Abstract
Major advances in the understanding of adenosine deaminases acting on RNA (ADARs) have come from the generation of ADAR mutant animals. In mice, ADAR1 is a widely expressed essential gene and loss of function in embryos leads to apoptosis through unknown mechanisms in many different cell types. Mammalian ADAR2 is required primarily to edit glutamate receptor transcripts in the nervous system. The Drosophila melanogaster genome contains one Adar gene; mutant flies are normal in morphology and lifespan, but severely compromised neurologically and behaviourally. In C. elegans, double mutants in Adr1 and Adr2 genes are viable with chemosensory defects that appear to arise from interactions between RNA editing and RNA interference. ADARs also extensively deaminate long double-stranded (ds) RNA in a process that has been proposed to have anti-viral effects. Genome sequences have facilitated progress in identifying edited RNAs. The majority of the twenty-three edited transcripts identified in Drosophila encode proteins involved in rapid chemical and electrical neurotransmission and extensive editing of embedded Alu RNAs has been found.
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Preview
Unable to display preview. Download preview PDF.
References
1. Bass BL, Weintraub H (1987) A developmental regulated activity that unwinds RNA duplexes. Cell 48:607-613
2. Bass BL, Weintraub H (1988) An unwinding activity that covalently modifies its double-strand RNA substrate. Cell 55:1089-1098
3. Bass BL, Weintraub H, Cattaneo R, Billeter MA (1989) Biased hypermutation of viral RNA genomes could be due to unwinding/modification of double-stranded RNA. Cell 56:331
4. Bhalla T, Rosenthal JJC, Holmgren M, Reenan R (2004) Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nature Struct Biol (in press)
5. Brusa R, Zimmermann F, Koh D-S, Feldmeyer D, Gass P, Seeburg PH, Sprengel R (1995) Early-onset epilepsy and postnatal lethality associated with editing-deficient GluR-B allele in mice. Science 270:1677-1680
6. Burnashev N, Monyer H, Seeburg PH, Sakmann B (1992) Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8:189-198
7. Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387:303-308
8. Chen CX, Cho DS, Wang Q, Lai F, Carter KC, Nishikura K (2000) A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. RNA 6:755-767
9. Cho DS, Yang W, Lee JT, Shiekhattar R, Murray JM, Nishikura K (2003) Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. J Biol Chem 278:17093-17102
10. Desterro JM, Keegan LP, Lafarga M, Berciano MT, O’Connell M, Carmo-Fonseca M (2003) Dynamic association of RNA-editing enzymes with the nucleolus. J Cell Sci 116:1805-1818
11. Gallo A, Keegan LP, Ring GM, O’Connell MA (2003) An ADAR that edits transcripts encoding ion channel subunits functions as a dimer. EMBO J 22:3421-3430
12. George CX, Samuel CE (1999) Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proc Natl Acad Sci USA 96:4621-4626
13. Grauso M, Reenan RA, Culetto E, Sattelle DB (2002) Novel putative nicotinic acetylcholine receptor subunit genes, Dalpha5, Dalpha6 and Dalpha7, in Drosophila melanogaster identify a new and highly conserved target of adenosine deaminase acting on RNA-mediated A-to-I pre-mRNA editing. Genetics 160:1519-1533
14. Greger IH, Khatri L, Kong X, Ziff EB (2003) AMPA receptor tetramerization is mediated by q/r editing. Neuron 40:763-774
15. Greger IH, Khatri L, Ziff EB (2002) RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum. Neuron 34:759-772
16. Gurevich I, Englander MT, Adlersberg M, Siegal NB, Schmauss C (2002a) Modulation of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission. J Neurosci 22:10529-10532
17. Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C (2002b) Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34:349-356
18. Hanrahan CJ, Palladino MJ, Bonneau LJ, Reenan RA (1998) RNA editing of a Drosophila sodium channel gene. Ann NY Acad Sci 868:51-66
19. Hanrahan CJ, Palladino MJ, Ganetzky B, Reenan RA (2000) RNA editing of the drosophila para Na(+) channel transcript. Evolutionary conservation and developmental regulation. Genetics 155:1149-1160
20. Harris ME, Hajduk SL (1992) Kinetoplastid RNA editing: in vitro formation of cytochrome b gRNA-mRNA chimeras from synthetic substrate RNAs. Cell 68:1091-1099
21. Hartner JC, Schmittwolf C, Kispert A, Muller AM, Higuchi M, Seeburg PH (2004) Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem 279:4894-4902
22. Haudenschild BL, Maydanovych O, Veliz EA, Macbeth MR, Bass BL, Beal PA (2004) A transition state analogue for an RNA-editing reaction. J Am Chem Soc 126:11213-11219
23. Herb A, Higuchi M, Sprengel R, Seeburg PH (1996) Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences. Proc Natl Acad Sci USA 93:1875-1880
24. Herbert A (1996) RNA editing, introns and evolution. Trends Genet 12:6-9
25. Herbert A, Schade M, Lowenhaupt K, Alfken J, Schwartz T, Shlyakhtenko LS, Lyubchenko YL, Rich A (1998) The Zalpha domain from human ADAR1 binds to the Z-DNA conformer of many different sequences. Nucleic Acids Res 26:3486-3493
26. Higuchi M, Maas S, Single FN, Hartner J, Rozov A, Burnashev N, Feldmeyer D, Sprengel R, Seeburg PH (2000) Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406:78-81
27. Higuchi M, Single FN, Köhler M, Sommer B, Sprengel R, Seeburg PH (1993) RNA editing of AMPA receptor subunit GluR-B: A base-paired intron-exon structure determines position and efficiency. Cell 75:1361-1370
28. Hoopengardner B, Bhalla T, Staber C, Reenan R (2003) Nervous system targets of RNA editing identified by comparative genomics. Science 301:832-836
29. Hough RF, Bass BL (1994) Purification of the Xenopus laevis dsRNA adenosine deaminase. J Biol Chem 269:9933-9939
30. Hough RF, Bass BL (1997) Analysis of Xenopus dsRNA adenosine deaminase cDNAs reveals similarities to DNA methlytransferases. RNA 3:356-370
31. Hough RF, Lingam AT, Bass BL (1999) Caenorhabditis elegans mRNAs that encode a protein similar to ADARs derive from an operon containing six genes. Nucleic Acids Res 27:3424-3432
32. Jaikaran DC, Collins CH, MacMillan AM (2002) Adenosine to inosine editing by ADAR2 requires formation of a ternary complex on the GluR-B R/G site. J Biol Chem 277:37624-37629
33. Kask K, Zamanillo D, Rozov A, Burnashev N, Sprengel R, Seeburg PH (1998) The AMPA receptor subunit GluR-B in its Q/R site-unedited form is not essential for brain development and function. Proc Natl Acad Sci USA 95:13777-13782
34. Kawahara Y, Ito K, Sun H, Aizawa H, Kanazawa I, Kwak S (2004) Glutamate receptors: RNA editing and death of motor neurons. Nature 427:801
35. Kawahara Y, Kwak S, Sun H, Ito K, Hashida H, Aizawa H, Jeong SY, Kanazawa I (2003) Human spinal motoneurons express low relative abundance of GluR2 mRNA: an implication for excitotoxicity in ALS. J Neurochem 85:680-689
36. Kawakubo K, Samuel CE (2000) Human RNA-specific adenosine deaminase (ADAR1) gene specifies transcripts that initiate from a constitutively active alternative promoter. Gene 258:165-172
37. Keegan LP, Leroy A, Sproul D, O’Connell MA (2004) Adenosine deaminases acting on RNA (ADARs): RNA-editing enzymes. Genome Biol 5:209
38. Kim DD, Kim TT, Walsh T, Kobayashi Y, Matise TC, Buyske S, Gabriel A (2004) Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res 14:1719-1725
39. Kim U, Garner TL, Sanford T, Speicher D, Murray JM, Nishikura K (1994a) Purification and characterization of double-stranded RNA adenosine deaminase from bovine nuclear extracts. J Biol Chem 269:13480-13489
40. Kim U, Wang Y, Sanford T, Zeng Y, Nishikura K (1994b) Molecular cloning of cDNAs for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. Proc Natl Acad Sci USA 91:11457-11461
41. Kumar M, Carmichael GC (1997) Nuclear antisense RNA induces extensive adenosine modifications and nuclear retention of target transcripts. Proc Natl Acad Sci USA 94:3542-3547
42. Kung SS, Chen YC, Lin WH, Chen CC, Chow WY (2001) Q/R RNA editing of the AMPA receptor subunit 2 (GRIA2) transcript evolves no later than the appearance of cartilaginous fishes. FEBS Lett 509:277-281
43. Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, Fligelman ZY, Shoshan A, Pollock SR, Sztybel D, Olshansky M, Rechavi G, Jantsch MF (2004) Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol 22:1001-1005
44. Lomeli H, Mosbacher J, Melcher T, Höger T, Geiger JR, Kuner T, Monyer H, Higuchi M, Bach A, Seeburg PH (1994) Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266:1709-1713
45. Luciano DJ, Mirsky H, Vendetti NJ, Maas S (2004) RNA editing of a miRNA precursor. RNA 10:1174-1177
46. Melcher T, Maas S, Herb A, Sprengel R, Higuchi M, Seeburg PH (1996a) RED2, a brain specific member of the RNA-specific adenosine deaminase family. J Biol Chem 271:31795-31798
47. Melcher T, Maas S, Herb A, Sprengel R, Seeburg PH, Higuchi M (1996b) A mammalian RNA editing enzyme. Nature 379:460-464
48. Miyamura Y, Suzuki T, Kono M, Inagaki K, Ito S, Suzuki N, Tomita Y (2003) Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet 73:693-699
49. Morse DP, Aruscavage PJ, Bass BL (2002) RNA hairpins in noncoding regions of human brain and Caenorhabditis elegans mRNA are edited by adenosine deaminases that act on RNA. Proc Natl Acad Sci USA 99:7906-7911
50. Morse DP, Bass BL (1997) Detection of inosine in messenger RNA by insine-specific cleavage. Biochemistry 36:8429-8434
51. Morse DP, Bass BL (1999) Long RNA hairpins that contain inosine are present in Caenorhabditis elegans poly(A)+ RNA. PNAS 96:6048-6053
52. Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB, Sanders-Bush E (1999) RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. J Biol Chem 274:9472-9478
53. Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, Emeson RB, Sanders-Bush E (2001) RNA editing of the human serotonin 5-HT2C receptor. Alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsychopharmacology 24:478-491
54. O’Connell MA, Gerber A, Keller W (1997) Purification of human double-stranded RNA-specific editase1 (hRed1), involved in editing of brain glutamate receptor B pre-mRNA. J Biol Chem 272:473-478
55. O’Connell MA, Keller W (1994) Purification and properties of double-stranded RNA-specific adenosine deaminase from calf thymus. Proc Natl Acad Sci USA 91:10596-10600
56. O’Connell MA, Krause S, Higuchi M, Hsuan JJ, Totty NF, Jenny A, Keller W (1995) Cloning of cDNAs encoding mammalian double-stranded RNA-specific adenosine deaminase. Mol Cell Biol 15:1389-1397
57. Ohman M, Kallman AM, Bass BL (2000) In vitro analysis of the binding of ADAR2 to the pre-mRNA encoding the GluR-B R/G site. RNA 6:687-697
58. Palladino MJ, Keegan LP, O’Connell MA, Reenan RA (2000a) dADAR, a Drosophila double-stranded RNA-specific adenosine deaminase is highly developmentally regulated and is itself a target for RNA editing. RNA 6:1004-1018
59. Palladino MJ, Keegan LP, O’Connell MA, Reenan RA (2000b) A-to-I pre-mRNA editing in Drosophila is primarily involved in adult nervous system function and integrity. Cell 102:437-449
60. Patton DE, Silva T, Bezanilla F (1997) RNA editing generates a diverse array of transcripts encoding squid Kv2 K+ channels with altered functional properties. Neuron 19:711-722
61. Paul M, Bass BL (1998) Inosine exists in mRNA at tissue-specific levels and is most abundant in brain mRNA. EMBO J 17: 1120-1127
62. Peters NT, Rohrbach JA, Zalewski BA, Byrkett CM, Vaughn JC (2003) RNA editing and regulation of Drosophila 4f-rnp expression by sas-10 antisense readthrough mRNA transcripts. RNA 9:698-710
63. Petschek JP, Mermer MJ, Scheckelhoff MR, Simone AA, Vaughn JC (1996) RNA editing in Drosophila 4f-rnp gene nuclear transcripts by multiple A-to-G conversions. J Mol Biol 259:885-890
64. Poulsen H, Nilsson J, Damgaard CK, Egebjerg J, Kjems J (2001) CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain. Mol Cell Biol 21:7862-7871
65. Rebagliati MR, Melton DA (1987) Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity. Cell 48:599-605
66. Rosenthal JJ, Bezanilla F (2002) Extensive editing of mRNAs for the squid delayed rectifier K(+) channel regulates subunit tetramerization. Neuron 34:743-757
67. Scadden AD, Smith CW (2001a) RNAi is antagonized by A$to$I hyper-editing. EMBO Rep 2:1107-1111
68. Scadden AD, Smith CW (2001b) Specific cleavage of hyper-edited dsRNAs. EMBO J 20:4243-4252
69. Schwartz T, Rould MA, Lowenhaupt K, Herbert A, Rich A (1999) Crystal structure of the Zalpha domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA. Science 284:1841-1845
70. Semenov EP, Pak WL (1999) Diversification of Drosophila chloride channel gene by multiple posttranscriptional mRNA modifications. J Neurochem 72:66-72
71. Serra MJ, Smolter PE, Westhof E (2004) Pronounced instability of tandem IU base pairs in RNA. Nucleic Acids Res 32:1824-1828
72. Shaw PJ, Eggett CJ (2000) Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol 247 Suppl 1:I17-27
73. Shaw PJ, Ince PG (1997) Glutamate, excitotoxicity and amyotrophic lateral sclerosis. J Neurol 244 Suppl 2:S3-S14
74. Smith LA, Peixoto AA, Hall JC (1998) RNA editing in the Drosophila DMCA1A calcium-channel alpha 1 subunit transcript. J Neurogenet 12:227-240
75. Sommer B, Köhler M, Sprengel R, Seeburg PH (1991) RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67:11-19
76. Stephens OM, Haudenschild BL, Beal PA (2004) The binding selectivity of ADAR2’s dsRBMs contributes to RNA-editing selectivity. Chem Biol 11:1239-1250
77. Tonkin LA, Bass BL (2003) Mutations in RNAi rescue aberrant chemotaxis of ADAR mutants. Science 302:1725
78. Tonkin LA, Saccomanno L, Morse DP, Brodigan T, Krause M, Bass BL (2002) RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. EMBO J 21:6025-6035
79. Vollmar W, Gloger J, Berger E, Kortenbruck G, Kohling R, Speckmann EJ, Musshoff U (2004) RNA editing (R/G site) and flip-flop splicing of the AMPA receptor subunit GluR2 in nervous tissue of epilepsy patients. Neurobiol Dis 15:371-379
80. Wagner RW, Nishikura K (1988) Cell cycle expression of RNA duplex unwindase activity in mammalian cells. Mol Cell Biol 8:770-777
81. Wang Q, Miyakoda M, Yang W, Khillan J, Stachura DL, Weiss MJ, Nishikura K (2004) Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem 279:4952-4961
82. Wong SK, Sato S, Lazinski DW (2003) Elevated activity of the large form of ADAR1 in vivo: very efficient RNA editing occurs in the cytoplasm. RNA 9:586-598
83. Zhang XJ, He PP, Li M, He CD, Yan KL, Cui Y, Yang S, Zhang KY, Gao M, Chen JJ, Li CR, Jin L, Chen HD, Xu SJ, Huang W (2004) Seven novel mutations of the ADAR gene in Chinese families and sporadic patients with dyschromatosis symmetrica hereditaria (DSH). Hum Mutat 23:629-630
84. Zhang Z, Carmichael GG (2001) The fate of dsRNA in the nucleus. A p54(nrb)-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell 106:465-475
Author information
Authors and Affiliations
Editor information
Rights and permissions
About this chapter
Cite this chapter
Hoopengardner, B., O’Connell, M.A., Reenan, R., Keegan, L.P. Adenosine to inosine RNA editing in animal cells. In: Grosjean, H. (eds) Fine-Tuning of RNA Functions by Modification and Editing. Topics in Current Genetics, vol 12. Springer, Berlin, Heidelberg. https://doi.org/10.1007/b106651
Download citation
DOI: https://doi.org/10.1007/b106651
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-24495-0
Online ISBN: 978-3-540-31454-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)