New insights into the biological role of mammalian ADARs; the RNA editing proteins

Biomolecules

Volumn 5, Issue 4, 2015, Pages 2338-2362

  Mannion, Niamh ^a   Arieti, Fabiana ^b   Gallo, Angela ^c   Keegan, Liam P ^b   O’Connell, Mary A ^b  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

^b MASARYK UNIVERSITY   (Czech Republic)

^c BAMBINO GESÙ CHILDREN S HOSPITAL   (Italy)

Author keywords

ADAR; Alu elements; Cancer; Deaminase domain; DsRBDs; RNA editing

Indexed keywords

ADENINE DEAMINASE ACTING ON RNA PROTEIN; ADENINE DEAMINASE ACTING ON RNA PROTEIN 1; ADENINE DEAMINASE ACTING ON RNA PROTEIN 2; ADENINE DEAMINASE ACTING ON RNA PROTEIN 3; ADENOSINE; AMPA RECEPTOR; DOUBLE STRANDED RNA; GLUTAMATE RECEPTOR 2; INOSINE; MESSENGER RNA; MICRORNA; PROTEIN; RNA BINDING PROTEIN; UNCLASSIFIED DRUG; ADENOSINE DEAMINASE;

AICARDI GOUTIERES SYNDROME; ALU SEQUENCE; AMYOTROPHIC LATERAL SCLEROSIS; CHRONIC MYELOID LEUKEMIA; DEAMINATION; DYSCHROMATOSIS SYMMETRICA HEREDITARIA; GENE MUTATION; GLIOBLASTOMA; HUMAN; INNATE IMMUNITY; LIVER CELL CARCINOMA; MAMMAL; NEUROLOGIC DISEASE; NONHUMAN; PROSTATE CANCER; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; RNA EDITING; SKIN DISEASE; ANIMAL; GENETICS; METABOLISM;

ADENOSINE DEAMINASE; ANIMALS; HUMANS; MAMMALS; RNA EDITING; RNA, DOUBLE-STRANDED; RNA-BINDING PROTEINS;

EID: 85012078057     PISSN: None     EISSN: 2218273X     Source Type: Journal    
DOI: 10.3390/biom5042338     Document Type: Review

References (141)

1. Machnicka, M.A.; Milanowska, K.; Osman Oglou, O.; Purta, E.; Kurkowska, M.; Olchowik, A.; Januszewski, W.; Kalinowski, S.; Dunin-Horkawicz, S.; Rother, K.M., et al. Modomics: A database of RNA modification pathways—2013 update. Nucleic Acids Res. 2013, 41, D262–D267.
2. Benne, R.; van den Burg, J.; Brakenhoff, J.; Sloof, P.; van Boom, J.H.; Tromp, M.C. Major transcript of the frameshifted coxii gene from trypanosome mitochondria contains four nucleotides that are not encoded in the DNA. Cell 1986, 46, 819–826.
3. Stuart, K.D.; Schnaufer, A.; Ernst, N.L.; Panigrahi, A.K. Complex management: RNA editing in trypanosomes. Trends Biochem. Sci. 2005, 30, 97–105.
4. Rebagliati, M.R.; Melton, D.A. Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity. Cell 1987, 48, 599–605.
5. Bass, B.L.; Weintraub, H. A developmental regulated activity that unwinds RNA duplexes. Cell 1987, 48, 607–613.
6. Bass, B.L.; Weintraub, H. An unwinding activity that covalently modifies its double-strand RNA substrate. Cell 1988, 55, 1089–1098.
7. Powell, L.M.; Wallis, S.C.; Pease, R.J.; Edwards, Y.H.; Knott, T.J.; Scott, J. A novel form of tissue-specific RNA processing produces apolipoprotein-48 in intestine. Cell 1987, 50, 831–840.
8. Gerber, A.P.; Keller, W. RNA editing by base deamination: More enzymes, more targets, new mysteries. Trends Biochem. Sci. 2001, 26, 376–384.
9. Hough, R.F.; Bass, B.L. Purification of the Xenopus laevis dsRNA adenosine deaminase. J. Biol. Chem. 1994, 269, 9933–9939.
10. Kim, U.; Garner, T.L.; Sanford, T.; Speicher, D.; Murray, J.M.; Nishikura, K. Purification and characterization of double-stranded RNA adenosine deaminase from bovine nuclear extracts. J. Biol. Chem. 1994, 269, 13480–13489.
11. O’Connell, M.A.; Keller, W. Purification and properties of double-stranded RNA-specific adenosine deaminase from calf thymus. Proc. Natl. Acad. Sci. USA 1994, 91, 10596–10600.
12. Maas, S.; Melcher, T.; Herb, A.; Seeburg, P.H.; Keller, W.; Krause, S.; Higuchi, M.; O’Connell, M.A. Structural requirements for RNA editing in glutamate receptor pre-mRNA by recombinant double-stranded RNA adenosine deaminase. J. Biol. Chem. 1996, 271, 12221–12226.
13. Melcher, T.; Maas, S.; Herb, A.; Sprengel, R.; Seeburg, P.H.; Higuchi, M. A mammalian RNA editing enzyme. Nature 1996, 379, 460–464.
14. O’Connell, M.A.; Gerber, A.; Keller, W. Purification of human double-stranded RNA-specific editase 1 (hred1) involved in editing of brain glutamate receptor b pre-mRNA. J. Biol. Chem. 1997, 272, 473–478.
15. Melcher, T.; Maas, S.; Herb, A.; Sprengel, R.; Higuchi, M.; Seeburg, P.H. Red2, a brain specific member of the RNA-specific adenosine deaminase family. J. Biol. Chem. 1996, 271, 31795–31798.
16. Schumacher, J.M.; Lee, K.; Edelhoff, S.; Braun, R.E. Distribution of tenr, an RNA-binding protein, in a lattice-like network within the spermatid nucleus in the mouse. Biol. Reprod. 1995, 52, 1274–1283.
17. Weier, H.U.; George, C.X.; Greulich, K.M.; Samuel, C.E. The interferon-inducible, double-stranded RNA-specific adenosine deaminase gene (dsrad) maps to human chromosome 1q21.1–21.2. Genomics 1995, 30, 372–375.
18. Wang, Y.; Zeng, Y.; Murray, J.M.; Nishikura, K. Genomic organization and chromosomal location of the human dsRNA adenosine deaminase gene: The enzyme for glutamate-activated ion channel RNA editing. J. Mol. Biol. 1995, 254, 184–195.
19. Patterson, J.B.; Samuel, C.E. 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. 1995, 15, 5376–5388.
20. Liu, Y.; George, C.X.; Patterson, J.B.; Samuel, C.E. 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. 1997, 272, 4419–4428.
21. George, C.X.; Samuel, C.E. 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 1999, 96, 4621–4626.
22. Kawakubo, K.; Samuel, C.E. Human RNA-specific adenosine deaminase (adar1) gene specifies transcripts that initiate from a constitutively active alternative promoter. Gene 2000, 258, 165–172.
23. George, C.X.; Wagner, M.V.; Samuel, C.E. 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. 2005, 280, 15020–15028.
24. Schwartz, T.; Lowenhaupt, K.; Kim, Y.G.; Li, L.; Brown, B.A., 2nd; Herbert, A.; Rich, A. Proteolytic dissection of zab, the z-DNA-binding domain of human adar1. J. Biol. Chem. 1999, 274, 2899–2906.
25. Wang, A.J.; Quigley, G.J.; Kolpak, F.J.; van der Marel, G.; van Boom, J.H.; Rich, A. Left-handed double helical DNA: Variations in the backbone conformation. Science 1981, 211, 171–176.
26. Herbert, A.; Alfken, J.; Kim, Y.G.; Mian, I.S.; Nishikura, K.; Rich, A. A z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. Proc. Natl. Acad. Sci. USA 1997, 94, 8421–8426.
27. Athanasiadis, A.; Placido, D.; Maas, S.; Brown, B.A., 2nd; Lowenhaupt, K.; Rich, A. The crystal structure of the zbeta domain of the RNA-editing enzyme adar1 reveals distinct conserved surfaces among z-domains. J. Mol. Biol. 2005, 351, 496–507.
28. Ng, S.K.; Weissbach, R.; Ronson, G.E.; Scadden, A.D. Proteins that contain a functional z-DNA-binding domain localize to cytoplasmic stress granules. Nucleic Acids Res. 2013, 41, 9786–9799.
29. Chen, C.X.; Cho, D.S.; Wang, Q.; Lai, F.; Carter, K.C.; Nishikura, K. A third member of the RNA-specific adenosine deaminase gene family, adar3, contains both single- and double-stranded RNA binding domains. RNA 2000, 6, 755–767.
30. Maas, S.; Gommans, W.M. Identification of a selective nuclear import signal in adenosine deaminases acting on RNA. Nucleic Acids Res. 2009, 37, 5822–5829.
31. St Johnston, D.; Brown, N.H.; Gall, J.G.; Jantsch, M. A conserved double-stranded RNA-binding domain. Proc. Natl. Acad. Sci. USA 1992, 89, 10979–10983.
32. Bycroft, M.; Grunert, S.; Murzin, A.G.; Proctor, M.; St Johnston, D. Nmr solution structure of a dsRNA binding domain from drosophila staufen protein reveals homology to the N-terminal domain of ribosomal protein S5. Embo J. 1995, 14, 3563–3571.
33. Kharrat, A.; Macias, M.J.; Gibson, T.J.; Nilges, M.; Pastore, A. Structure of the dsRNA binding domain of E. Coli RNAse III. Embo J. 1995, 14, 3572–3584.
34. Nanduri, S.; Carpick, B.W.; Yang, Y.; Williams, B.R.; Qin, J. Structure of the double-stranded RNA-binding domain of the protein kinase pkr reveals the molecular basis of its dsRNA-mediated activation. Embo J. 1998, 17, 5458–5465.
35. Ryter, J.M.; Schultz, S.C. Molecular basis of double-stranded RNA-protein interactions: Structure of a dsRNA-binding domain complexed with dsRNA. EMBO J. 1998, 17, 7505–7513.
36. Stefl, R.; Xu, M.; Skrisovska, L.; Emeson, R.B.; Allain, F.H. Structure and specific RNA binding of adar2 double-stranded RNA binding motifs. Structure 2006, 14, 345–355.
37. Stefl, R.; Oberstrass, F.C.; Hood, J.L.; Jourdan, M.; Zimmermann, M.; Skrisovska, L.; Maris, C.; Peng, L.; Hofr, C.; Emeson, R.B., et al. The solution structure of the adar2 dsrbm-RNA complex reveals a sequence-specific readout of the minor groove. Cell 2010, 143, 225–237.
38. Xu, M.; Wells, K.S.; Emeson, R.B. Substrate-dependent contribution of double-stranded RNA-binding motifs to adar2 function. Mol. Biol. Cell 2006, 17, 3211–3220.
39. Liu, Y.; Lei, M.; Samuel, C.E. Chimeric double-stranded RNA-specific adenosine deaminase adar1 proteins reveal functional selectivity of double-stranded RNA-binding domains from adar1 and protein kinase pkr. Proc. Natl. Acad. Sci. USA 2000, 97, 12541–12546.
40. Lai, F.; Drakas, R.; Nishikura, K. Mutagenic analysis of double-stranded RNA adenosine deaminase, a candidate enzyme for RNA editing of glutamate-gated ion channel transcripts. J. Biol. Chem. 1995, 270, 17098–17105.
41. Macbeth, M.R.; Schubert, H.L.; Vandemark, A.P.; Lingam, A.T.; Hill, C.P.; Bass, B.L. Inositol hexakisphosphate is bound in the adar2 core and required for RNA editing. Science 2005, 309, 1534–1539.
42. Betts, L.; Xiang, S.; Short, S.A.; Wolfenden, R.; Carter, C.W.,. Cytidine deaminase. The 2.3 a crystal structure of an enzyme: Transition-state analog complex. J. Mol. Biol. 1994, 235, 635–656.
43. Holden, L.G.; Prochnow, C.; Chang, Y.P.; Bransteitter, R.; Chelico, L.; Sen, U.; Stevens, R.C.; Goodman, M.F.; Chen, X.S. Crystal structure of the anti-viral apobec3g catalytic domain and functional implications. Nature 2008, 456, 121–124.
44. Kuratani, M.; Ishii, R.; Bessho, Y.; Fukunaga, R.; Sengoku, T.; Shirouzu, M.; Sekine, S.; Yokoyama, S. Crystal structure of tRNA adenosine deaminase (TADA) from aquifex aeolicus. J. Biol. Chem. 2005, 280, 16002–16008.
45. Prochnow, C.; Bransteitter, R.; Klein, M.G.; Goodman, M.F.; Chen, X.S. The apobec-2 crystal structure and functional implications for the deaminase aid. Nature 2007, 445, 447–451.
46. Verbsky, J.W.; Chang, S.C.; Wilson, M.P.; Mochizuki, Y.; Majerus, P.W. The pathway for the production of inositol hexakisphosphate in human cells. J. Biol. Chem. 2005, 280, 1911–1920.
47. Schmauss, C. Regulation of serotonin 2c receptor pre-mRNA editing by serotonin. Int. Rev. Neurobiol. 2005, 63, 83–100.
48. Polson, A.G.; Bass, B.L. Preferential selection of adenosines for modification by double-stranded RNA adenosine deaminase. EMBO J. 1994, 13, 5701–5711.
49. Mizrahi, R.A.; Phelps, K.J.; Ching, A.Y.; Beal, P.A. Nucleoside analog studies indicate mechanistic differences between RNA-editing adenosine deaminases. Nucleic Acids Res. 2012, 40, 9825–9835.
50. Stephens, O.M.; Yi-Brunozzi, H.Y.; Beal, P.A. Analysis of the RNA-editing reaction of adar2 with structural and fluorescent analogues of the glur-b r/g editing site. Biochemistry 2000, 39, 12243–12251.
51. Ward, D.C.; Reich, E.; Stryer, L. Fluorescence studies of nucleotides and polynucleotides. I. Formycin, 2-aminopurine riboside, 2,6-diaminopurine riboside, and their derivatives. J. Biol. Chem. 1969, 244, 1228–1237.
52. Hart, K.; Nystrom, B.; Ohman, M.; Nilsson, L. Molecular dynamics simulations and free energy calculations of base flipping in dsRNA. RNA 2005, 11, 609–618.
53. Yi-Brunozzi, H.Y.; Stephens, O.M.; Beal, P.A. Conformational changes that occur during an RNA editing adenosine deamination reaction. J. Biol. Chem. 2001, 276, 37827–37833.
54. Gallo, A.; Keegan, L.P.; Ring, G.M.; O’Connell, M.A. An adar that edits transcripts encoding ion channel subunits functions as a dimer. Embo J. 2003, 22, 3421–3430.
55. Poulsen, H.; Jorgensen, R.; Heding, A.; Nielsen, F.C.; Bonven, B.; Egebjerg, J. Dimerization of adar2 is mediated by the double-stranded RNA binding domain. RNA 2006, 12, 1350–1360.
56. Chilibeck, K.A.; Wu, T.; Liang, C.; Schellenberg, M.J.; Gesner, E.M.; Lynch, J.M.; MacMillan, A.M. Fret analysis of in vivo dimerization by RNA-editing enzymes. J. Biol. Chem. 2006, 281, 16530–16535.
57. Macbeth, M.R.; Lingam, A.T.; Bass, B.L. Evidence for auto-inhibition by the N terminus of hadar2 and activation by dsRNA binding. RNA 2004, 10, 1563–1571.
58. Valente, L.; Nishikura, K. RNA binding-independent dimerization of adenosine deaminases acting on RNA and dominant negative effects of nonfunctional subunits on dimer functions. J. Biol. Chem. 2007, 282, 16054–16061.
59. Nishikura, K.; Yoo, C.; Kim, U.; Murray, J.M.; Estes, P.A.; Cash, F.E.; Liebhaber, S.A. Substrate specificity of the dsRNA unwinding/modifying activity. EMBO J. 1991, 10, 3523–3532.
60. Athanasiadis, A.; Rich, A.; Maas, S. Widespread a-to-i RNA editing of alu-containing mRNAs in the human transcriptome. PLoS Biol. 2004, 2, e391.
61. Blow, M.; Futreal, P.A.; Wooster, R.; Stratton, M.R. A survey of RNA editing in human brain. Genome Res. 2004, 14, 2379–2387.
62. Levanon, E.Y.; Eisenberg, E.; Yelin, R.; Nemzer, S.; Hallegger, M.; Shemesh, R.; Fligelman, Z.Y.; Shoshan, A.; Pollock, S.R.; Sztybel, D., et al. Systematic identification of abundant a-to-i editing sites in the human transcriptome. Nat. Biotechnol. 2004, 22, 1001–1005.
63. Kim, D.D.; Kim, T.T.; Walsh, T.; Kobayashi, Y.; Matise, T.C.; Buyske, S.; Gabriel, A. Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res. 2004, 14, 1719–1725.
64. Peng, Z.; Cheng, Y.; Tan, B.C.; Kang, L.; Tian, Z.; Zhu, Y.; Zhang, W.; Liang, Y.; Hu, X.; Tan, X., et al. Comprehensive analysis of RNA-seq data reveals extensive RNA editing in a human transcriptome. Nat. Biotechnol. 2012, 30, 253–260.
65. Neeman, Y.; Levanon, E.Y.; Jantsch, M.F.; Eisenberg, E. RNA editing level in the mouse is determined by the genomic repeat repertoire. RNA 2006, 12, 1802–1809.
66. Mannion, N.M.; Greenwood, S.M.; Young, R.; Cox, S.; Brindle, J.; Read, D.; Nellaker, C.; Vesely, C.; Ponting, C.P.; McLaughlin, P.J., et al. The RNA-editing enzyme adar1 controls innate immune responses to RNA. Cell Rep. 2014, 9, 1482–1494.
67. Vitali, P.; Scadden, A.D. Double-stranded RNAs containing multiple iu pairs are sufficient to suppress interferon induction and apoptosis. Nat. Struct. Mol. Biol. 2010, 17, 1043–1050.
68. Paro, S.; Li, X.; O’Connell, M.A.; Keegan, L.P. Regulation and functions of adar in Drosophila. Curr. Top. Microbiol. Immunol. 2012, 353, 221–236.
69. Garrett, S.; Rosenthal, J.J. RNA editing underlies temperature adaptation in K+ channels from polar octopuses. Science 2012, 335, 848–851.
70. Sommer, B.; Kohler, M.; Sprengel, R.; Seeburg, P.H. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 1991, 67, 11–19.
71. Higuchi, M.; Maas, S.; Single, F.N.; Hartner, J.; Rozov, A.; Burnashev, N.; Feldmeyer, D.; Sprengel, R.; Seeburg, P.H. Point mutation in an ampa receptor gene rescues lethality in mice deficient in the RNA-editing enzyme adar2. Nature 2000, 406, 78–81.
72. Hollmann, M.; Hartley, M.; Heinemann, S. Ca2+ permeability of ka-ampa-gated glutamate receptor channels depends on subunit composition. Science 1991, 252, 851–853.
73. Verdoorn, T.A.; Burnashev, N.; Monyer, H.; Seeburg, P.H.; Sakmann, B. Structural determinants of ion flow through recombinant glutamate receptor channels. Science 1991, 252, 1715–1718.
74. Higuchi, M.; Single, F.N.; Kohler, M.; Sommer, B.; Sprengel, R.; Seeburg, P.H. RNA editing of ampa receptor subunit glur-b: A base-paired intron-exon structure determines position and efficiency. Cell 1993, 75, 1361–1370.
75. Greger, I.H.; Khatri, L.; Ziff, E.B. RNA editing at arg607 controls ampa receptor exit from the endoplasmic reticulum. Neuron 2002, 34, 759–772.
76. Greger, I.H.; Khatri, L.; Kong, X.; Ziff, E.B. Ampa receptor tetramerization is mediated by q/r editing. Neuron 2003, 40, 763–774.
77. Brusa, R.; Zimmermann, F.; Koh, D.-S.; Feldmeyer, D.; Gass, P.; Seeburg, P.H.; Sprengel, R. Early-onset epilepsy and postnatal lethality associated with editing-deficient glur-b allele in mice. Science 1995, 270, 1677–1680.
78. Feldmeyer, D.; Kask, K.; Brusa, R.; Kornau, H.C.; Kolhekar, R.; Rozov, A.; Burnashev, N.; Jensen, V.; Hvalby, O.; Sprengel, R., et al. Neurological dysfunctions in mice expressing different levels of the q/r site-unedited ampar subunit glur-b. Nat. Neurosci. 1999, 2, 57–64.
79. Lomeli, H.; Mosbacher, J.; Melcher, T.; Höger, T.; Geiger, J.R.; Kuner, T.; Monyer, H.; Higuchi, M.; Bach, A.; Seeburg, P.H. Control of kinetic properties of ampa receptor channels by nuclear RNA editing. Science 1994, 266, 1709–1713.
80. Köhler, M.; Burnashev, N.; Sakmann, B.; Seeburg, P.H. Determinants of Ca2+ permeability in both tm1 and tm2 of high affinity kainate receptor channels: Diversity by RNA editing. Neuron 1993, 10, 491–500.
81. Burns, C.M.; Chu, H.; Rueter, S.M.; Hutchinson, L.K.; Canton, H.; Sanders-Bush, E.; Emeson, R.B. Regulation of serotonin-2c receptor g-protein coupling by RNA editing. Nature 1997, 387, 303–308.
82. Bhalla, T.; Rosenthal, J.J.; Holmgren, M.; Reenan, R. Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nat. Struct. Mol. Biol. 2004, 11, 950–956.
83. Ohlson, J.; Pedersen, J.S.; Haussler, D.; Ohman, M. Editing modifies the gaba(a) receptor subunit alpha3. RNA 2007, 13, 698–703.
84. Daniel, C.; Wahlstedt, H.; Ohlson, J.; Bjork, P.; Ohman, M. Adenosine-to-inosine RNA editing affects trafficking of the gamma-aminobutyric acid type a (gaba(a)) receptor. J. Biol. Chem. 2011, 286, 2031–2040.
85. Bazak, L.; Haviv, A.; Barak, M.; Jacob-Hirsch, J.; Deng, P.; Zhang, R.; Isaacs, F.J.; Rechavi, G.; Li, J.B.; Eisenberg, E., et al. A-to-i RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res. 2013, doi:10.1101/gr.164749.113.
86. Levanon, E.Y.; Hallegger, M.; Kinar, Y.; Shemesh, R.; Djinovic-Carugo, K.; Rechavi, G.; Jantsch, M.F.; Eisenberg, E. Evolutionarily conserved human targets of adenosine to inosine RNA editing. Nucleic Acids Res. 2005, 33, 1162–1168.
87. Batzer, M.A.; Deininger, P.L. Alu repeats and human genomic diversity. Nat. Rev. Genet 2002, 3, 370–379.
88. Korenberg, J.R.; Rykowski, M.C. Human genome organization: Alu, lines, and the molecular structure of metaphase chromosome bands. Cell 1988, 53, 391–400.
89. Deininger, P.L.; Batzer, M.A. Alu repeats and human disease. Mol. Genet Metab. 1999, 67, 183–193.
90. Barak, M.; Levanon, E.Y.; Eisenberg, E.; Paz, N.; Rechavi, G.; Church, G.M.; Mehr, R. Evidence for large diversity in the human transcriptome created by alu RNA editing. Nucleic Acids Res. 2009, 37, 6905–6915.
91. Ohman, M. A-to-i editing challenger or ally to the microRNA process. Biochimie 2007, 89, 1171–1176.
92. Yang, W.; Chendrimada, T.P.; Wang, Q.; Higuchi, M.; Seeburg, P.H.; Shiekhattar, R.; Nishikura, K. Modulation of microRNA processing and expression through RNA editing by adar deaminases. Nat. Struct. Mol. Biol. 2006, 13, 13–21.
93. Kawahara, Y.; Zinshteyn, B.; Chendrimada, T.P.; Shiekhattar, R.; Nishikura, K. RNA editing of the microRNA-151 precursor blocks cleavage by the dicer-trbp complex. EMBO Rep. 2007, 8, 763–769.
94. Iizasa, H.; Wulff, B.E.; Alla, N.R.; Maragkakis, M.; Megraw, M.; Hatzigeorgiou, A.; Iwakiri, D.; Takada, K.; Wiedmer, A.; Showe, L., et al. Editing of epstein-barr virus-encoded bart6 microRNAs controls their dicer targeting and consequently affects viral latency. J. Biol. Chem. 2010, 285, 33358–33370.
95. Kawahara, Y.; Zinshteyn, B.; Sethupathy, P.; Iizasa, H.; Hatzigeorgiou, A.G.; Nishikura, K. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 2007, 315, 1137–1140.
96. Heale, B.S.; Keegan, L.P.; McGurk, L.; Michlewski, G.; Brindle, J.; Stanton, C.M.; Caceres, J.F.; O’Connell, M.A. Editing independent effects of adars on the miRNA/siRNA pathways. Embo J. 2009, 28, 3145–3156.
97. Ota, H.; Sakurai, M.; Gupta, R.; Valente, L.; Wulff, B.E.; Ariyoshi, K.; Iizasa, H.; Davuluri, R.V.; Nishikura, K. Adar1 forms a complex with dicer to promote microRNA processing and RNA-induced gene silencing. Cell 2013, 153, 575–589.
98. Brubaker, S.W.; Bonham, K.S.; Zanoni, I.; Kagan, J.C. Innate immune pattern recognition: A cell biological perspective. Annu. Rev. Immunol. 2015, 33, 257–290.
99. Yoneyama, M.; Kikuchi, M.; Natsukawa, T.; Shinobu, N.; Imaizumi, T.; Miyagishi, M.; Taira, K.; Akira, S.; Fujita, T. The RNA helicase rig-i has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 2004, 5, 730–737.
100. Kang, D.C.; Gopalkrishnan, R.V.; Wu, Q.; Jankowsky, E.; Pyle, A.M.; Fisher, P.B. Mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent atpase activity and melanoma growth-suppressive properties. Proc. Natl. Acad. Sci. USA 2002, 99, 637–642.
101. Sato, M.; Suemori, H.; Hata, N.; Asagiri, M.; Ogasawara, K.; Nakao, K.; Nakaya, T.; Katsuki, M.; Noguchi, S.; Tanaka, N., et al. Distinct and essential roles of transcription factors irf-3 and irf-7 in response to viruses for ifn-alpha/beta gene induction. Immunity 2000, 13, 539–548.
102. Cattaneo, R.; Schmid, A.; Eschle, D.; Baczko, K.; ter Meulen, V.; Billeter, M.A. Biased hypermuation and other genetic changes in defective measles viruses in human brain infections. Cell 1988, 55, 255–265.
103. Bass, B.L.; Weintraub, H.; Cattaneo, R.; Billeter, M.A. Biased hypermutation of viral RNA genomes could be due to unwinding/modification of double-stranded RNA. Cell 1989, 56, doi:10.1016/0092-8674(89)90234-1.
104. Taylor, D.R.; Puig, M.; Darnell, M.E.; Mihalik, K.; Feinstone, S.M. New antiviral pathway that mediates hepatitis c virus replicon interferon sensitivity through adar1. J. Virol. 2005, 79, 6291–6298.
105. Ward, S.V.; George, C.X.; Welch, M.J.; Liou, L.Y.; Hahm, B.; Lewicki, H.; de la Torre, J.C.; Samuel, C.E.; Oldstone, M.B. RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. Proc. Natl. Acad. Sci. USA 2011, 108, 331–336.
106. Samuel, C.E. Adenosine deaminases acting on RNA (adars) are both antiviral and proviral. Virology 2011, 411, 180–193.
107. Hartner, J.C.; Schmittwolf, C.; Kispert, A.; Muller, A.M.; Higuchi, M.; Seeburg, P.H. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme adar1. J. Biol. Chem. 2004, 279, 4894–4902.
108. Hartner, J.C.; Walkley, C.R.; Lu, J.; Orkin, S.H. Adar1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat. Immunol. 2009, 10, 109–115.
109. Wang, Q.; Miyakoda, M.; Yang, W.; Khillan, J.; Stachura, D.L.; Weiss, M.J.; Nishikura, K. Stress-induced apoptosis associated with null mutation of adar1 RNA editing deaminase gene. J. Biol. Chem. 2004, 279, 4952–4961.
110. Aicardi, J.; Goutieres, F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann. Neurol. 1984, 15, 49–54.
111. Rice, G.; Patrick, T.; Parmar, R.; Taylor, C.F.; Aeby, A.; Aicardi, J.; Artuch, R.; Montalto, S.A.; Bacino, C.A.; Barroso, B., et al. Clinical and molecular phenotype of aicardi-goutieres syndrome. Am. J. Hum. Genet 2007, 81, 713–725.
112. Crow, Y.J.; Rehwinkel, J. Aicardi-goutieres syndrome and related phenotypes: Linking nucleic acid metabolism with autoimmunity. Hum. Mol. Genet 2009, 18, R130–R136.
113. Rice, G.I.; Kasher, P.R.; Forte, G.M.; Mannion, N.M.; Greenwood, S.M.; Szynkiewicz, M.; Dickerson, J.E.; Bhaskar, S.S.; Zampini, M.; Briggs, T.A., et al. Mutations in adar1 cause aicardi-goutieres syndrome associated with a type I interferon signature. Nat. Genet. 2012, 44, 1243–1248.
114. Livingston, J.H.; Lin, J.P.; Dale, R.C.; Gill, D.; Brogan, P.; Munnich, A.; Kurian, M.A.; Gonzalez-Martinez, V.; de Goede, C.G.; Falconer, A., et al. A type i interferon signature identifies bilateral striatal necrosis due to mutations in adar1. J. Med. Genet 2014, 51, 76–82.
115. Crow, Y.J. Aicardi-goutieres syndrome. Handb. Clin. Neurol. 2013, 113, 1629–1635.
116. Suzuki, N.; Suzuki, T.; Inagaki, K.; Ito, S.; Kono, M.; Fukai, K.; Takama, H.; Sato, K.; Ishikawa, O.; Abe, M., et al. Mutation analysis of the adar1 gene in dyschromatosis symmetrica hereditaria and genetic differentiation from both dyschromatosis universalis hereditaria and acropigmentatio reticularis. J. Investig. Dermatol. 2005, 124, 1186–1192.
117. Hou, Y.; Chen, J.; Gao, M.; Zhou, F.; Du, W.; Shen, Y.; Yang, S.; Zhang, X.J. Five novel mutations of RNA-specific adenosine deaminase gene with dyschromatosis symmetrica hereditaria. Acta Derm.-Venereol. 2007, 87, 18–21.
118. Oyama, M.; Shimizu, H.; Ohata, Y.; Tajima, S.; Nishikawa, T. Dyschromatosis symmetrica hereditaria (reticulate acropigmentation of dohi): Report of a japanese family with the condition and a literature review of 185 cases. Br. J. Dermatol. 1999, 140, 491–496.
119. Miyamura, Y.; Suzuki, T.; Kono, M.; Inagaki, K.; Ito, S.; Suzuki, N.; Tomita, Y. Mutations of the RNA-specific adenosine deaminase gene (dsrad) are involved in dyschromatosis symmetrica hereditaria. Am. J. Hum. Genet. 2003, 73, 693–699.
120. Rosen, D.R.; Siddique, T.; Patterson, D.; Figlewicz, D.A.; Sapp, P.; Hentati, A.; Donaldson, D.; Goto, J.; O’Regan, J.P.; Deng, H.X., et al. Mutations in cu/zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993, 362, 59–62.
121. Arai, T.; Hasegawa, M.; Akiyama, H.; Ikeda, K.; Nonaka, T.; Mori, H.; Mann, D.; Tsuchiya, K.; Yoshida, M.; Hashizume, Y., et al. Tdp-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 2006, 351, 602–611.
122. Kawahara, Y.; Ito, K.; Sun, H.; Aizawa, H.; Kanazawa, I.; Kwak, S. Glutamate receptors: RNA editing and death of motor neurons. Nature 2004, 427, 801.
123. Hideyama, T.; Yamashita, T.; Suzuki, T.; Tsuji, S.; Higuchi, M.; Seeburg, P.H.; Takahashi, R.; Misawa, H.; Kwak, S. Induced loss of adar2 engenders slow death of motor neurons from q/r site-unedited glur2. J. Neurosci. 2010, 30, 11917–11925.
124. Yamashita, T.; Chai, H.L.; Teramoto, S.; Tsuji, S.; Shimazaki, K.; Muramatsu, S.; Kwak, S. Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous aav9-adar2 delivery to motor neurons. EMBO Mol. Med. 2013, 5, 1710–1719.
125. Paz, N.; Levanon, E.Y.; Amariglio, N.; Heimberger, A.B.; Ram, Z.; Constantini, S.; Barbash, Z.S.; Adamsky, K.; Safran, M.; Hirschberg, A., et al. Altered adenosine-to-inosine RNA editing in human cancer. Genome Res. 2007, 17, 1586–1595.
126. Gallo, A.; Locatelli, F. Adars: Allies or enemies? The importance of a-to-i RNA editing in human disease: From cancer to hiv-1. Biol. Rev. 2012, 87, 95–110.
127. Salameh, A.; Lee, A.K.; Cardo-Vila, M.; Nunes, D.N.; Efstathiou, E.; Staquicini, F.I.; Dobroff, A.S.; Marchio, S.; Navone, N.M.; Hosoya, H., et al. Prune2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA pca3. Proc. Natl. Acad. Sci. USA 2015, 112, 8403–8408.
128. Chen, L.; Li, Y.; Lin, C.H.; Chan, T.H.; Chow, R.K.; Song, Y.; Liu, M.; Yuan, Y.F.; Fu, L.; Kong, K.L., et al. Recoding RNA editing of azin1 predisposes to hepatocellular carcinoma. Nat. Med. 2013, 19, 209–216.
129. Gallo, A. RNA editing enters the limelight in cancer. Nat. Med. 2013, 19, 130–131.
130. Chan, T.H.; Lin, C.H.; Qi, L.; Fei, J.; Li, Y.; Yong, K.J.; Liu, M.; Song, Y.; Chow, R.K.; Ng, V.H., et al. A disrupted RNA editing balance mediated by adars (adenosine deaminases that act on RNA) in human hepatocellular carcinoma. Gut 2014, 63, 832–843.
131. Liu, W.H.; Chen, C.H.; Yeh, K.H.; Li, C.L.; Wu, Y.J.; Chen, D.S.; Chen, P.J.; Yeh, S.H. Adar2-mediated editing of mir-214 and mir-122 precursor and antisense RNA transcripts in liver cancers. PLoS ONE 2013, 8, e81922.
132. Jiang, Q.; Crews, L.A.; Barrett, C.L.; Chun, H.J.; Court, A.C.; Isquith, J.M.; Zipeto, M.A.; Goff, D.J.; Minden, M.; Sadarangani, A., et al. Adar1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc. Natl. Acad. Sci. USA 2013, 110, 1041–1046.
133. Steinman, R.A.; Yang, Q.; Gasparetto, M.; Robinson, L.J.; Liu, X.; Lenzner, D.E.; Hou, J.; Smith, C.; Wang, Q. Deletion of the RNA-editing enzyme adar1 causes regression of established chronic myelogenous leukemia in mice. Int. J. Cancer 2013, 132, 1741–1750.
134. Cenci, C.; Barzotti, R.; Galeano, F.; Corbelli, S.; Rota, R.; Massimi, L.; di Rocco, C.; O’Connell, M.A.; Gallo, A. Down-regulation of RNA editing in pediatric astrocytomas: Adar2 editing activity inhibits cell migration and proliferation. J. Biol. Chem. 2008, 283, 7251–7260.
135. Galeano, F.; Rossetti, C.; Tomaselli, S.; Cifaldi, L.; Lezzerini, M.; Pezzullo, M.; Boldrini, R.; Massimi, L.; di Rocco, C.M.; Locatelli, F., et al. Adar2-editing activity inhibits glioblastoma growth through the modulation of the cdc14b/skp2/p21/p27 axis. Oncogene 2013, 32, 998–1009.
136. Ishiuchi, S.; Tsuzuki, K.; Yoshida, Y.; Yamada, N.; Hagimura, N.; Okado, H.; Miwa, A.; Kurihara, H.; Nakazato, Y.; Tamura, M., et al. Blockage of Ca(2+)-permeable ampa receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat. Med. 2002, 8, 971–978.
137. Maas, S.; Patt, S.; Schrey, M.; Rich, A. Underediting of glutamate receptor glur-b mRNA in malignant gliomas. Proc. Natl. Acad. Sci. USA 2001, 98, 14687–14692.
138. Alon, S.; Mor, E.; Vigneault, F.; Church, G.M.; Locatelli, F.; Galeano, F.; Gallo, A.; Shomron, N.; Eisenberg, E. Systematic identification of edited microRNAs in the human brain. Genome Res. 2012, 22, 1533–1540.
139. Tomaselli, S.; Galeano, F.; Alon, S.; Raho, S.; Galardi, S.; Polito, V.A.; Presutti, C.; Vincenti, S.; Eisenberg, E.; Locatelli, F., et al. Modulation of microRNA editing, expression and processing by adar2 deaminase in glioblastoma. Genome Biol. 2015, 16, doi:10.1186/s13059-014-0575-z.
140. Choudhury, Y.; Tay, F.C.; Lam, D.H.; Sandanaraj, E.; Tang, C.; Ang, B.T.; Wang, S. Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. J. Clin. Investig. 2012, 122, 4059–4076.
141. Ishiuchi, S.; Yoshida, Y.; Sugawara, K.; Aihara, M.; Ohtani, T.; Watanabe, T.; Saito, N.; Tsuzuki, K.; Okado, H.; Miwa, A., et al. Ca2+-permeable ampa receptors regulate growth of human glioblastoma via akt activation. J. Neurosci. 2007, 27, 7987–8001.