Skip to main content
Log in

Activity Regulation of Adenosine Deaminases Acting on RNA (ADARs)

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Adenosine deaminases acting on RNA (ADARs) are the enzymes that are responsible for the A to I RNA editing process in mammals, which is an important mechanism that increases molecular diversity. A to I RNA editing consists of an enzymatic conversion of specific adenosine in pre-mRNA, leading to alteration of the properties of both the RNA itself and the translated protein. Currently, the importance of this phenomenon is increasingly recognized as it affects a diverse set of cellular pathways. ADAR function within the cell, especially in the neurons, is to diversify the features of a limited set of unique transcripts, mostly neurotransmitter receptors; however, a growing set of target is going to be discovered, increasing the importance of the RNA editing event in the proper physiology of the cell. Despite the functional relevance of these enzymes, there is a gap of knowledge in the mechanisms that regulate ADAR activity and consequently about the modulation of RNA editing process. This review summarizes ongoing investigations of ADAR regulation at the transcriptional, post-transcriptional and post-translational level and addresses new hypothetical mechanisms that are capable of modulating ADAR activity, including subcellular localization, dimerization and interaction with trans-acting factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gerber AP, Keller W (2001) RNA editing by base deamination: more enzymes, more targets, new mysteries. Trends Biochem Sci 26(6):376–384

    Article  PubMed  CAS  Google Scholar 

  2. Bass BL (2002) RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 71:817–846

    Article  PubMed  CAS  Google Scholar 

  3. Maas S, Rich A, Nishikura K (2003) A-to-I RNA editing: recent news and residual mysteries. J Biol Chem 278(3):1391–1394

    Article  PubMed  CAS  Google Scholar 

  4. Bass BL, Nishikura K, Keller W, Seeburg PH, Emeson RB, O’Connell MA, Samuel CE, Herbert A (1997) A standardized nomenclature for adenosine deaminases that act on RNA. RNA 3(9):947–949

    PubMed  CAS  Google Scholar 

  5. Sommer B, Kohler M, Sprengel R, Seeburg PH (1991) RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67(1):11–19

    Article  PubMed  CAS  Google Scholar 

  6. Higuchi M, Single FN, Kohler 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(7):1361–1370

    Article  PubMed  CAS  Google Scholar 

  7. Lomeli H, Mosbacher J, Melcher T, Hoger 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(5191):1709–1713

    Article  PubMed  CAS  Google Scholar 

  8. Stefl R, Xu M, Skrisovska L, Emeson RB, Allain FH (2006) Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. Structure 14(2):345–355. doi:10.1016/j.str.2005.11.013

    Article  PubMed  CAS  Google Scholar 

  9. Basilio C, Wahba AJ, Lengyel P, Speyer JF, Ochoa S (1962) Synthetic polynucleotides and the amino acid code. V Proc Natl Acad Sci U S A 48:613–616

    Article  CAS  Google Scholar 

  10. Rosenberg BR, Hamilton CE, Mwangi MM, Dewell S, Papavasiliou FN (2011) Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3′ UTRs. Nat Struct Mol Biol

  11. Rueter SM, Dawson TR, Emeson RB (1999) Regulation of alternative splicing by RNA editing. Nature 399(6731):75–80

    Article  PubMed  CAS  Google Scholar 

  12. Nishikura K (2010) Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem 79:321–349

    Article  PubMed  CAS  Google Scholar 

  13. Wu T, Zhao Y, Hao Z, Zhao H, Wang W (2009) Involvement of PU.1 in mouse ADAR-1 gene transcription induced by high-dose esiRNA. Int J Biol Macromol 45(2):157–162

    Article  PubMed  CAS  Google Scholar 

  14. Dupuis DE, Maas S (2010) MiRNA editing. Methods Mol Biol 667:267–279

    Article  PubMed  CAS  Google Scholar 

  15. George CX, Gan Z, Liu Y, Samuel CE (2011) Adenosine deaminases acting on RNA, RNA editing, and interferon action. J Interferon Cytokine Res 31(1):99–117

    Article  PubMed  CAS  Google Scholar 

  16. Habig JW, Dale T, Bass BL (2007) miRNA editing—we should have inosine this coming. Mol Cell 25(6):792–793

    Article  PubMed  CAS  Google Scholar 

  17. Heale BS, Keegan LP, O’Connell MA (2009) ADARs have effects beyond RNA editing. Cell Cycle 8(24):4011–4012

    Article  PubMed  CAS  Google Scholar 

  18. Yang W, Chendrimada TP, Wang Q, Higuchi M, Seeburg PH, Shiekhattar R, Nishikura K (2006) Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol 13(1):13–21

    Article  PubMed  CAS  Google Scholar 

  19. Barbon A, Barlati S (2000) Genomic organization, proposed alternative splicing mechanisms, and RNA editing structure of GRIK1. Cytogenet Cell Genet 88(3–4):236–239

    Article  PubMed  CAS  Google Scholar 

  20. 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 U S A 93(5):1875–1880

    Article  PubMed  CAS  Google Scholar 

  21. Kohler M, Burnashev N, Sakmann B, Seeburg PH (1993) Determinants of Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing. Neuron 10(3):491–500

    Article  PubMed  CAS  Google Scholar 

  22. 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(6630):303–308

    Article  PubMed  CAS  Google Scholar 

  23. Niswender CM, Sanders-Bush E, Emeson RB (1998) Identification and characterization of RNA editing events within the 5-HT2C receptor. Ann N Y Acad Sci 861:38–48

    Article  PubMed  CAS  Google Scholar 

  24. Bhalla T, Rosenthal JJ, Holmgren M, Reenan R (2004) Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nat Struct Mol Biol 11(10):950–956

    Article  PubMed  CAS  Google Scholar 

  25. Ohlson J, Pedersen JS, Haussler D, Ohman M (2007) Editing modifies the GABA(A) receptor subunit alpha3. RNA 13(5):698–703

    Article  PubMed  CAS  Google Scholar 

  26. Rula EY, Lagrange AH, Jacobs MM, Hu N, Macdonald RL, Emeson RB (2008) Developmental modulation of GABA(A) receptor function by RNA editing. J Neurosci 28(24):6196–6201

    Article  PubMed  CAS  Google Scholar 

  27. Kim U, Garner TL, Sanford T, Speicher D, Murray JM, Nishikura K (1994) Purification and characterization of double-stranded RNA adenosine deaminase from bovine nuclear extracts. J Biol Chem 269(18):13480–13489

    PubMed  CAS  Google Scholar 

  28. Kim U, Wang Y, Sanford T, Zeng Y, Nishikura K (1994) Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. Proc Natl Acad Sci U S A 91(24):11457–11461

    Article  PubMed  CAS  Google Scholar 

  29. 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(3):1389–1397

    PubMed  Google Scholar 

  30. Gerber A, O’Connell MA, Keller W (1997) Two forms of human double-stranded RNA-specific editase 1 (hRED1) generated by the insertion of an Alu cassette. RNA 3(5):453–463

    PubMed  CAS  Google Scholar 

  31. Lai F, Chen CX, Carter KC, Nishikura K (1997) Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases. Mol Cell Biol 17(5):2413–2424

    PubMed  CAS  Google Scholar 

  32. Melcher T, Maas S, Herb A, Sprengel R, Seeburg PH, Higuchi M (1996) A mammalian RNA editing enzyme. Nature 379(6564):460–464

    Article  PubMed  CAS  Google Scholar 

  33. 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(5):755–767

    Article  PubMed  CAS  Google Scholar 

  34. Melcher T, Maas S, Herb A, Sprengel R, Higuchi M, Seeburg PH (1996) RED2, a brain-specific member of the RNA-specific adenosine deaminase family. J Biol Chem 271(50):31795–31798

    Article  PubMed  CAS  Google Scholar 

  35. Maas S, Kawahara Y, Tamburro KM, Nishikura K (2006) A-to-I RNA editing and human disease. RNA Biol 3(1):1–9

    Article  PubMed  CAS  Google Scholar 

  36. Hideyama T, Yamashita T, Nishimoto Y, Suzuki T, Kwak S (2010) Novel etiological and therapeutic strategies for neurodiseases: RNA editing enzyme abnormality in sporadic amyotrophic lateral sclerosis. J Pharmacol Sci 113(1):9–13

    Article  PubMed  CAS  Google Scholar 

  37. Hideyama T, Yamashita T, Suzuki T, Tsuji S, Higuchi M, Seeburg PH, Takahashi R, Misawa H, Kwak S (2010) Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. J Neurosci 30(36):11917–11925

    Article  PubMed  CAS  Google Scholar 

  38. Kwak S, Kawahara Y (2005) Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. J Mol Med 83(2):110–120

    Article  PubMed  CAS  Google Scholar 

  39. Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C (2002) Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34(3):349–356

    Article  PubMed  CAS  Google Scholar 

  40. Iwamoto K, Kato T (2003) RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders. Neurosci Lett 346(3):169–172

    Article  PubMed  CAS  Google Scholar 

  41. Iwamoto K, Nakatani N, Bundo M, Yoshikawa T, Kato T (2005) Altered RNA editing of serotonin 2C receptor in a rat model of depression. Neurosci Res 53(1):69–76

    Article  PubMed  CAS  Google Scholar 

  42. 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(5):478–491

    Article  PubMed  CAS  Google Scholar 

  43. Simmons M, Meador-Woodruff JH, Sodhi MS (2010) Increased cortical expression of an RNA editing enzyme occurs in major depressive suicide victims. Neuroreport 21(15):993–997

    PubMed  CAS  Google Scholar 

  44. Kortenbruck G, Berger E, Speckmann EJ, Musshoff U (2001) RNA editing at the Q/R site for the glutamate receptor subunits GluR2, GluR5, and GluR6 in hippocampus and temporal cortex from epileptic patients. Neurobiol Dis 8(3):459–468

    Article  PubMed  CAS  Google Scholar 

  45. 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(2):371–379

    Article  PubMed  CAS  Google Scholar 

  46. 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(3):693–699

    Article  PubMed  CAS  Google Scholar 

  47. 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(6):629–630

    Article  PubMed  CAS  Google Scholar 

  48. Patterson JB, Samuel CE (1995) Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol Cell Biol 15(10):5376–5388

    PubMed  CAS  Google Scholar 

  49. Brown BA 2nd, Lowenhaupt K, Wilbert CM, Hanlon EB, Rich A (2000) The zalpha domain of the editing enzyme dsRNA adenosine deaminase binds left-handed Z-RNA as well as Z-DNA. Proc Natl Acad Sci U S A 97(25):13532–13536

    Article  PubMed  CAS  Google Scholar 

  50. Herbert A, Lowenhaupt K, Spitzner J, Rich A (1995) Chicken double-stranded RNA adenosine deaminase has apparent specificity for Z-DNA. Proc Natl Acad Sci U S A 92(16):7550–7554

    Article  PubMed  CAS  Google Scholar 

  51. Herbert A, Alfken J, Kim YG, Mian IS, Nishikura K, Rich A (1997) A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. Proc Natl Acad Sci U S A 94(16):8421–8426

    Article  PubMed  CAS  Google Scholar 

  52. Jacobs MM, Fogg RL, Emeson RB, Stanwood GD (2009) ADAR1 and ADAR2 expression and editing activity during forebrain development. Dev Neurosci 31(3):223–237

    Article  PubMed  CAS  Google Scholar 

  53. Paupard MC, O’Connell MA, Gerber AP, Zukin RS (2000) Patterns of developmental expression of the RNA editing enzyme rADAR2. Neuroscience 95(3):869–879

    Article  CAS  Google Scholar 

  54. Wahlstedt H, Daniel C, Enstero M, Ohman M (2009) Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res 19(6):978–986

    Article  PubMed  CAS  Google Scholar 

  55. Barbon A, Fumagalli F, Caracciolo L, Madaschi L, Lesma E, Mora C, Carelli S, Slotkin TA, Racagni G, Di Giulio AM, Gorio A, Barlati S (2010) Acute spinal cord injury persistently reduces R/G RNA editing of AMPA receptors. J Neurochem 114(2):397–407

    Article  PubMed  CAS  Google Scholar 

  56. Maas S, Patt S, Schrey M, Rich A (2001) Underediting of glutamate receptor GluR-B mRNA in malignant gliomas. Proc Natl Acad Sci U S A 98(25):14687–14692

    Article  PubMed  CAS  Google Scholar 

  57. Barbon A, Orlandi C, La Via L, Caracciolo L, Tardito D, Musazzi L, Mallei A, Gennarelli M, Racagni G, Popoli M, Barlati S (2011) Antidepressant treatments change 5-HT2C receptor mRNA expression in rat prefrontal/frontal cortex and hippocampus. Neuropsychobiology 63(3):160–168

    Article  PubMed  CAS  Google Scholar 

  58. Barbon A, Popoli M, La Via L, Moraschi S, Vallini I, Tardito D, Tiraboschi E, Musazzi L, Giambelli R, Gennarelli M, Racagni G, Barlati S (2006) Regulation of editing and expression of glutamate alpha-amino-propionic-acid (AMPA)/kainate receptors by antidepressant drugs. Biol Psychiatry 59(8):713–720

    Article  PubMed  CAS  Google Scholar 

  59. Englander MT, Dulawa SC, Bhansali P, Schmauss C (2005) How stress and fluoxetine modulate serotonin 2C receptor pre-mRNA editing. J Neurosci 25(3):648–651

    Article  PubMed  CAS  Google Scholar 

  60. Li B, Zhang S, Zhang H, Hertz L (2011) Fluoxetine affects GluK2 editing, glutamate-evoked Ca(2+) influx and extracellular signal-regulated kinase phosphorylation in mouse astrocytes. J Psychiatry Neurosci 36(1):100094

    Google Scholar 

  61. Liu Y, George CX, Patterson JB, Samuel CE (1997) Functionally distinct double-stranded RNA-binding domains associated with alternative splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase. J Biol Chem 272(7):4419–4428

    Article  PubMed  CAS  Google Scholar 

  62. Wang Y, Zeng Y, Murray JM, Nishikura K (1995) Genomic organization and chromosomal location of the human dsRNA adenosine deaminase gene: the enzyme for glutamate-activated ion channel RNA editing. J Mol Biol 254(2):184–195

    Article  PubMed  CAS  Google Scholar 

  63. 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 U S A 96(8):4621–4626

    Article  PubMed  CAS  Google Scholar 

  64. Kawakubo K, Samuel CE (2000) Human RNA-specific adenosine deaminase (ADAR1) gene specifies transcripts that initiate from a constitutively active alternative promoter. Gene 258(1–2):165–172

    Article  PubMed  CAS  Google Scholar 

  65. Lykke-Andersen S, Pinol-Roma S, Kjems J (2007) Alternative splicing of the ADAR1 transcript in a region that functions either as a 5′-UTR or an ORF. RNA 13(10):1732–1744

    Article  PubMed  CAS  Google Scholar 

  66. George CX, Wagner MV, Samuel CE (2005) Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing. J Biol Chem 280(15):15020–15028

    Article  PubMed  CAS  Google Scholar 

  67. Shtrichman R, Heithoff DM, Mahan MJ, Samuel CE (2002) Tissue selectivity of interferon-stimulated gene expression in mice infected with Dam(+) versus Dam(−) Salmonella enterica serovar Typhimurium strains. Infect Immun 70(10):5579–5588

    Article  PubMed  CAS  Google Scholar 

  68. Liu Y, Samuel CE (1999) Editing of glutamate receptor subunit B pre-mRNA by splice-site variants of interferon-inducible double-stranded RNA-specific adenosine deaminase ADAR1. J Biol Chem 274(8):5070–5077

    Article  PubMed  CAS  Google Scholar 

  69. Liu Y, Emeson RB, Samuel CE (1999) Serotonin-2C receptor pre-mRNA editing in rat brain and in vitro by splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase ADAR1. J Biol Chem 274(26):18351–18358

    Article  PubMed  CAS  Google Scholar 

  70. Schmauss C, Zimnisky R, Mehta M, Shapiro LP (2010) The roles of phospholipase C activation and alternative ADAR1 and ADAR2 pre-mRNA splicing in modulating serotonin 2C-receptor editing in vivo. RNA 16(9):1779–1785

    Article  PubMed  CAS  Google Scholar 

  71. Yang JH, Nie Y, Zhao Q, Su Y, Pypaert M, Su H, Rabinovici R (2003) Intracellular localization of differentially regulated RNA-specific adenosine deaminase isoforms in inflammation. J Biol Chem 278(46):45833–45842. doi:10.1074/jbc.M308612200

    Article  PubMed  CAS  Google Scholar 

  72. Maas S, Gommans WM (2009) Novel exon of mammalian ADAR2 extends open reading frame. PLoS One 4(1):e4225

    Article  PubMed  CAS  Google Scholar 

  73. Slavov D, Gardiner K (2002) Phylogenetic comparison of the pre-mRNA adenosine deaminase ADAR2 genes and transcripts: conservation and diversity in editing site sequence and alternative splicing patterns. Gene 299(1–2):83–94

    Article  PubMed  CAS  Google Scholar 

  74. Singh M, Kesterson RA, Jacobs MM, Joers JM, Gore JC, Emeson RB (2007) Hyperphagia-mediated obesity in transgenic mice misexpressing the RNA-editing enzyme ADAR2. J Biol Chem 282(31):22448–22459

    Article  PubMed  CAS  Google Scholar 

  75. Feng Y, Sansam CL, Singh M, Emeson RB (2006) Altered RNA editing in mice lacking ADAR2 autoregulation. Mol Cell Biol 26(2):480–488

    Article  PubMed  CAS  Google Scholar 

  76. Tan BZ, Huang H, Lam R, Soong TW (2009) Dynamic regulation of RNA editing of ion channels and receptors in the mammalian nervous system. Mol Brain 2(1):13

    Article  PubMed  CAS  Google Scholar 

  77. Dawson TR, Sansam CL, Emeson RB (2004) Structure and sequence determinants required for the RNA editing of ADAR2 substrates. J Biol Chem 279(6):4941–4951

    Article  PubMed  CAS  Google Scholar 

  78. Villard L, Tassone F, Haymowicz M, Welborn R, Gardiner K (1997) Map location, genomic organization and expression patterns of the human RED1 RNA editase. Somat Cell Mol Genet 23(2):135–145

    Article  PubMed  CAS  Google Scholar 

  79. Kawahara Y, Ito K, Ito M, Tsuji S, Kwak S (2005) Novel splice variants of human ADAR2 mRNA: skipping of the exon encoding the dsRNA-binding domains, and multiple C-terminal splice sites. Gene 363:193–201

    Article  PubMed  CAS  Google Scholar 

  80. Peng PL, Zhong X, Tu W, Soundarapandian MM, Molner P, Zhu D, Lau L, Liu S, Liu F, Lu Y (2006) ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 49(5):719–733. doi:10.1016/j.neuron.2006.01.025

    Article  PubMed  CAS  Google Scholar 

  81. 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(6):4894–4902

    Article  PubMed  CAS  Google Scholar 

  82. Wang Q, Khillan J, Gadue P, Nishikura K (2000) Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290(5497):1765–1768

    Article  PubMed  CAS  Google Scholar 

  83. 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(6791):78–81

    Article  PubMed  CAS  Google Scholar 

  84. Keegan LP, Gallo A, O’Connell MA (2000) Development. Survival is impossible without an editor. Science 290(5497):1707–1709

    Article  PubMed  CAS  Google Scholar 

  85. Horsch M, Seeburg PH, Adler T, Aguilar-Pimentel JA, Becker L, Calzada-Wack J, Garrett L, Gotz A, Hans W, Higuchi M, Holter SM, Naton B, Prehn C, Puk O, Racz I, Rathkolb B, Rozman J, Schrewe A, Adamski J, Busch DH, Esposito I, Graw J, Ivandic B, Klingenspor M, Klopstock T, Mempel M, Ollert M, Schulz H, Wolf E, Wurst W, Zimmer A, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Beckers J (2011) Requirement of the RNA editing enzyme ADAR2 for normal physiology in mice. J Biol Chem

  86. Hang PN, Tohda M, Matsumoto K (2008) Developmental changes in expression and self-editing of adenosine deaminase type 2 pre-mRNA and mRNA in rat brain and cultured cortical neurons. Neurosci Res 61(4):398–403

    Article  PubMed  CAS  Google Scholar 

  87. Kawahara Y, Ito K, Sun H, Ito M, Kanazawa I, Kwak S (2004) Regulation of glutamate receptor RNA editing and ADAR mRNA expression in developing human normal and Down’s syndrome brains. Brain Res Dev Brain Res 148(1):151–155

    Article  PubMed  CAS  Google Scholar 

  88. Paschen W, Dux E, Djuricic B (1994) Developmental changes in the extent of RNA editing of glutamate receptor subunit GluR5 in rat brain. Neurosci Lett 174(1):109–112

    Article  PubMed  CAS  Google Scholar 

  89. Wang Q, O’Brien PJ, Chen CX, Cho DS, Murray JM, Nishikura K (2000) Altered G protein-coupling functions of RNA editing isoform and splicing variant serotonin 2C receptors. J Neurochem 74(3):1290–1300

    Article  PubMed  CAS  Google Scholar 

  90. Melcher T, Maas S, Higuchi M, Keller W, Seeburg PH (1995) Editing of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR-B pre-mRNA in vitro reveals site-selective adenosine to inosine conversion. J Biol Chem 270(15):8566–8570

    Article  PubMed  CAS  Google Scholar 

  91. Lai F, Chen CX, Lee VM, Nishikura K (1997) Dramatic increase of the RNA editing for glutamate receptor subunits during terminal differentiation of clonal human neurons. J Neurochem 69(1):43–52

    Article  PubMed  CAS  Google Scholar 

  92. Eckmann CR, Neunteufl A, Pfaffstetter L, Jantsch MF (2001) The human but not the Xenopus RNA-editing enzyme ADAR1 has an atypical nuclear localization signal and displays the characteristics of a shuttling protein. Mol Biol Cell 12(7):1911–1924

    PubMed  CAS  Google Scholar 

  93. Strehblow A, Hallegger M, Jantsch MF (2002) Nucleocytoplasmic distribution of human RNA-editing enzyme ADAR1 is modulated by double-stranded RNA-binding domains, a leucine-rich export signal, and a putative dimerization domain. Mol Biol Cell 13(11):3822–3835

    Article  PubMed  CAS  Google Scholar 

  94. Maas S, Gommans WM (2009) Identification of a selective nuclear import signal in adenosine deaminases acting on RNA. Nucleic Acids Res 37(17):5822–5829

    Article  PubMed  CAS  Google Scholar 

  95. 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(Pt 9):1805–1818

    Article  PubMed  CAS  Google Scholar 

  96. Sansam CL, Wells KS, Emeson RB (2003) Modulation of RNA editing by functional nucleolar sequestration of ADAR2. Proc Natl Acad Sci U S A 100(24):14018–14023

    Article  PubMed  CAS  Google Scholar 

  97. Hough RF, Bass BL (1997) Analysis of Xenopus dsRNA adenosine deaminase cDNAs reveals similarities to DNA methyltransferases. RNA 3(4):356–370

    PubMed  CAS  Google Scholar 

  98. 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(22):7862–7871

    Article  PubMed  CAS  Google Scholar 

  99. Fritz J, Strehblow A, Taschner A, Schopoff S, Pasierbek P, Jantsch MF (2009) RNA-regulated interaction of transportin-1 and exportin-5 with the double-stranded RNA-binding domain regulates nucleocytoplasmic shuttling of ADAR1. Mol Cell Biol 29(6):1487–1497

    Article  PubMed  CAS  Google Scholar 

  100. 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(5):586–598

    Article  PubMed  CAS  Google Scholar 

  101. Samuel CE (2011) Adenosine deaminases acting on RNA (ADARs) are both antiviral and proviral. Virology 411(2):180–193

    Article  PubMed  CAS  Google Scholar 

  102. Vitali P, Basyuk E, Le Meur E, Bertrand E, Muscatelli F, Cavaille J, Huttenhofer A (2005) ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited by C/D small nucleolar RNAs. J Cell Biol 169(5):745–753

    Article  PubMed  CAS  Google Scholar 

  103. Leung AK, Andersen JS, Mann M, Lamond AI (2003) Bioinformatic analysis of the nucleolus. Biochem J 376(Pt 3):553–569

    Article  PubMed  CAS  Google Scholar 

  104. Desterro JM, Keegan LP, Jaffray E, Hay RT, O’Connell MA, Carmo-Fonseca M (2005) SUMO-1 modification alters ADAR1 editing activity. Mol Biol Cell 16(11):5115–5126

    Article  PubMed  CAS  Google Scholar 

  105. Chilibeck KA, Wu T, Liang C, Schellenberg MJ, Gesner EM, Lynch JM, MacMillan AM (2006) FRET analysis of in vivo dimerization by RNA-editing enzymes. J Biol Chem 281(24):16530–16535

    Article  PubMed  CAS  Google Scholar 

  106. 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(19):17093–17102

    Article  PubMed  CAS  Google Scholar 

  107. 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(40):37624–37629

    Article  PubMed  CAS  Google Scholar 

  108. 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(13):3421–3430

    Article  PubMed  CAS  Google Scholar 

  109. Cenci C, Barzotti R, Galeano F, Corbelli S, Rota R, Massimi L, Di Rocco C, O’Connell MA, Gallo A (2008) Down-regulation of RNA editing in pediatric astrocytomas: ADAR2 editing activity inhibits cell migration and proliferation. J Biol Chem 283(11):7251–7260

    Article  PubMed  CAS  Google Scholar 

  110. 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(5):687–697

    Article  PubMed  CAS  Google Scholar 

  111. Poulsen H, Jorgensen R, Heding A, Nielsen FC, Bonven B, Egebjerg J (2006) Dimerization of ADAR2 is mediated by the double-stranded RNA binding domain. RNA 12(7):1350–1360

    Article  PubMed  CAS  Google Scholar 

  112. Valente L, Nishikura K (2007) RNA binding-independent dimerization of adenosine deaminases acting on RNA and dominant negative effects of nonfunctional subunits on dimer functions. J Biol Chem 282(22):16054–16061

    Article  PubMed  CAS  Google Scholar 

  113. Gareau JR, Lima CD (2010) The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 11(12):861–871

    Article  PubMed  CAS  Google Scholar 

  114. Hay RT (2005) SUMO: a history of modification. Mol Cell 18(1):1–12

    Article  PubMed  CAS  Google Scholar 

  115. Carmo-Fonseca M, Mendes-Soares L, Campos I (2000) To be or not to be in the nucleolus. Nat Cell Biol 2(6):E107–E112

    Article  PubMed  CAS  Google Scholar 

  116. Macbeth MR, Schubert HL, Vandemark AP, Lingam AT, Hill CP, Bass BL (2005) Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309(5740):1534–1539

    Article  PubMed  CAS  Google Scholar 

  117. Shears SB (2001) Assessing the omnipotence of inositol hexakisphosphate. Cell Signal 13(3):151–158

    Article  PubMed  CAS  Google Scholar 

  118. York JD, Odom AR, Murphy R, Ives EB, Wente SR (1999) A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science 285(5424):96–100

    Article  PubMed  CAS  Google Scholar 

  119. Hoy M, Efanov AM, Bertorello AM, Zaitsev SV, Olsen HL, Bokvist K, Leibiger B, Leibiger IB, Zwiller J, Berggren PO, Gromada J (2002) Inositol hexakisphosphate promotes dynamin I-mediated endocytosis. Proc Natl Acad Sci U S A 99(10):6773–6777

    Article  PubMed  CAS  Google Scholar 

  120. Steger DJ, Haswell ES, Miller AL, Wente SR, O’Shea EK (2003) Regulation of chromatin remodeling by inositol polyphosphates. Science 299(5603):114–116

    Article  PubMed  CAS  Google Scholar 

  121. Sasakawa N, Sharif M, Hanley MR (1995) Metabolism and biological activities of inositol pentakisphosphate and inositol hexakisphosphate. Biochem Pharmacol 50(2):137–146

    Article  PubMed  CAS  Google Scholar 

  122. Valastro B, Girard M, Gagne J, Martin F, Parent AT, Baudry M, Massicotte G (2001) Inositol hexakisphosphate-mediated regulation of glutamate receptors in rat brain sections. Hippocampus 11(6):673–682

    Article  PubMed  CAS  Google Scholar 

  123. Fitzgerald LW, Iyer G, Conklin DS, Krause CM, Marshall A, Patterson JP, Tran DP, Jonak GJ, Hartig PR (1999) Messenger RNA editing of the human serotonin 5-HT2C receptor. Neuropsychopharmacology 21(2 Suppl):82S–90S

    PubMed  CAS  Google Scholar 

  124. 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(14):9472–9478

    Article  PubMed  CAS  Google Scholar 

  125. Mahajan SS, Thai KH, Chen K, Ziff E (2011) Exposure of neurons to excitotoxic levels of glutamate induces cleavage of the RNS editing enzyme, adenosine deaminase acting on RNA 2, and loss of GluR2 editing. Neuroscience

  126. Burnett G, Kennedy EP (1954) The enzymatic phosphorylation of proteins. J Biol Chem 211(2):969–980

    PubMed  CAS  Google Scholar 

  127. Hornbeck PV, Chabra I, Kornhauser JM, Skrzypek E, Zhang B (2004) PhosphoSite: a bioinformatics resource dedicated to physiological protein phosphorylation. Proteomics 4(6):1551–1561

    Article  PubMed  CAS  Google Scholar 

  128. Dinkel H, Chica C, Via A, Gould CM, Jensen LJ, Gibson TJ, Diella F (2011) Phospho.ELM: a database of phosphorylation sites—update 2011. Nucleic Acids Res 39(Database issue):D261–D267

    Article  PubMed  CAS  Google Scholar 

  129. Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villen J, Li J, Cohn MA, Cantley LC, Gygi SP (2004) Large-scale characterization of HeLa cell nuclear phosphoproteins. Proc Natl Acad Sci U S A 101(33):12130–12135

    Article  PubMed  CAS  Google Scholar 

  130. Beausoleil SA, Villen J, Gerber SA, Rush J, Gygi SP (2006) A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol 24(10):1285–1292

    Article  PubMed  CAS  Google Scholar 

  131. Cantin GT, Yi W, Lu B, Park SK, Xu T, Lee JD, Yates JR 3rd (2008) Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis. J Proteome Res 7(3):1346–1351

    Article  PubMed  CAS  Google Scholar 

  132. Chen RQ, Yang QK, Lu BW, Yi W, Cantin G, Chen YL, Fearns C, Yates JR 3rd, Lee JD (2009) CDC25B mediates rapamycin-induced oncogenic responses in cancer cells. Cancer Res 69(6):2663–2668

    Article  PubMed  CAS  Google Scholar 

  133. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M (2008) Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell 31(3):438–448

    Article  PubMed  CAS  Google Scholar 

  134. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP (2008) A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A 105(31):10762–10767

    Article  PubMed  CAS  Google Scholar 

  135. Huttlin EL, Jedrychowski MP, Elias JE, Goswami T, Rad R, Beausoleil SA, Villen J, Haas W, Sowa ME, Gygi SP (2010) A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143(7):1174–1189

    Article  PubMed  CAS  Google Scholar 

  136. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK (2009) Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein–protein interactions. Sci Signal 2(84):ra46

    Article  PubMed  Google Scholar 

  137. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127(3):635–648

    Article  PubMed  CAS  Google Scholar 

  138. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M (2010) Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal 3(104):ra3

    Article  PubMed  CAS  Google Scholar 

  139. Raijmakers R, Kraiczek K, de Jong AP, Mohammed S, Heck AJ (2010) Exploring the human leukocyte phosphoproteome using a microfluidic reversed-phase-TiO2-reversed-phase high-performance liquid chromatography phosphochip coupled to a quadrupole time-of-flight mass spectrometer. Anal Chem 82(3):824–832

    Article  PubMed  CAS  Google Scholar 

  140. Tsai CF, Wang YT, Chen YR, Lai CY, Lin PY, Pan KT, Chen JY, Khoo KH, Chen YJ (2008) Immobilized metal affinity chromatography revisited: pH/acid control toward high selectivity in phosphoproteomics. J Proteome Res 7(9):4058–4069

    Article  PubMed  CAS  Google Scholar 

  141. Van Hoof D, Munoz J, Braam SR, Pinkse MW, Linding R, Heck AJ, Mummery CL, Krijgsveld J (2009) Phosphorylation dynamics during early differentiation of human embryonic stem cells. Cell Stem Cell 5(2):214–226

    Article  PubMed  CAS  Google Scholar 

  142. Gnad F, Gunawardena J, Mann M (2011) PHOSIDA 2011: the posttranslational modification database. Nucleic Acids Res 39(Database issue):D253–D260

    Article  PubMed  CAS  Google Scholar 

  143. Gnad F, Ren S, Cox J, Olsen JV, Macek B, Oroshi M, Mann M (2007) PHOSIDA (phosphorylation site database): management, structural and evolutionary investigation, and prediction of phosphosites. Genome Biol 8(11):R250

    Article  PubMed  CAS  Google Scholar 

  144. Oppermann FS, Gnad F, Olsen JV, Hornberger R, Greff Z, Keri G, Mann M, Daub H (2009) Large-scale proteomics analysis of the human kinome. Mol Cell Proteomics 8(7):1751–1764

    Article  PubMed  CAS  Google Scholar 

  145. Hashimoto Y, Akita H, Hibino M, Kohri K, Nakanishi M (2002) Identification and characterization of Nek6 protein kinase, a potential human homolog of NIMA histone H3 kinase. Biochem Biophys Res Commun 293(2):753–758

    Article  PubMed  CAS  Google Scholar 

  146. Yin MJ, Shao L, Voehringer D, Smeal T, Jallal B (2003) The serine/threonine kinase Nek6 is required for cell cycle progression through mitosis. J Biol Chem 278(52):52454–52460

    Article  PubMed  CAS  Google Scholar 

  147. Marcucci R, Brindle J, Paro S, Casadio A, Hempel S, Morrice N, Bisso A, Keegan LP, Del Sal G, O’Connell MA (2011) Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. Embo J

  148. Cavaille J, Buiting K, Kiefmann M, Lalande M, Brannan CI, Horsthemke B, Bachellerie JP, Brosius J, Huttenhofer A (2000) Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc Natl Acad Sci U S A 97(26):14311–14316

    Article  PubMed  CAS  Google Scholar 

  149. Doe CM, Relkovic D, Garfield AS, Dalley JW, Theobald DE, Humby T, Wilkinson LS, Isles AR (2009) Loss of the imprinted snoRNA MBII-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour. Hum Mol Genet 18(12):2140–2148

    Article  PubMed  CAS  Google Scholar 

  150. Werry TD, Loiacono R, Sexton PM, Christopoulos A (2008) RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function. Pharmacol Ther 119(1):7–23

    Article  PubMed  CAS  Google Scholar 

  151. Lei M, Liu Y, Samuel CE (1998) Adenovirus VAI RNA antagonizes the RNA-editing activity of the ADAR adenosine deaminase. Virology 245(2):188–196

    Article  PubMed  CAS  Google Scholar 

  152. Macbeth MR, Lingam AT, Bass BL (2004) Evidence for auto-inhibition by the N terminus of hADAR2 and activation by dsRNA binding. RNA 10(10):1563–1571

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This work was supported by Grants from MIUR (PRIN 2009BRMW4W) and by NEDD project Regione Lombardia (ID 14546-A SAL7). We would like to thank the “Nature Publishing Group Language Editing” for revising the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sergio Barlati.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Orlandi, C., Barbon, A. & Barlati, S. Activity Regulation of Adenosine Deaminases Acting on RNA (ADARs). Mol Neurobiol 45, 61–75 (2012). https://doi.org/10.1007/s12035-011-8220-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-011-8220-2

Keywords

Navigation