the human 2C subtype of serotonin receptor. The positions of amino acid alterations in the second intracellular loop of the receptor, which result from A-to-I editing events, are indicated, along with possible amino acid residues that result from permutations of editing at five distinct sites. (b) Secondary structure of the region of major editing modifications in the pre-mRNA transcript encoding the 5-HT2CR, as predicted by RNA folding algorithms (Zuker, 1989); the positions of the five edited adenosine residues (labeled A–E) and the exon–intron boundary are indicated. The codons altered by RNA editing are emboldened and shaded to match the amino acid positions shown in (a).
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 References
    Anant S, MacGinnitie AJ and Davidson NO (1995) The binding of apobec-1 to mammalian apoB RNA is stabilized by the presence of complementation factors which are required for post-transcriptional editing. Nucleic Acids Symposium Series 33: 99–102.
    Applegate CD and Tecott LH (1998) Global increases in seizure susceptibility in mice lacking 5-HT2C receptors: a behavioral analysis. Experimental Neurology 154: 522–530.
    Backus JW and Smith HC (1992) Three distinct RNA sequence elements are required for efficient apolipoprotein B (apoB) RNA editing in vitro. Nucleic Acids Research 20: 6007–6014.
    Benne R, Van den Burg J, Brakenhoff JP, et al. (1986) Major transcript of the frameshifted coxII gene from trypanosome mitochondria contains four nucleotides that are not encoded in the DNA. Cell 46: 819–826.
    Bettler B, Egebjerg J, Sharma G, et al. (1992) Cloning of a putative glutamate receptor: a low affinity kainate-binding subunit. Neuron 8: 257–265.
    Boulter J, Hollmann M, O'Shea-Greenfield A, et al. (1990) Molecular cloning and functional expression of glutamate receptor subunit genes. Science 249: 1033–1037.
    Brennan TJ, Seeley WW, Kilgard M, Schreiner CE and Tecott LH (1997) Sound-induced seizures in serotonin 5-HT2c receptor mutant mice. Nature Genetics 16: 387–390.
    Brusa R, Zimmermann F, Koh DS, et al. (1995) Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice. Science 270: 1677–1680.
    Burns CM, Chu H, Rueter SM, et al. (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387: 303–308.
    Collingridge GL and Singer W (1990) Excitatory amino acid receptors and synaptic plasticity. Trends in Pharmacological Sciences 11: 290–296.
    Davidson NO and Shelness GS (2000) APOLIPOPROTEIN B: mRNA editing, lipoprotein assembly, and presecretory degradation. Annual Reviews in Nutrition 20: 169–193.
    Dingledine R, Hume RI and Heinemann SF (1992) Structural determinants of barium permeation and rectification in non-NMDA glutamate receptor channels. Journal of Neuroscience 12: 4080–4087.
    Driscoll DM, Wynne JK, Wallis SC and Scott J (1989) An in vitro system for the editing of apolipoprotein B mRNA. Cell 58: 519–525.
    Dubovsky SL and Thomas M (1995) Beyond specificity: effects of serotonin and serotonergic treatments on psychobiological dysfunction. Journal of Psychosomatic Research 39: 429–444.
    Egebjerg J, Bettler B, Hermans-Borgmeyer I and Heinemann S (1991) Cloning of a cDNA for a glutamate receptor subunit activated by kainate but not AMPA. Nature 351: 745–748.
    Egebjerg J and Heinemann SF (1993)  Ca2+ permeability of unedited and edited versions of the kainate selective glutamate receptor GluR6. Proceedings of the National Academy of Sciences of the United States of America 90: 755–759.
    book Emeson R and Singh M (2001) "Adenosine-to-inosine RNA editing: substrates and consequences". In: Bass B (ed.) RNA Editing, pp. 109–138. New York, NY: Oxford University Press.
    Goldberg Y, Dibbern K, Klein J, Riccardi VM and Graham Jr JM (1996) Neurofibromatosis type 1 – an update and review for the primary pediatrician. Clinical Pediatrics (Philadelphia) 35: 545–561.
    Gott JM and Emeson RB (2000) Functions and mechanisms of RNA editing. Annual Reviews in Genetics 34: 499–531.
    Grosjean H, Auxilien S, Constantinesco F, et al. (1996) Enzymatic conversion of adenosine to inosine and to N1-methylinosine in transfer RNAs: a review. Biochimie 78: 488–501.
    Gurevich I, Tamir H, Arango V, et al. (2002) Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34: 349–356.
    Herb A, Burnashev N, Werner P, et al. (1992) The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits. Neuron 8: 775–785.
    Higuchi M, Single FN, Kohler M, et al. (1993) RNA editing of AMPA receptor subunit GluR-B: a base-paired intron–exon structure determines position and efficiency. Cell 75: 1361–1370.
    Hodges PE, Navaratnam N, Greeve JC and Scott J (1991) Site-specific creation of uridine from cytidine in apolipoprotein B mRNA editing. Nucleic Acids Research 19: 1197–1201.
    Holley RW (1965) Structure of an alanine transfer ribonucleic acid. Journal of the American Medical Association 194: 868–871.
    Hollmann M and Heinemann S (1994) Cloned glutamate receptors. Annual Reviews in Neuroscience 17: 31–108.
    Honjo T, Kinoshita K and Muramatsu M (2002) Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annual Reviews in Immunology 20: 165–196.
    Hough RF and Bass BL (1994) Purification of the Xenopus laevis double-stranded RNA adenosine deaminase. Journal of Biological Chemistry 269: 9933–9939.
    Hoyer D, Clarke DE, Fozard JR, et al. (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacological Reviews 46: 157–203.
    Hume RI, Dingledine R and Heinemann SF (1991) Identification of a site in glutamate receptor subunits that controls calcium permeability. Science 253: 1028–1031.
    Julius D (1991) Molecular biology of serotonin receptors. Annual Reviews in Neuroscience 14: 335–360.
    Keinanen K, Wisden W, Sommer B, et al. (1990) A family of AMPA-selective glutamate receptors. Science 249: 556–560.
    Keller W, Wolf J and Gerber A (1999) Editing of messenger RNA precursors and of tRNAs by adenosine to inosine conversion. FEBS Letters 452: 71–76.
    Kim U, Garner TL, Sanford T, et al. (1994) Purification and characterization of double-stranded RNA adenosine deaminase from bovine nuclear extracts. Journal of Biological Chemistry 269: 13480–13489.
    Kohler M, Burnashev N, Sakmann B and Seeburg PH (1993) Determinants of  Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing. Neuron 10: 491–500.
    Lau PP, Xiong WJ, Zhu HJ, Chen SH and Chan L (1991) Apolipoprotein B mRNA editing is an intranuclear event that occurs posttranscriptionally coincident with splicing and polyadenylation. Journal of Biological Chemistry 266: 20550–20554.
    Lomeli H, Mosbacher J, Melcher T, et al. (1994) Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266: 1709–1713.
    Martin A, Bardwell PD, Woo CJ, et al. (2002) Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 415: 802–806.
    Mehta A and Driscoll DM (2002) Identification of domains in apobec-1 complementation factor required for RNA binding and apolipoprotein-B mRNA editing. RNA 8: 69–82.
    Mehta A, Kinter MT, Sherman NE and Driscoll DM (2000) Molecular cloning of apobec-1 complementation factor, a novel RNA-binding protein involved in the editing of apolipoprotein B mRNA. Molecular and Cellular Biology 20: 1846–1854.
    Melcher T, Maas S, Herb A, et al. (1996) A mammalian RNA editing enzyme. Nature 379: 460–464.
    Morse DP, Aruscavage PJ and Bass BL (2002) RNA hairpins in noncoding regions of human brain and Caenorhabditis elegans mRNA are edited by adenosine deaminases that act on RNA. Proceedings of the National Academy of Sciences of the United States of America 99: 7906–7911.
    Muramatsu M, Sankaranand VS, Anant S, et al. (1999) Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. Journal of Biological Chemistry 274: 18470–18476.
    Nakanishi N, Shneider NA and Axel R (1990) A family of glutamate receptor genes: evidence for the formation of heteromultimeric receptors with distinct channel properties. Neuron 5: 569–581.
    Nicoll RA and Malenka RC (1999) Expression mechanisms underlying NMDA receptor-dependent long-term potentiation. Annals of the New York Academy of Sciences 868: 515–525.
    Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB and Sanders-Bush E (1999) RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. Journal of Biological Chemistry 274: 9472–9478.
    Niswender CM, Herrick-Davis K, Dilley GE, et al. (2001) RNA editing of the human serotonin 5-HT2C receptor. Alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsychopharmacology 24: 478–491.
    Nonogaki K, Strack AM, Dallman MF and Tecott LH (1998) Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nature Medicine 4: 1152–1156.
    Notarangelo LD, Duse M and Ugazio AG (1992) Immunodeficiency with hyper-IgM (HIM). Immunodeficiency Reviews 3: 101–121.
    O'Connell MA, Krause S, Higuchi M, et al. (1995) Cloning of cDNAs encoding mammalian double-stranded RNA-specific adenosine deaminase. Molecular and Cellular Biology 15: 1389–1397.
    Pandey SC, Davis JM and Pandey GN (1995) Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates. Journal of Psychiatry and Neuroscience 20: 215–225.
    Paul MS and Bass BL (1998) Inosine exists in mRNA at tissue-specific levels and is most abundant in brain mRNA. The EMBO Journal 17: 1120–1127.
    Pin JP, Joly C, Heinemann SF and Bockaert J (1994) Domains involved in the specificity of G protein activation in phospholipase C-coupled metabotropic glutamate receptors. The EMBO Journal 13: 342–348.
    Polson AG, Crain PF, Pomerantz SC, McCloskey JA and Bass BL (1991) The mechanism of adenosine to inosine conversion by the double-stranded RNA unwinding/modifying activity: a high-performance liquid chromatography-mass spectrometry analysis. Biochemistry 30: 11507–11514.
    Powell LM, Wallis SC, Pease RJ, et al. (1987) A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell 50: 831–840.
    Revy P, Muto T, Levy Y, et al. (2000) Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell 102: 565–575.
    Ruano D, Lambolez B, Rossier J, Paternain AV and Lerma J (1995) Kainate receptor subunits expressed in single cultured hippocampal neurons: molecular and functional variants by RNA editing. Neuron 14: 1009–1017.
    book Rueter S and Emeson R (1998) "Adenosine-to-inosine conversion in mRNA". In: Grosjean H and Benne R (eds.) Modification and Editing of RNA, pp. 343–361. Washington, DC: ASM Press.
    Rueter SM, Burns CM, Coode SA, Mookherjee P and Emeson RB (1995) Glutamate receptor RNA editing in vitro by enzymatic conversion of adenosine to inosine. Science 267: 1491–1494.
    Rueter SM, Dawson TR and Emeson RB (1999) Regulation of alternative splicing by RNA editing. Nature 399: 75–80.
    Sailer A, Swanson GT, Perez-Otano I, et al. (1999) Generation and analysis of GluR5(Q636R) kainate receptor mutant mice. Journal of Neuroscience 19: 8757–8764.
    Sakimura K, Bujo H, Kushiya E, et al. (1990) Functional expression from cloned cDNAs of glutamate receptor species responsive to kainate and quisqualate. FEBS Letters 272: 73–80.
    Seeburg PH (1993) The TiPS/TINS lecture: the molecular biology of mammalian glutamate receptor channels. Trends in Pharmacological Sciences 14: 297–303.
    Shah RR, Knott TJ, Legros JE, et al. (1991) Sequence requirements for the editing of apolipoprotein B mRNA. Journal of Biological Chemistry 266: 16301–16304.
    Skuse GR and Cappione AJ (1997) RNA processing and clinical variability in neurofibromatosis type I (NF1). Human Molecular Genetics 6: 1707–1712.
    Skuse GR, Cappione AJ, Sowden M, Metheny LJ and Smith HC (1996) The neurofibromatosis type I messenger RNA undergoes base-modification RNA editing. Nucleic Acids Research 24: 478–485.
    Sodhi MS, Burnet PW, Makoff AJ, Kerwin RW and Harrison PJ (2001) RNA editing of the 5-HT2C receptor is reduced in schizophrenia. Molecular Psychiatry 6: 373–379.
    Sommer B, Burnashev N, Verdoorn TA, et al. (1992) A glutamate receptor channel with high affinity for domoate and kainate. The EMBO Journal 11: 1651–1656.
    Sommer B, Kohler M, Sprengel R and Seeburg PH (1991) RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67: 11–19.
    Tecott LH, Logue SF, Wehner JM and Kauer JA (1998) Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice. Proceedings of the National Academy of Sciences of the United States of America 95: 15026–15031.
    Tecott LH, Sun LM, Akana SF, et al. (1995) Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374: 542–546.
    Teitler M and Herrick-Davis K (1994) Multiple serotonin receptor subtypes: molecular cloning and functional expression. Critical Reviews in Neurobiology 8: 175–188.
    Teng B, Burant CF and Davidson NO (1993) Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science 260: 1816–1819.
    Venter JC, Adams MD, Myers EW, et al. (2001) The sequence of the human genome. Science 291: 1304–1351.
    Wissinger B, Schuster W and Brennicke A (1991) Trans splicing in Oenothera mitochondria: nad1 mRNAs are edited in exon and trans-splicing group II intron sequences. Cell 65: 473–482.
    Wong SK, Parker EM and Ross EM (1990) Chimeric muscarinic cholinergic: -adrenergic receptors that activate Gs in response to muscarinic agonists. Journal of Biological Chemistry 265: 6219–6224.
    Zuker M (1989) On finding all suboptimal foldings of an RNA molecule. Science 244: 48–52.
 Further Reading
    book Bass BL (ed.) (2001) RNA Editing. New York, NY: Oxford University Press.
    book Grosjean H and Benne R (eds.) (1998) Modification and Editing of RNA. Washington, DC: ASM Press.
    Papavasiliou FN and Schatz DG (2002) Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell 109(supplement): S35–S44.
 Web Links
    ePath 5-Hydroxytrypamine (serotonin) receptor 2C (HTR2C); LocusID: 3358. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3358
    ePath Apolipoprotein B (APOB); LocusID: 338. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=338
    ePath Glutamate receptor, metabotropic 5 (GRM5); LocusID: 2915. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2915
    ePath Neurofibromin 1 (NF1). LocusID: 4763. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4763
    ePath 5-Hydroxytrypamine (serotonin) receptor 2C (HTR2C); MIM number: 312861. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?312861
    ePath Apolipoprotein B (APOB); MIM number: 107730. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?107730
    ePath Glutamate receptor, metabotropic 5 (GRM5); MIM number: 604102. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?604102
    ePath Neurofibromin 1 (NF1) MIM number: 162200. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?162200

Related Sub-Topics:

Basic Cell Biology, Protein, RNA and DNA | RNA Structure and Function | Posttranscriptional Modification | Nucleic Acids: Structure, Function, Metabolism
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Article Title: mRNA Editing
 
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Sansam, Christopher L, and Emeson, Ronald B(Sep 2005) mRNA Editing. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005041]