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ncRNA Editing: Functional Characterization and Computational Resources

  • Giovanni NigitaEmail author
  • Gioacchino P. Marceca
  • Luisa Tomasello
  • Rosario Distefano
  • Federica Calore
  • Dario Veneziano
  • Giulia Romano
  • Serge Patrick Nana-Sinkam
  • Mario Acunzo
  • Carlo M. Croce
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1912)

Abstract

Noncoding RNAs (ncRNAs) have received much attention due to their central role in gene expression and translational regulation as well as due to their involvement in several biological processes and disease development. Small noncoding RNAs (sncRNAs), such as microRNAs and piwiRNAs, have been thoroughly investigated and functionally characterized. Long noncoding RNAs (lncRNAs), known to play an important role in chromatin-interacting transcription regulation, posttranscriptional regulation, cell-to-cell signaling, and protein regulation, are also being investigated to further elucidate their functional roles.

Next-generation sequencing (NGS) technologies have greatly aided in characterizing the ncRNAome. Moreover, the coupling of NGS technology together with bioinformatics tools has been essential to the genome-wide detection of RNA modifications in ncRNAs. RNA editing, a common human co-transcriptional and posttranscriptional modification, is a dynamic biological phenomenon able to alter the sequence and the structure of primary transcripts (both coding and noncoding RNAs) during the maturation process, consequently influencing the biogenesis, as well as the function, of ncRNAs. In particular, the dysregulation of the RNA editing machineries have been associated with the onset of human diseases.

In this chapter we discuss the potential functions of ncRNA editing and describe the knowledge base and bioinformatics resources available to investigate such phenomenon.

Key words

A-to-I RNA editing ncRNA editing 3′UTR Introns miRNA lncRNA Bioinformatics NGS 

References

  1. 1.
    Watson JD, Crick FH (1953) Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171:737–738CrossRefGoogle Scholar
  2. 2.
    Brachet J (1942) La localization des acides pentosenucleiques dans les tissues animaux et les oufs d’Amphibiens en voie de developpement. Archs Biol 53:207–257Google Scholar
  3. 3.
    Caspersson T (1947) The relations between nucleic acid and protein synthesis. Symp Soc Exp Biol 1:127–151Google Scholar
  4. 4.
    Palade GE, Siekevitz P (1956) Liver microsomes; an integrated morphological and biochemical study. J Biophys Biochem Cytol 2:171–200CrossRefGoogle Scholar
  5. 5.
    Zamecnik PC, Keller EB, Littlefield JW et al (1956) Mechanism of incorporation of labeled amino acids into protein. J Cell Physiol Suppl 47:81–101CrossRefGoogle Scholar
  6. 6.
    Hoagland MB, Stephenson ML, Scott JF et al (1958) A soluble ribonucleic acid intermediate in protein synthesis. J Biol Chem 231:241–257PubMedGoogle Scholar
  7. 7.
    Crick FH (1958) On protein synthesis. Symp Soc Exp Biol 12:138–163PubMedGoogle Scholar
  8. 8.
    Brenner S, Jacob F, Meselson M (1961) An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature 190:576–581CrossRefGoogle Scholar
  9. 9.
    Gros F, Hiatt H, Gilbert W et al (1961) Unstable ribonucleic acid revealed by pulse labelling of Escherichia Coli. Nature 190:581–585.  https://doi.org/10.1038/190581a0 CrossRefPubMedGoogle Scholar
  10. 10.
    Nirenberg MW, Matthaei JH (1961) The dependence of cell-free protein synthesis in E. coli upon naturally occurring or synthetic polyribonucleotides. Proc Natl Acad Sci U S A 47:1588–1602CrossRefGoogle Scholar
  11. 11.
    Chow LT, Roberts JM, Lewis JB, Broker TR (1977) A map of cytoplasmic RNA transcripts from lytic adenovirus type 2, determined by electron microscopy of RNA:DNA hybrids. Cell 11:819–836.  https://doi.org/10.1016/0092-8674(77)90294-X CrossRefPubMedGoogle Scholar
  12. 12.
    Berk AJ, Sharp PA (1977) Sizing and mapping of early adenovirus mRNAs by gel electrophoresis of S1 endonuclease-digested hybrids. Cell 12:721–732CrossRefGoogle Scholar
  13. 13.
    Berget SM, Sharp PA (1977) A spliced sequence at the 5′-terminus of adenovirus late mRNA. Brookhaven Symp Biol 29:332–344Google Scholar
  14. 14.
    Busch H, Reddy R, Rothblum L, Choi YC (1982) SnRNAs, SnRNPs, and RNA processing. Annu Rev Biochem 51:617–654.  https://doi.org/10.1146/annurev.bi.51.070182.003153 CrossRefPubMedGoogle Scholar
  15. 15.
    Krainer AR, Maniatis T (1985) Multiple factors including the small nuclear ribonucleoproteins U1 and U2 are necessary for pre-mRNA splicing in vitro. Cell 42:725–736CrossRefGoogle Scholar
  16. 16.
    Konarska MM, Sharp PA (1986) Electrophoretic separation of complexes involved in the splicing of precursors to mRNAs. Cell 46:845–855CrossRefGoogle Scholar
  17. 17.
    Eliceiri GL (1999) Small nucleolar RNAs. Cell Mol Life Sci 56:22–31CrossRefGoogle Scholar
  18. 18.
    Brannan CI, Dees EC, Ingram RS, Tilghman SM (1990) The product of the H19 gene may function as an RNA. Mol Cell Biol 10:28–36CrossRefGoogle Scholar
  19. 19.
    Bartolomei MS, Zemel S, Tilghman SM (1991) Parental imprinting of the mouse H19 gene. Nature 351:153–155.  https://doi.org/10.1038/351153a0 CrossRefPubMedGoogle Scholar
  20. 20.
    Borsani G, Tonlorenzi R, Simmler MC et al (1991) Characterization of a murine gene expressed from the inactive X chromosome. Nature 351:325–329.  https://doi.org/10.1038/351325a0 CrossRefPubMedGoogle Scholar
  21. 21.
    Kelley RL, Kuroda MI (2000) Noncoding RNA genes in dosage compensation and imprinting. Cell 103:9–12CrossRefGoogle Scholar
  22. 22.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854CrossRefGoogle Scholar
  23. 23.
    Reinhart BJ, Slack FJ, Basson M et al (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906.  https://doi.org/10.1038/35002607 CrossRefGoogle Scholar
  24. 24.
    Siomi H, Siomi MC (2009) On the road to reading the RNA-interference code. Nature 457:396–404.  https://doi.org/10.1038/nature07754 CrossRefPubMedGoogle Scholar
  25. 25.
    Thompson DM, Parker R (2009) The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae. J Cell Biol 185:43–50.  https://doi.org/10.1083/jcb.200811119 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Garcia-Silva MR, Cabrera-Cabrera F, Güida MC, Cayota A (2012) Hints of tRNA-derived small RNAs role in RNA silencing mechanisms. Genes (Basel) 3:603–614.  https://doi.org/10.3390/genes3040603 CrossRefGoogle Scholar
  27. 27.
    Martens-Uzunova ES, Olvedy M, Jenster G (2013) Beyond microRNA—novel RNAs derived from small non-coding RNA and their implication in cancer. Cancer Lett 340:201–211.  https://doi.org/10.1016/j.canlet.2012.11.058 CrossRefPubMedGoogle Scholar
  28. 28.
    Kumar P, Anaya J, Mudunuri SB, Dutta A (2014) Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets. BMC Biol 12:78.  https://doi.org/10.1186/PREACCEPT-5867533061403216 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hoogsteen K (1963) The crystal and molecular structure of a hydrogen-bonded complex between 1-methylthymine and 9-methyladenine. Acta Crystallogr 16:907–916.  https://doi.org/10.1107/S0365110X63002437 CrossRefGoogle Scholar
  30. 30.
    Crick FH (1966) Codon--anticodon pairing: the wobble hypothesis. J Mol Biol 19:548–555CrossRefGoogle Scholar
  31. 31.
    Varani G, McClain WH (2000) The G x U wobble base pair. A fundamental building block of RNA structure crucial to RNA function in diverse biological systems. EMBO Rep 1:18–23.  https://doi.org/10.1093/embo-reports/kvd001 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Leontis NB, Westhof E (2001) Geometric nomenclature and classification of RNA base pairs. RNA 7:499–512CrossRefGoogle Scholar
  33. 33.
    Bjork GR, Ericson JU, Gustafsson CED et al (1987) Transfer RNA modification. Annu Rev Biochem 56:263–285.  https://doi.org/10.1146/annurev.bi.56.070187.001403 CrossRefPubMedGoogle Scholar
  34. 34.
    Maden BE (1990) The numerous modified nucleotides in eukaryotic ribosomal RNA. Prog Nucleic Acid Res Mol Biol 39:241–303CrossRefGoogle Scholar
  35. 35.
    Phizicky EM, Hopper AK (2010) tRNA biology charges to the front. Genes Dev 24:1832–1860.  https://doi.org/10.1101/gad.1956510 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Sharma S, Lafontaine DLJ (2015) “View from a bridge”: a new perspective on eukaryotic rRNA base modification. Trends Biochem Sci 40:560–575.  https://doi.org/10.1016/j.tibs.2015.07.008 CrossRefPubMedGoogle Scholar
  37. 37.
    Liu M, Douthwaite S (2002) Methylation at nucleotide G745 or G748 in 23S rRNA distinguishes Gram-negative from Gram-positive bacteria. Mol Microbiol 44:195–204CrossRefGoogle Scholar
  38. 38.
    Pan T (2018) Modifications and functional genomics of human transfer RNA. Cell Res 28:395–404.  https://doi.org/10.1038/s41422-018-0013-y CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Rozenski J, Crain PF, McCloskey JA (1999) The RNA modification database: 1999 update. Nucleic Acids Res 27:196–197CrossRefGoogle Scholar
  40. 40.
    Limbach PA, Crain PF, McCloskey JA (1994) Summary: the modified nucleosides of RNA. Nucleic Acids Res 22:2183–2196.  https://doi.org/10.1093/nar/22.12.2183 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Cantara WA, Crain PF, Rozenski J et al (2011) The RNA modification database, RNAMDB: 2011 update. Nucleic Acids Res 39:D195–D201.  https://doi.org/10.1093/nar/gkq1028 CrossRefPubMedGoogle Scholar
  42. 42.
    Boccaletto P, Machnicka MA, Purta E et al (2018) MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res 46:D303–D307.  https://doi.org/10.1093/nar/gkx1030 CrossRefPubMedGoogle Scholar
  43. 43.
    Kellner S, Burhenne J, Helm M (2010) Detection of RNA modifications. RNA Biol 7:237–247.  https://doi.org/10.4161/rna.7.2.11468 CrossRefPubMedGoogle Scholar
  44. 44.
    Helm M, Motorin Y (2017) Detecting RNA modifications in the epitranscriptome: predict and validate. Nat Rev Genet 18:275–291.  https://doi.org/10.1038/nrg.2016.169 CrossRefPubMedGoogle Scholar
  45. 45.
    Davis FF, Allen FW (1957) Ribonucleic acids from yeast which contain a fifth nucleotide. J Biol Chem 227:907–915PubMedGoogle Scholar
  46. 46.
    Fu Y, Dominissini D, Rechavi G, He C (2014) Gene expression regulation mediated through reversible m6A RNA methylation. Nat Rev Genet 15:293–306.  https://doi.org/10.1038/nrg3724 CrossRefPubMedGoogle Scholar
  47. 47.
    Jia G, Fu Y, He C (2013) Reversible RNA adenosine methylation in biological regulation. Trends Genet 29:108–115.  https://doi.org/10.1016/j.tig.2012.11.003 CrossRefPubMedGoogle Scholar
  48. 48.
    Liu F, Clark W, Luo G et al (2016) ALKBH1-mediated tRNA demethylation regulates translation. Cell 167:816–828.e16.  https://doi.org/10.1016/j.cell.2016.09.038 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Frye M, Nishikura K, Jaffrey SR et al (2016) A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol 17:83–96.  https://doi.org/10.1038/nrm.2015.4 CrossRefGoogle Scholar
  50. 50.
    Gait MJ, Moore MJ, Zimmermann RA (1998) Incorporation of modified nucleotides into RNA for studies on RNA structure, function and intermolecular interactions. In: Modification and editing of RNA. American Society of Microbiology, Washington, DC, pp 59–84Google Scholar
  51. 51.
    Vermeulen A, McCallum SA, Pardi A (2005) Comparison of the global structure and dynamics of native and unmodified tRNAval. Biochemistry 44:6024–6033.  https://doi.org/10.1021/bi0473399 CrossRefPubMedGoogle Scholar
  52. 52.
    Davis DR (1998) Biophysical and conformational properties of modified nucleosides in RNA (nuclear magnetic resonance studies). In: Modification and editing of RNA. American Society of Microbiology, Washington, DC, pp 85–102Google Scholar
  53. 53.
    Helm M (2006) Post-transcriptional nucleotide modification and alternative folding of RNA. Nucleic Acids Res 34:721–733.  https://doi.org/10.1093/nar/gkj471 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Motorin Y, Helm M (2010) tRNA stabilization by modified nucleotides. Biochemistry 49:4934–4944.  https://doi.org/10.1021/bi100408z CrossRefPubMedGoogle Scholar
  55. 55.
    Price DH, Gray MW (1998) Editing of tRNA. In: Modification and editing of RNA. American Society of Microbiology, Washington, DC, pp 289–305Google Scholar
  56. 56.
    Li L, Song Y, Shi X et al (2018) The landscape of miRNA editing in animals and its impact on miRNA biogenesis and targeting. Genome Res 28:132–143.  https://doi.org/10.1101/gr.224386.117 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Wang Y, Xu X, Yu S et al (2017) Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers. Genome Res 27:1112–1125.  https://doi.org/10.1101/gr.219741.116 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Jin Y-F, Zhang W, Li Q (2009) Origins and evolution of ADAR-mediated RNA editing. IUBMB Life 61:572–578.  https://doi.org/10.1002/iub.207 CrossRefPubMedGoogle Scholar
  59. 59.
    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 96:4621–4626.  https://doi.org/10.1073/pnas.96.8.4621 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    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 12:1911–1924.  https://doi.org/10.1091/mbc.12.7.1911 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Poulsen H, Nilsson J, Damgaard CK et al (2001) CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain. Mol Cell Biol 21:7862–7871.  https://doi.org/10.1128/MCB.21.22.7862-7871.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Desterro JMP, Keegan LP, Lafarga M et al (2003) Dynamic association of RNA-editing enzymes with the nucleolus. J Cell Sci 116:1805–1818.  https://doi.org/10.1242/jcs.00371 CrossRefPubMedGoogle Scholar
  63. 63.
    Lykke-Andersen S, Piñol-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 13:1732–1744.  https://doi.org/10.1261/rna.567807 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    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 272:4419–4428.  https://doi.org/10.1074/jbc.272.7.4419 CrossRefPubMedGoogle Scholar
  65. 65.
    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 16:1779–1785.  https://doi.org/10.1261/rna.2188110 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Melcher T, Maas S, Herb A et al (1996) A mammalian RNA editing enzyme. Nature 379:460–464.  https://doi.org/10.1038/379460a0 CrossRefPubMedGoogle Scholar
  67. 67.
    Peng PL, Zhong X, Tu W et al (2006) ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 49:719–733.  https://doi.org/10.1016/j.neuron.2006.01.025 CrossRefPubMedGoogle Scholar
  68. 68.
    Yang L, Huang P, Li F et al (2012) c-Jun amino-terminal kinase-1 mediates glucose-responsive upregulation of the RNA editing enzyme ADAR2 in pancreatic Beta-cells. PLoS One 7:e48611.  https://doi.org/10.1371/journal.pone.0048611 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Sansam CL, Wells KS, Emeson RB (2003) Modulation of RNA editing by functional nucleolar sequestration of ADAR2. Proc Natl Acad Sci U S A 100:14018–14023.  https://doi.org/10.1073/pnas.2336131100 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Filippini A, Bonini D, Giacopuzzi E et al (2018) Differential enzymatic activity of Rat ADAR2 splicing variants is due to altered capability to interact with RNA in the deaminase domain. Genes (Basel) 9:79.  https://doi.org/10.3390/genes9020079 CrossRefGoogle Scholar
  71. 71.
    Chen C-X, Cho D-SC, Wang Q et al (2000) A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. RNA 6:755–767CrossRefGoogle Scholar
  72. 72.
    Tan MH, Li Q, Shanmugam R et al (2017) Dynamic landscape and regulation of RNA editing in mammals. Nature 550:249–254.  https://doi.org/10.1038/nature24041 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Oakes E, Anderson A, Cohen-Gadol A, Hundley HA (2017) Adenosine deaminase that acts on RNA 3 (ADAR3) binding to glutamate receptor subunit B pre-mRNA inhibits RNA editing in glioblastoma. J Biol Chem 292:4326–4335.  https://doi.org/10.1074/jbc.M117.779868 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Mladenova D, Barry G, Konen LM et al (2018) Adar3 is involved in learning and memory in mice. Front Neurosci 12:e118.  https://doi.org/10.3389/fnins.2018.00243 CrossRefGoogle Scholar
  75. 75.
    Macbeth MR, Schubert HL, VanDemark AP et al (2005) Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309:1534–1539.  https://doi.org/10.1126/science.1113150 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Matthews MM, Thomas JM, Zheng Y et al (2016) Structures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity. Nat Struct Mol Biol 23:426–433.  https://doi.org/10.1038/nsmb.3203 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Stefl R, Xu M, Skrisovska L et al (2006) Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. Structure 14:345–355.  https://doi.org/10.1016/j.str.2005.11.013 CrossRefPubMedGoogle Scholar
  78. 78.
    Chang KY, Ramos A (2005) The double-stranded RNA-binding motif, a versatile macromolecular docking platform. FEBS J 272:2109–2117.  https://doi.org/10.1111/j.1742-4658.2005.04652.x CrossRefPubMedGoogle Scholar
  79. 79.
    Lai F, Drakas R, Nishikura K (1995) Mutagenic analysis of double-stranded RNA adenosine deaminase, a candidate enzyme for RNA editing of glutamate-gated ion channel transcripts. J Biol Chem 270:17098–17105.  https://doi.org/10.1074/jbc.270.29.17098 CrossRefPubMedGoogle Scholar
  80. 80.
    Liu Y, Lei M, Samuel CE (2000) 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 U S A 97:12541–12546.  https://doi.org/10.1073/pnas.97.23.12541 CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Xu M, Wells KS, Emeson RB (2006) Substrate-dependent contribution of double-stranded RNA-binding motifs to ADAR2 function. Mol Biol Cell 17:3211–3220.  https://doi.org/10.1091/mbc.E06-02-0162 CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    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 282:16054–16061.  https://doi.org/10.1074/jbc.M611392200 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    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 13:3822–3835.  https://doi.org/10.1091/mbc.E02-03-0161 CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Barraud P, Banerjee S, Mohamed WI et al (2014) A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1. Proc Natl Acad Sci U S A 111:E1852–E1861.  https://doi.org/10.1073/pnas.1323698111 CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Schwartz T, Rould MA, Lowenhaupt K et al (1999) Crystal structure of the Zalpha domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA. Science 284:1841–1845CrossRefGoogle Scholar
  86. 86.
    Koeris M, Funke L, Shrestha J et al (2005) Modulation of ADAR1 editing activity by Z-RNA in vitro. Nucleic Acids Res 33:5362–5370.  https://doi.org/10.1093/nar/gki849 CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Oh D-B, Kim Y-G, Rich A (2002) Z-DNA-binding proteins can act as potent effectors of gene expression in vivo. Proc Natl Acad Sci U S A 99:16666–16671.  https://doi.org/10.1073/pnas.262672699 CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Kang H-J, Le TVT, Kim K et al (2014) Novel interaction of the Z-DNA binding domain of human ADAR1 with the oncogenic c-Myc promoter G-quadruplex. J Mol Biol 426:2594–2604.  https://doi.org/10.1016/j.jmb.2014.05.001 CrossRefPubMedGoogle Scholar
  89. 89.
    Athanasiadis A, Placido D, Maas S et al (2005) The crystal structure of the Zβ domain of the RNA-editing enzyme ADAR1 reveals distinct conserved surfaces among Z-domains. J Mol Biol 351:496–507.  https://doi.org/10.1016/j.jmb.2005.06.028 CrossRefPubMedGoogle Scholar
  90. 90.
    Maas S, Gommans WM (2009) Identification of a selective nuclear import signal in adenosine deaminases acting on RNA. Nucleic Acids Res 37:5822–5829.  https://doi.org/10.1093/nar/gkp599 CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Martin FH, Castro MM, Aboul-ela F, Tinoco I (1985) Base pairing involving deoxyinosine: implications for probe design. Nucleic Acids Res 13:8927–8938.  https://doi.org/10.1093/nar/13.24.8927 CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Valente L, Nishikura K (2005) ADAR gene family and A-to-I RNA editing: diverse roles in posttranscriptional gene regulation. Prog Nucleic Acid Res Mol Biol 79:299–338.  https://doi.org/10.1016/S0079-6603(04)79006-6 CrossRefPubMedGoogle Scholar
  93. 93.
    Liddicoat BJ, Piskol R, Chalk AM et al (2015) RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349:1115–1120.  https://doi.org/10.1126/science.aac7049 CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Siomi H, Siomi MC (2010) Posttranscriptional regulation of microRNA biogenesis in animals. Mol Cell 38:323–332.  https://doi.org/10.1016/j.molcel.2010.03.013 CrossRefPubMedGoogle Scholar
  95. 95.
    Laurencikiene J, Källman AM, Fong N et al (2006) RNA editing and alternative splicing: the importance of co-transcriptional coordination. EMBO Rep 7:303–307.  https://doi.org/10.1038/sj.embor.7400621 CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Ryman K, Fong N, Bratt E et al (2007) The C-terminal domain of RNA Pol II helps ensure that editing precedes splicing of the GluR-B transcript. RNA 13:1071–1078.  https://doi.org/10.1261/rna.404407 CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Daniel C, Widmark A, Rigardt D, Öhman M (2017) Editing inducer elements increases A-to-I editing efficiency in the mammalian transcriptome. Genome Biol 18:195.  https://doi.org/10.1186/s13059-017-1324-x CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Athanasiadis A, Rich A, Maas S (2004) Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol 2:e391.  https://doi.org/10.1371/journal.pbio.0020391.st001 CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Kim DDY, Kim TTY, Walsh T et al (2004) Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res 14:1719–1725.  https://doi.org/10.1101/gr.2855504 CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Levanon EY, Eisenberg E, Yelin R et al (2004) Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol 22:1001–1005.  https://doi.org/10.1038/nbt996 CrossRefPubMedGoogle Scholar
  101. 101.
    Bazak L, Levanon EY, Eisenberg E (2014) Genome-wide analysis of Alu editability. Nucleic Acids Res 42:6876–6884.  https://doi.org/10.1093/nar/gku414 CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Bazak L, Haviv A, Barak M et al (2014) A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res 24:365–376.  https://doi.org/10.1101/gr.164749.113 CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Consortium IHGS (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921.  https://doi.org/10.1038/35057062 CrossRefGoogle Scholar
  104. 104.
    Picardi E, Manzari C, Mastropasqua F et al (2015) Profiling RNA editing in human tissues: towards the inosinome Atlas. Sci Rep 5:14941.  https://doi.org/10.1038/srep14941 CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Zhang Q, Xiao X (2015) Genome sequence-independent identification of RNA editing sites. Nat Methods 12:347–350.  https://doi.org/10.1038/nmeth.3314 CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Soundararajan R, Stearns TM, Griswold AJ et al (2015) Detection of canonical A-to-G editing events at 3′ UTRs and microRNA target sites in human lungs using next-generation sequencing. Oncotarget 6:35726–35736.  https://doi.org/10.18632/oncotarget.6132 CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Brümmer A, Yang Y, Chan TW, Xiao X (2017) Structure-mediated modulation of mRNA abundance by A-to-I editing. Nat Commun 8:1255.  https://doi.org/10.1038/s41467-017-01459-7 CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Ramaswami G, Lin W, Piskol R et al (2012) Accurate identification of human Alu and non-Alu RNA editing sites. Nat Methods 9:579–581.  https://doi.org/10.1038/nmeth.1982 CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Ramaswami G, Zhang R, Piskol R et al (2013) Identifying RNA editing sites using RNA sequencing data alone. Nat Methods 10:128–132.  https://doi.org/10.1038/nmeth.2330 CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Riedmann EM, Schopoff S, Hartner JC, Jantsch MF (2008) Specificity of ADAR-mediated RNA editing in newly identified targets. RNA 14:1110–1118.  https://doi.org/10.1261/rna.923308 CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Polson AG, Bass BL (1994) Preferential selection of adenosines for modification by double-stranded RNA adenosine deaminase. EMBO J 13:5701–5711CrossRefGoogle Scholar
  112. 112.
    Lehmann KA, Bass BL (2000) Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. Biochemistry 39:12875–12884.  https://doi.org/10.1021/bi001383g CrossRefPubMedGoogle Scholar
  113. 113.
    Kawahara Y, Megraw M, Kreider E et al (2008) Frequency and fate of microRNA editing in human brain. Nucleic Acids Res 36:5270–5280.  https://doi.org/10.1093/nar/gkn479 CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Solomon O, Di Segni A, Cesarkas K et al (2017) RNA editing by ADAR1 leads to context-dependent transcriptome-wide changes in RNA secondary structure. Nat Commun 8:1440.  https://doi.org/10.1038/s41467-017-01458-8 CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Bass BL (2002) RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 71:817–846.  https://doi.org/10.1146/annurev.biochem.71.110601.135501 CrossRefPubMedGoogle Scholar
  116. 116.
    Wahlstedt H, Öhman M (2011) Site-selective versus promiscuous A-to-I editing. Wiley Interdiscip Rev RNA 2:761–771.  https://doi.org/10.1002/wrna.89 CrossRefPubMedGoogle Scholar
  117. 117.
    Halvorsen M, Martin JS, Broadaway S, Laederach A (2010) Disease-associated mutations that alter the RNA structural ensemble. PLoS Genet 6:e1001074.  https://doi.org/10.1371/journal.pgen.1001074 CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Salari R, Kimchi-Sarfaty C, Gottesman MM, Przytycka TM (2013) Sensitive measurement of single-nucleotide polymorphism-induced changes of RNA conformation: application to disease studies. Nucleic Acids Res 41:44–53.  https://doi.org/10.1093/nar/gks1009 CrossRefPubMedGoogle Scholar
  119. 119.
    Seeburg PH, Higuchi M, Sprengel R (1998) RNA editing of brain glutamate receptor channels: mechanism and physiology. Brain Res Brain Res Rev 26:217–229CrossRefGoogle Scholar
  120. 120.
    Fritz J, Strehblow A, Taschner A et al (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 29:1487–1497.  https://doi.org/10.1128/MCB.01519-08 CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Brownawell AM, Macara IG (2002) Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins. J Cell Biol 156:53–64.  https://doi.org/10.1083/jcb.200110082 CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Lu KP, Liou YC, Vincent I (2003) Proline-directed phosphorylation and isomerization in mitotic regulation and in Alzheimer’s disease. BioEssays 25:174–181.  https://doi.org/10.1002/bies.10223 CrossRefPubMedGoogle Scholar
  123. 123.
    Marcucci R, Brindle J, Paro S et al (2011) Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO J 30:4211–4222.  https://doi.org/10.1038/emboj.2011.303 CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Yaffe MB, Schutkowski M, Shen M et al (1997) Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science 278:1957–1960.  https://doi.org/10.1126/science.278.5345.1957 CrossRefPubMedGoogle Scholar
  125. 125.
    Desterro JMP, Keegan LP, Jaffray E et al (2005) SUMO-1 modification alters ADAR1 editing activity. Mol Biol Cell 16:5115–5126.  https://doi.org/10.1091/mbc.E05-06-0536 CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Garncarz W, Tariq A, Handl C et al (2013) A high-throughput screen to identify enhancers of ADAR-mediated RNA-editing. RNA Biol 10:192–204.  https://doi.org/10.4161/rna.23208 CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Eidem TM, Kugel JF, Goodrich JA (2016) Noncoding RNAs: regulators of the mammalian transcription machinery. J Mol Biol 428:2652–2659.  https://doi.org/10.1016/j.jmb.2016.02.019 CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Su Y, Wu H, Pavlosky A et al (2016) Regulatory non-coding RNA: new instruments in the orchestration of cell death. Cell Death Dis 7:e2333–e2333.  https://doi.org/10.1038/cddis.2016.210 CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Nilsen TW, Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463:457–463.  https://doi.org/10.1038/nature08909 CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Khurana E, Fu Y, Chakravarty D et al (2016) Role of non-coding sequence variants in cancer. Nat Rev Genet 17:93–108.  https://doi.org/10.1038/nrg.2015.17 CrossRefPubMedGoogle Scholar
  131. 131.
    Tilgner H, Knowles DG, Johnson R et al (2012) Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs. Genome Res 22:1616–1625.  https://doi.org/10.1101/gr.134445.111 CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Roy SW, Gilbert W (2006) The evolution of spliceosomal introns: patterns, puzzles and progress. Nat Rev Genet 7:211–221.  https://doi.org/10.1038/nrg1807 CrossRefPubMedGoogle Scholar
  133. 133.
    Steitz TA, Steitz JA (1993) A general two-metal-ion mechanism for catalytic RNA. Proc Natl Acad Sci U S A 90:6498–6502CrossRefGoogle Scholar
  134. 134.
    Lim KH, Ferraris L, Filloux ME et al (2011) Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. Proc Natl Acad Sci U S A 108:11093–11098.  https://doi.org/10.1073/pnas.1101135108 CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Taggart AJ, DeSimone AM, Shih JS et al (2012) Large-scale mapping of branchpoints in human pre-mRNA transcripts in vivo. Nat Struct Mol Biol 19:719–721.  https://doi.org/10.1038/nsmb.2327 CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Lee Y, Rio DC (2015) Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem 84:291–323.  https://doi.org/10.1146/annurev-biochem-060614-034316 CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Fedorova L, Fedorov A (2003) Introns in gene evolution. In: Origin and evolution of new gene functions. Springer, Dordrecht, pp 123–131CrossRefGoogle Scholar
  138. 138.
    Wong JJL, Au AYM, Ritchie W, Rasko JEJ (2015) Intron retention in mRNA: no longer nonsense. BioEssays 38:41–49.  https://doi.org/10.1002/bies.201500117 CrossRefPubMedGoogle Scholar
  139. 139.
    Bicknell AA, Cenik C, Chua HN et al (2012) Introns in UTRs: why we should stop ignoring them. BioEssays 34:1025–1034.  https://doi.org/10.1002/bies.201200073 CrossRefPubMedGoogle Scholar
  140. 140.
    Lykke-Andersen S, Jensen TH (2015) Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol 16:665–677.  https://doi.org/10.1038/nrm4063 CrossRefPubMedGoogle Scholar
  141. 141.
    Hsiao Y-HE, Bahn JH, Yang Y et al (2018) RNA editing in nascent RNA affects pre-mRNA splicing. Genome Res 28:812–823.  https://doi.org/10.1101/gr.231209.117 CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Rueter SM, Dawson TR, Emeson RB (1999) Regulation of alternative splicing by RNA editing. Nature 399:75–80.  https://doi.org/10.1038/19992 CrossRefPubMedGoogle Scholar
  143. 143.
    Feng Y, Sansam CL, Singh M, Emeson RB (2006) Altered RNA editing in mice lacking ADAR2 autoregulation. Mol Cell Biol 26:480–488.  https://doi.org/10.1128/MCB.26.2.480-488.2006 CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Maas S, Kawahara Y, Tamburro KM, Nishikura K (2006) A-to-I RNA editing and human disease. RNA Biol 3:1–9CrossRefGoogle Scholar
  145. 145.
    Flomen R, Knight J, Sham P et al (2004) Evidence that RNA editing modulates splice site selection in the 5-HT2C receptor gene. Nucleic Acids Res 32:2113–2122.  https://doi.org/10.1093/nar/gkh536 CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Chen Y-T, Chang IY-F, Liu H et al (2018) Tumor-associated intronic editing of HNRPLL generates a novel splicing variant linked to cell proliferation. J Biol Chem 293:10158–10171.  https://doi.org/10.1074/jbc.RA117.001197 CrossRefPubMedGoogle Scholar
  147. 147.
    Siepel A, Bejerano G, Pedersen JS et al (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15:1034–1050.  https://doi.org/10.1101/gr.3715005 CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Gingerich TJ, Feige J-J, LaMarre J (2004) AU-rich elements and the control of gene expression through regulated mRNA stability. Anim Health Res Rev 5:49–63CrossRefGoogle Scholar
  149. 149.
    Halees AS, Hitti E, Al-Saif M et al (2011) Global assessment of GU-rich regulatory content and function in the human transcriptome. RNA Biol 8:681–691.  https://doi.org/10.4161/rna.8.4.16283 CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Chen J-M, Férec C, Cooper DN (2006) A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes I: general principles and overview. Hum Genet 120:1–21.  https://doi.org/10.1007/s00439-006-0180-7 CrossRefPubMedGoogle Scholar
  151. 151.
    Sandberg R, Neilson JR, Sarma A et al (2008) Proliferating cells express mRNAs with shortened 3' untranslated regions and fewer MicroRNA target sites. Science 320:1643–1647.  https://doi.org/10.1126/science.1155390 CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Chen J, Kastan MB (2010) 5′–3′-UTR interactions regulate p53 mRNA translation and provide a target for modulating p53 induction after DNA damage. Genes Dev 24:2146–2156.  https://doi.org/10.1101/gad.1968910 CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Djuranovic S, Nahvi A, Green R (2012) miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science 336:237–240.  https://doi.org/10.1126/science.1215691 CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Vasudevan S, Tong Y, Steitz JA (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318:1931–1934.  https://doi.org/10.1126/science.1149460 CrossRefPubMedGoogle Scholar
  155. 155.
    Ghosh T, Soni K, Scaria V et al (2008) MicroRNA-mediated up-regulation of an alternatively polyadenylated variant of the mouse cytoplasmic β-actin gene. Nucleic Acids Res 36:6318–6332.  https://doi.org/10.1093/nar/gkn624 CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Lee I, Ajay SS, Yook JI et al (2009) New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites. Genome Res 19:1175–1183.  https://doi.org/10.1101/gr.089367.108 CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Chen L-L, DeCerbo JN, Carmichael GG (2008) Alu element-mediated gene silencing. EMBO J 27:1694–1705.  https://doi.org/10.1038/emboj.2008.94 CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Zhang Z, Carmichael GG (2001) The fate of dsRNA in the nucleus: a p54nrb-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell 106:465–476.  https://doi.org/10.1016/S0092-8674(01)00466-4 CrossRefPubMedGoogle Scholar
  159. 159.
    Wang Q, Hui H, Guo Z et al (2013) ADAR1 regulates ARHGAP26 gene expression through RNA editing by disrupting miR-30b-3p and miR-573 binding. RNA 19:1525–1536.  https://doi.org/10.1261/rna.041533.113 CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Zhang L, Yang C-S, Varelas X, Monti S (2016) Altered RNA editing in 3′ UTR perturbs microRNA-mediated regulation of oncogenes and tumor-suppressors. Sci Rep 6:23226.  https://doi.org/10.1038/srep23226 CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Borchert GM, Gilmore BL, Spengler RM et al (2009) Adenosine deamination in human transcripts generates novel microRNA binding sites. Hum Mol Genet 18:4801–4807.  https://doi.org/10.1093/hmg/ddp443 CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Saxena S, Jónsson ZO, Dutta A (2003) Small RNAs with imperfect match to endogenous mRNA repress translation implications for off-target activity of small inhibitory RNA in mammalian cells. J Biol Chem 278:44312–44319.  https://doi.org/10.1074/jbc.M307089200 CrossRefPubMedGoogle Scholar
  163. 163.
    Doench JG, Sharp PA (2004) Specificity of microRNA target selection in translational repression. Genes Dev 18:504–511.  https://doi.org/10.1101/gad.1184404 CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Kertesz M, Iovino N, Unnerstall U et al (2007) The role of site accessibility in microRNA target recognition. Nat Publ Group 39:1278–1284.  https://doi.org/10.1038/ng2135 CrossRefGoogle Scholar
  165. 165.
    Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15:509–524.  https://doi.org/10.1038/nrm3838 CrossRefPubMedGoogle Scholar
  166. 166.
    Kleinberger Y, Eisenberg E (2010) Large-scale analysis of structural, sequence and thermodynamic characteristics of A-to-I RNA editing sites in human Alu repeats. BMC Genomics 11:453.  https://doi.org/10.1186/1471-2164-11-453 CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (2001) Identification of novel genes coding for small expressed RNAs. Science 294:853–858.  https://doi.org/10.1126/science.1064921 CrossRefPubMedGoogle Scholar
  168. 168.
    Lau NC, Lim LP, Weinstein EG, Bartel DP (2001) An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294:858–862.  https://doi.org/10.1126/science.1065062 CrossRefPubMedGoogle Scholar
  169. 169.
    Lee RC, Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294:862–864.  https://doi.org/10.1126/science.1065329 CrossRefPubMedGoogle Scholar
  170. 170.
    Kozomara A, Griffiths-Jones S (2014) miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 42:D68–D73.  https://doi.org/10.1093/nar/gkt1181 CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Kim Y-K, Kim VN (2007) Processing of intronic microRNAs. EMBO J 26:775–783.  https://doi.org/10.1038/sj.emboj.7601512 CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Westholm JO, Lai EC (2011) Mirtrons: microRNA biogenesis via splicing. Biochimie 93:1897–1904.  https://doi.org/10.1016/j.biochi.2011.06.017 CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Moretti F, Thermann R, Hentze MW (2010) Mechanism of translational regulation by miR-2 from sites in the 5′ untranslated region or the open reading frame. RNA 16:2493–2502.  https://doi.org/10.1261/rna.2384610 CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Forman JJ, Legesse-Miller A, Coller HA (2008) A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc Natl Acad Sci U S A 105:14879–14884.  https://doi.org/10.1073/pnas.0803230105 CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Shin C, Nam J-W, Farh KK-H et al (2010) Expanding the MicroRNA targeting code: functional sites with centered pairing. Mol Cell 38:789–802.  https://doi.org/10.1016/j.molcel.2010.06.005 CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Roberts JT, Borchert GM (2017) Computational prediction of MicroRNA target genes, target prediction databases, and web resources. In: Bioinformatics in MicroRNA research. Humana Press, New York, pp 109–122CrossRefGoogle Scholar
  177. 177.
    Blow MJ, Grocock RJ, Van Dongen S et al (2006) RNA editing of human microRNAs. Genome Biol 7:R27.  https://doi.org/10.1186/gb-2006-7-4-r27 CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Alon S, Mor E, Vigneault F et al (2012) Systematic identification of edited microRNAs in the human brain. Genome Res 22:1533–1540.  https://doi.org/10.1101/gr.131573.111 CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Nigita G, Acunzo M, Romano G et al (2016) microRNA editing in seed region aligns with cellular changes in hypoxic conditions. Nucleic Acids Res 44:6298–6308.  https://doi.org/10.1093/nar/gkw532 CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Pinto Y, Buchumenski I, Levanon EY, Eisenberg E (2018) Human cancer tissues exhibit reduced A-to-I editing of miRNAs coupled with elevated editing of their targets. Nucleic Acids Res 46:71–82.  https://doi.org/10.1093/nar/gkx1176 CrossRefPubMedGoogle Scholar
  181. 181.
    Yang W, Chendrimada TP, Wang Q et al (2006) Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol 13:13–21.  https://doi.org/10.1038/nsmb1041 CrossRefPubMedGoogle Scholar
  182. 182.
    Liu Z, Wang J, Li G, Wang H-W (2014) Structure of precursor microRNA’s terminal loop regulates human Dicer’s dicing activity by switching DExH/D domain. Protein Cell 6:185–193.  https://doi.org/10.1007/s13238-014-0124-2 CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Jankowsky E, Bowers H (2006) Remodeling of ribonucleoprotein complexes with DExH/D RNA helicases. Nucleic Acids Res 34:4181–4188.  https://doi.org/10.1093/nar/gkl410 CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Yan KS, Yan S, Farooq A et al (2003) Structure and conserved RNA binding of the PAZ domain. Nature 426:469–474.  https://doi.org/10.1038/nature02129 CrossRefGoogle Scholar
  185. 185.
    Park J-E, Heo I, Tian Y et al (2011) Dicer recognizes the 5′ end of RNA for efficient and accurate processing. Nature 475:201–205.  https://doi.org/10.1038/nature10198 CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Tsutsumi A, Kawamata T, Izumi N et al (2011) Recognition of the pre-miRNA structure by Drosophila Dicer-1. Nat Struct Mol Biol 18:1153–1158.  https://doi.org/10.1038/nsmb.2125 CrossRefPubMedGoogle Scholar
  187. 187.
    Kawahara Y, Zinshteyn B, Chendrimada TP et al (2007) RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex. EMBO Rep 8:763–769.  https://doi.org/10.1038/sj.embor.7401011 CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Kawahara Y, Zinshteyn B, Sethupathy P et al (2007) Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315:1137–1140.  https://doi.org/10.1126/science.1138050 CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Choudhury Y, Tay FC, Lam DH et al (2012) Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. J Clin Invest 122:4059–4076.  https://doi.org/10.1172/JCI62925 CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Cesarini V, Silvestris DA, Tassinari V et al (2018) ADAR2/miR-589-3p axis controls glioblastoma cell migration/invasion. Nucleic Acids Res 46:2045–2059.  https://doi.org/10.1093/nar/gkx1257 CrossRefPubMedGoogle Scholar
  191. 191.
    Gregory PA, Bert AG, Paterson EL et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601.  https://doi.org/10.1038/ncb1722 CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Park S-M, Gaur AB, Lengyel E, Peter ME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907.  https://doi.org/10.1101/gad.1640608 CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Shoshan E, Mobley AK, Braeuer RR et al (2015) Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat Cell Biol 17:311–321.  https://doi.org/10.1038/ncb3110 CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Velazquez-Torres G, Shoshan E, Ivan C et al (2018) A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression. Nat Commun 9:461.  https://doi.org/10.1038/s41467-018-02851-7 CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Moran VA, Perera RJ, Khalil AM (2012) Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs. Nucleic Acids Res 40:6391–6400.  https://doi.org/10.1093/nar/gks296 CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Harrow J, Frankish A, Gonzalez JM et al (2012) GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res 22:1760–1774.  https://doi.org/10.1101/gr.135350.111 CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Quek XC, Thomson DW, Maag JLV et al (2015) lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs. Nucleic Acids Res 43:D168–D173.  https://doi.org/10.1093/nar/gku988 CrossRefPubMedGoogle Scholar
  198. 198.
    St Laurent G, Wahlestedt C, Kapranov P (2015) The landscape of long noncoding RNA classification. Trends Genet 31:239–251.  https://doi.org/10.1016/j.tig.2015.03.007 CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Housman G, Ulitsky I (2016) Methods for distinguishing between protein-coding and long noncoding RNAs and the elusive biological purpose of translation of long noncoding RNAs. Biochim Biophys Acta 1859:31–40.  https://doi.org/10.1016/j.bbagrm.2015.07.017 CrossRefPubMedGoogle Scholar
  200. 200.
    Nelson BR, Makarewich CA, Anderson DM et al (2016) A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science 351:271–275.  https://doi.org/10.1126/science.aad4076 CrossRefPubMedPubMedCentralGoogle Scholar
  201. 201.
    Ruiz-Orera J, Verdaguer-Grau P, Villanueva-Cañas JL, et al (2017) Evidence for functional and non-functional classes of peptides translated from long non-coding RNAs. bioRxiv: 064915. doi:  https://doi.org/10.1101/064915
  202. 202.
    Thomson DW, Dinger ME (2016) Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet 17:272–283.  https://doi.org/10.1038/nrg.2016.20 CrossRefPubMedGoogle Scholar
  203. 203.
    Wang X, Arai S, Song X et al (2008) Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454:126–130.  https://doi.org/10.1038/nature06992 CrossRefPubMedPubMedCentralGoogle Scholar
  204. 204.
    Schaukowitch K, Joo J-Y, Liu X et al (2014) Enhancer RNA facilitates NELF release from immediate early genes. Mol Cell 56:29–42.  https://doi.org/10.1016/j.molcel.2014.08.023 CrossRefPubMedPubMedCentralGoogle Scholar
  205. 205.
    Sigova AA, Abraham BJ, Ji X et al (2015) Transcription factor trapping by RNA in gene regulatory elements. Science 350:978–981.  https://doi.org/10.1126/science.aad3346 CrossRefPubMedPubMedCentralGoogle Scholar
  206. 206.
    Mondal T, Subhash S, Vaid R et al (2015) MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures. Nat Commun 6:7743.  https://doi.org/10.1038/ncomms8743 CrossRefPubMedPubMedCentralGoogle Scholar
  207. 207.
    Postepska-Igielska A, Giwojna A, Gasri-Plotnitsky L et al (2015) LncRNA Khps1 regulates expression of the proto-oncogene SPHK1 via triplex-mediated changes in chromatin structure. Mol Cell 60:626–636.  https://doi.org/10.1016/j.molcel.2015.10.001 CrossRefPubMedGoogle Scholar
  208. 208.
    Gong J, Liu C, Liu W et al (2017) LNCediting: a database for functional effects of RNA editing in lncRNAs. Nucleic Acids Res 45:D79–D84.  https://doi.org/10.1093/nar/gkw835 CrossRefPubMedGoogle Scholar
  209. 209.
    Picardi E, D’Erchia AM, Gallo A et al (2014) Uncovering RNA editing sites in long non-coding RNAs. Front Bioeng Biotechnol 2:64.  https://doi.org/10.3389/fbioe.2014.00064 CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Luo H, Fang S, Sun L et al (2017) Comprehensive characterization of the RNA editomes in cancer development and progression. Front Genet 8:230.  https://doi.org/10.3389/fgene.2017.00230 CrossRefPubMedGoogle Scholar
  211. 211.
    Novikova IV, Hennelly SP, Sanbonmatsu KY (2012) Structural architecture of the human long non-coding RNA, steroid receptor RNA activator. Nucleic Acids Res 40:5034–5051.  https://doi.org/10.1093/nar/gks071 CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Mahlab S, Tuller T, Linial M (2012) Conservation of the relative tRNA composition in healthy and cancerous tissues. RNA 18:640–652.  https://doi.org/10.1261/rna.030775.111 CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Itoh Y, Sekine S-I, Suetsugu S, Yokoyama S (2013) Tertiary structure of bacterial selenocysteine tRNA. Nucleic Acids Res 41:6729–6738.  https://doi.org/10.1093/nar/gkt321 CrossRefPubMedPubMedCentralGoogle Scholar
  214. 214.
    Bunn CC, Mathews MB (1987) Autoreactive epitope defined as the anticodon region of alanine transfer RNA. Science 238:1116–1119CrossRefGoogle Scholar
  215. 215.
    Becker HF, Corda Y, Mathews MB et al (1999) Inosine and N1-methylinosine within a synthetic oligomer mimicking the anticodon loop of human tRNA(Ala) are major epitopes for anti-PL-12 myositis autoantibodies. RNA 5:865–875CrossRefGoogle Scholar
  216. 216.
    Torres AG, Piñeyro D, Filonava L et al (2014) A-to-I editing on tRNAs: biochemical, biological and evolutionary implications. FEBS Lett 588:4279–4286.  https://doi.org/10.1016/j.febslet.2014.09.025 CrossRefPubMedGoogle Scholar
  217. 217.
    Gerber AP, Keller W (2001) RNA editing by base deamination: more enzymes, more targets, new mysteries. Trends Biochem Sci 26:376–384.  https://doi.org/10.1016/S0968-0004(01)01827-8 CrossRefPubMedGoogle Scholar
  218. 218.
    Maas S, Gerber AP, Rich A (1999) Identification and characterization of a human tRNA-specific adenosine deaminase related to the ADAR family of pre-mRNA editing enzymes. Proc Natl Acad Sci U S A 96:8895–8900CrossRefGoogle Scholar
  219. 219.
    Bjork GR, Jacobsson K, Nilsson K et al (2001) A primordial tRNA modification required for the evolution of life? EMBO J 20:231–239.  https://doi.org/10.1093/emboj/20.1.231 CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Gerber AP, Keller W (1999) An adenosine deaminase that generates inosine at the wobble position of tRNAs. Science 286:1146–1149CrossRefGoogle Scholar
  221. 221.
    Torres AG, Piñeyro D, Rodríguez-Escribà M et al (2015) Inosine modifications in human tRNAs are incorporated at the precursor tRNA level. Nucleic Acids Res 43:5145–5157.  https://doi.org/10.1093/nar/gkv277 CrossRefPubMedPubMedCentralGoogle Scholar
  222. 222.
    Alazami AM, Hijazi H, Al-Dosari MS et al (2013) Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus. J Med Genet 50:425–430.  https://doi.org/10.1136/jmedgenet-2012-101378 CrossRefPubMedGoogle Scholar
  223. 223.
    Morse DP, Bass BL (1999) Long RNA hairpins that contain inosine are present in Caenorhabditis elegans poly(A)+ RNA. Proc Natl Acad Sci U S A 96:6048–6053CrossRefGoogle Scholar
  224. 224.
    Hoopengardner B, Bhalla T, Staber C, Reenan R (2003) Nervous system targets of RNA editing identified by comparative genomics. Science 301:832–836.  https://doi.org/10.1126/science.1086763 CrossRefPubMedGoogle Scholar
  225. 225.
    Boguski MS, Lowe T, Tolstoshev CM (1993) dbEST—database for “expressed sequence tags”. Nat Genet 4:332–333.  https://doi.org/10.1038/ng0893-332 CrossRefPubMedGoogle Scholar
  226. 226.
    Veneziano D, Di Bella S, Nigita G et al (2016) Noncoding RNA: current deep sequencing data analysis approaches and challenges. Hum Mutat 37:1283–1298.  https://doi.org/10.1002/humu.23066 CrossRefPubMedGoogle Scholar
  227. 227.
    Li JB, Levanon EY, Yoon J-K et al (2009) Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324:1210–1213.  https://doi.org/10.1126/science.1170995 CrossRefPubMedGoogle Scholar
  228. 228.
    Nigita G, Veneziano D, Ferro A (2015) A-to-I RNA editing: current knowledge sources and computational approaches with special emphasis on non-coding RNA molecules. Front Bioeng Biotechnol 3:37.  https://doi.org/10.3389/fbioe.2015.00037 CrossRefPubMedPubMedCentralGoogle Scholar
  229. 229.
    de Hoon MJL, Taft RJ, Hashimoto T et al (2010) Cross-mapping and the identification of editing sites in mature microRNAs in high-throughput sequencing libraries. Genome Res 20:257–264.  https://doi.org/10.1101/gr.095273.109 CrossRefPubMedPubMedCentralGoogle Scholar
  230. 230.
    Alon S, Eisenberg E (2013) Identifying RNA editing sites in miRNAs by deep sequencing. Methods Mol Biol 1038:159–170.  https://doi.org/10.1007/978-1-62703-514-9_9 CrossRefPubMedGoogle Scholar
  231. 231.
    Alon S, Erew M, Eisenberg E (2015) DREAM: a webserver for the identification of editing sites in mature miRNAs using deep sequencing data. Bioinformatics 31:2568–2570.  https://doi.org/10.1093/bioinformatics/btv187 CrossRefPubMedGoogle Scholar
  232. 232.
    Sakurai M, Yano T, Kawabata H et al (2010) Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. Nat Chem Biol 6:733–740.  https://doi.org/10.1038/nchembio.434 CrossRefPubMedGoogle Scholar
  233. 233.
    Sakurai M, Ueda H, Yano T et al (2014) A biochemical landscape of A-to-I RNA editing in the human brain transcriptome. Genome Res 24:522–534.  https://doi.org/10.1101/gr.162537.113 CrossRefPubMedPubMedCentralGoogle Scholar
  234. 234.
    Kiran A, Baranov PV (2010) DARNED: a DAtabase of RNa EDiting in humans. Bioinformatics 26:1772–1776.  https://doi.org/10.1093/bioinformatics/btq285 CrossRefPubMedGoogle Scholar
  235. 235.
    Laganà A, Paone A, Veneziano D et al (2012) miR-EdiTar: a database of predicted A-to-I edited miRNA target sites. Bioinformatics 28:3166–3168.  https://doi.org/10.1093/bioinformatics/bts589 CrossRefPubMedPubMedCentralGoogle Scholar
  236. 236.
    Kiran AM, O'Mahony JJ, Sanjeev K, Baranov PV (2013) Darned in 2013: inclusion of model organisms and linking with Wikipedia. Nucleic Acids Res 41:D258–D261.  https://doi.org/10.1093/nar/gks961 CrossRefPubMedGoogle Scholar
  237. 237.
    Picardi E, D'Antonio M, Carrabino D et al (2011) ExpEdit: a webserver to explore human RNA editing in RNA-Seq experiments. Bioinformatics 27:1311–1312.  https://doi.org/10.1093/bioinformatics/btr117 CrossRefPubMedGoogle Scholar
  238. 238.
    Distefano R, Nigita G, Macca V et al (2013) VIRGO: visualization of A-to-I RNA editing sites in genomic sequences. BMC Bioinformatics 14(Suppl 7):S5.  https://doi.org/10.1186/1471-2105-14-S7-S5 CrossRefPubMedPubMedCentralGoogle Scholar
  239. 239.
    Wahlstedt H, Luciano DJ, Enstero M, Öhman M (2009) Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res 19:978–986.  https://doi.org/10.1101/gr.089409.108 CrossRefPubMedPubMedCentralGoogle Scholar
  240. 240.
    Solomon O, Bazak L, Levanon EY et al (2014) Characterizing of functional human coding RNA editing from evolutionary, structural, and dynamic perspectives. Proteins 82:3117–3131.  https://doi.org/10.1002/prot.24672 CrossRefPubMedGoogle Scholar
  241. 241.
    Ramaswami G, Li JB (2014) RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Res 42:D109–D113.  https://doi.org/10.1093/nar/gkt996 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Giovanni Nigita
    • 1
    Email author
  • Gioacchino P. Marceca
    • 1
    • 2
  • Luisa Tomasello
    • 1
  • Rosario Distefano
    • 1
  • Federica Calore
    • 1
  • Dario Veneziano
    • 1
  • Giulia Romano
    • 3
  • Serge Patrick Nana-Sinkam
    • 3
  • Mario Acunzo
    • 3
  • Carlo M. Croce
    • 1
  1. 1.Department of Cancer Biology and Genetics, Comprehensive Cancer CenterThe Ohio State UniversityColumbusUSA
  2. 2.Department of Clinical and Experimental MedicineUniversity of CataniaCataniaItaly
  3. 3.Division of Pulmonary Diseases and Critical Care MedicineVirginia Commonwealth UniversityRichmondUSA

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