Skip to main content

Controlling the Editor: The Many Roles of RNA-Binding Proteins in Regulating A-to-I RNA Editing

  • Chapter
  • First Online:
RNA Processing

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 907))

Abstract

RNA editing is a cellular process used to expand and diversify the RNA transcripts produced from a generally immutable genome. In animals, the most prevalent type of RNA editing is adenosine (A) to inosine (I) deamination catalyzed by the ADAR family. Throughout development, A-to-I editing levels increase while ADAR expression is constant, suggesting cellular mechanisms to regulate A-to-I editing exist. Furthermore, in several disease states, ADAR expression levels are similar to the normal state, but A-to-I editing levels are altered. Therefore, understanding how these enzymes are regulated in normal tissues and misregulated in disease states is of profound importance. This chapter will both discuss how to identify A-to-I editing sites across the transcriptome and explore the mechanisms that regulate ADAR editing activity, with particular focus on the diverse types of RNA-binding proteins implicated in regulating A-to-I editing in vivo.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Chen M, Manley JL (2009) Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 10(11):741–754. doi:10.1038/nrm2777

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Farajollahi S, Maas S (2010) Molecular diversity through RNA editing: a balancing act. Trends Genet 26(5):221–230. doi:10.1016/j.tig.2010.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tariq A, Jantsch MF (2012) Transcript diversification in the nervous system: a to I RNA editing in CNS function and disease development. Front Neurosci 6:99. doi:10.3389/fnins.2012.00099

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Bass BL, Weintraub H (1988) An unwinding activity that covalently modifies its double-stranded-RNA substrate. Cell 55(6):1089–1098. doi:10.1016/0092-8674(88)90253-x

    Article  CAS  PubMed  Google Scholar 

  5. Benne R, Van Den Burg J, Brakenhoff JPJ, Sloof P, Van Boom JH, Tromp MC (1986) Major transcript of the frameshifted coxll gene from trypanosome mitochondria contains four nucleotides that are not encoded in the DNA. Cell 46(6):819–826. doi:10.1016/0092-8674(86)90063-2

    Article  CAS  PubMed  Google Scholar 

  6. Gott JM, Emeson RB (2000) Functions and mechanisms of RNA editing. Annu Rev Genet 34(1):499–531. doi:10.1146/annurev.genet.34.1.499

    Article  CAS  PubMed  Google Scholar 

  7. Keegan LP, Gallo A, O’Connell MA (2001) The many roles of an RNA editor. Nat Rev Genet 2(11):869–878

    Article  CAS  PubMed  Google Scholar 

  8. Blanc V, Davidson NO (2010) APOBEC-1-mediated RNA editing. Wiley Interdiscip Rev Syst Biol Med 2(5):594–602. doi:10.1002/wsbm.82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nishikura K (2010) Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem 79:321–349. doi:10.1146/annurev-biochem-060208-105251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bazak L, Haviv A, Barak M, Jacob-Hirsch J, Deng P, Zhang R, Isaacs FJ, Rechavi G, Li JB, Eisenberg E, Levanon EY (2014) A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res 24(3):365–376. doi:10.1101/gr.164749.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Blanc V, Park E, Schaefer S, Miller M, Lin Y, Kennedy S, Billing A, Hamidane H, Graumann J, Mortazavi A, Nadeau J, Davidson N (2014) Genome-wide identification and functional analysis of Apobec-1-mediated C-to-U RNA editing in mouse small intestine and liver. Genome Biol 15(6):R79

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Hamilton CE, Papavasiliou FN, Rosenberg BR (2010) Diverse functions for DNA and RNA editing in the immune system. RNA Biol 7(2):220–228

    Article  CAS  PubMed  Google Scholar 

  13. Savva YA, Rieder LE, Reenan RA (2012) The ADAR protein family. Genome Biol 13(12):252. doi:10.1186/gb-2012-13-12-252

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Rosenthal JJ, Seeburg PH (2012) A-to-I RNA editing: effects on proteins key to neural excitability. Neuron 74(3):432–439. doi:10.1016/j.neuron.2012.04.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rieder LE, Reenan RA (2012) The intricate relationship between RNA structure, editing, and splicing. Semin Cell Dev Biol 23(3):281–288. doi:10.1016/j.semcdb.2011.11.004

    Article  CAS  PubMed  Google Scholar 

  16. Tomaselli S, Bonamassa B, Alisi A, Nobili V, Locatelli F, Gallo A (2013) ADAR enzyme and miRNA story: a nucleotide that can make the difference. Int J Mol Sci 14(11):22796–22816. doi:10.3390/ijms141122796

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Hundley HA, Bass BL (2010) ADAR editing in double-stranded UTRs and other noncoding RNA sequences. Trends Biochem Sci 35(7):377–383. doi:10.1016/j.tibs.2010.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wahlstedt H, Ohman M (2011) Site-selective versus promiscuous A-to-I editing. Wiley Interdiscip Rev RNA 2(6):761–771. doi:10.1002/wrna.89

    Article  CAS  PubMed  Google Scholar 

  19. Wulff BE, Nishikura K (2012) Modulation of microRNA expression and function by ADARs. Curr Top Microbiol Immunol 353:91–109. doi:10.1007/82_2011_151

    CAS  PubMed  Google Scholar 

  20. 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. doi:10.1016/0092-8674(93)90622-w

    Article  CAS  PubMed  Google Scholar 

  21. 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. doi:10.1126/science.290.5497.1765

    Article  CAS  PubMed  Google Scholar 

  22. Palladino MJ, Keegan LP, O’Connell MA, Reenan RA (2000) A-to-I pre-mRNA editing in Drosophila is primarily involved in adult nervous system function and integrity. Cell 102(4):437–449. doi:10.1016/S0092-8674(00)00049-0

    Article  CAS  PubMed  Google Scholar 

  23. Tonkin LA, Saccomanno L, Morse DP, Brodigan T, Krause M, Bass BL (2002) RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. EMBO J 21(22):6025–6035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gaisler-Salomon I, Kravitz E, Feiler Y, Safran M, Biegon A, Amariglio N, Rechavi G (2014) Hippocampus-specific deficiency in RNA editing of GluA2 in Alzheimer’s disease. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2014.02.018

    PubMed  Google Scholar 

  25. Galeano F, Rossetti C, Tomaselli S, Cifaldi L, Lezzerini M, Pezzullo M, Boldrini R, Massimi L, Di Rocco CM, Locatelli F, Gallo A (2013) ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. Oncogene 32(8):998–1009. doi:10.1038/onc.2012

    Article  CAS  PubMed  Google Scholar 

  26. Krestel H, Raffel S, von Lehe M, Jagella C, Moskau-Hartmann S, Becker A, Elger CE, Seeburg PH, Nirkko A (2013) Differences between RNA and DNA due to RNA editing in temporal lobe epilepsy. Neurobiol Dis 56:66–73. doi:10.1016/j.nbd.2013.04.006

    Article  CAS  PubMed  Google Scholar 

  27. Silberberg G, Lundin D, Navon R, Öhman M (2011) Deregulation of the A-to-I RNA editing mechanism in psychiatric disorders. Hum Mol Genet 21(2):311–321. doi:10.1093/hmg/ddr461

    Article  PubMed  CAS  Google Scholar 

  28. Yamashita T, Kwak S (2013) The molecular link between inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in motor neurons of sporadic amyotrophic lateral sclerosis patients. Brain Res 1584:28–38. doi:10.1016/j.brainres.2013.12.011

    Article  PubMed  CAS  Google Scholar 

  29. Hideyama T, Yamashita T, Aizawa H, Tsuji S, Kakita A, Takahashi H, Kwak S (2012) Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons. Neurobiol Dis 45(3):1121–1128. doi:10.1016/j.nbd.2011.12.033

    Article  CAS  PubMed  Google Scholar 

  30. 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. doi:10.1073/pnas.251531398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wahlstedt H, Daniel C, Ensterö M, Öhman M (2009) Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res 19(6):978–986. doi:10.1101/gr.089409.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jin YF, Zhang WJ, Li Q (2009) Origins and evolution of ADAR-mediated RNA editing. IUBMB Life 61(6):572–578. doi:10.1002/iub.207

    Article  CAS  PubMed  Google Scholar 

  33. Lehmann KA, Bass BL (2000) Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. Biochemistry 39(42):12875–12884. doi:10.1021/bi001383g

    Article  CAS  PubMed  Google Scholar 

  34. Bahn JH, Lee JH, Li G, Greer C, Peng G, Xiao X (2012) Accurate identification of A-to-I RNA editing in human by transcriptome sequencing. Genome Res 22(1):142–150. doi:10.1101/gr.124107.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. St Laurent G, Tackett MR, Nechkin S, Shtokalo D, Antonets D, Savva YA, Maloney R, Kapranov P, Lawrence CE, Reenan RA (2013) Genome-wide analysis of A-to-I RNA editing by single-molecule sequencing in Drosophila. Nat Struct Mol Biol 20(11):1333–1339. doi:10.1038/nsmb.2675

    Article  CAS  PubMed  Google Scholar 

  36. Wong SK, Sato S, Lazinski DW (2001) Substrate recognition by ADAR1 and ADAR2. RNA 7(6):846–858. doi:10.1017/s135583820101007x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Eggington JM, Greene T, Bass BL (2011) Predicting sites of ADAR editing in double-stranded RNA. Nat Commun 2:319. doi:10.1038/ncomms1324

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Kuttan A, Bass BL (2012) Mechanistic insights into editing-site specificity of ADARs. Proc Natl Acad Sci U S A 109(48):E3295–E3304. doi:10.1073/pnas.1212548109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Goodman RA, Macbeth MR, Beal PA (2012) ADAR proteins: structure and catalytic mechanism. Curr Top Microbiol Immunol 353:1–33. doi:10.1007/82_2011_144

    CAS  PubMed  Google Scholar 

  40. 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(23):12541–12546. doi:10.1073/pnas.97.23.12541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Barraud P, Heale BS, O’Connell MA, Allain FH (2012) Solution structure of the N-terminal dsRBD of Drosophila ADAR and interaction studies with RNA. Biochimie 94(7):1499–1509. doi:10.1016/j.biochi.2011.12.017

    Article  CAS  PubMed  Google Scholar 

  42. Stefl R, Oberstrass FC, Hood JL, Jourdan M, Zimmermann M, Skrisovska L, Maris C, Peng L, Hofr C, Emeson RB, Allain FH (2010) The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence-specific readout of the minor groove. Cell 143(2):225–237. doi:10.1016/j.cell.2010.09.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Eisenberg E (2012) Bioinformatic approaches for identification of A-to-I editing sites. Curr Top Microbiol Immunol 353:145–162. doi:10.1007/82_2011_147

    CAS  PubMed  Google Scholar 

  44. 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. doi:10.1016/0092-8674(91)90568-j

    Article  CAS  PubMed  Google Scholar 

  45. Morse DP, Bass BL (1997) Detection of inosine in messenger RNA by inosine-specific cleavage. Biochemistry 36(28):8429–8434. doi:10.1021/bi9709607

    Article  CAS  PubMed  Google Scholar 

  46. Sakurai M, Yano T, Kawabata H, Ueda H, Suzuki T (2010) Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. Nat Chem Biol 6(10):733–740. doi:10.1038/nchembio.434

    Article  CAS  PubMed  Google Scholar 

  47. Morse DP, Aruscavage PJ, Bass BL (2002) RNA hairpins in noncoding regions of human brain and Caenorhabditis elegans mRNA are edited by adenosine deaminases that act on RNA. Proc Natl Acad Sci U S A 99(12):7906–7911. doi:10.1073/pnas.112704299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Morse DP, Bass BL (1999) Long RNA hairpins that contain inosine are present in Caenorhabditis elegans poly(A) + RNA. Proc Natl Acad Sci 96(11):6048–6053. doi:10.1073/pnas.96.11.6048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sakurai M, Ueda H, Yano T, Okada S, Terajima H, Mitsuyama T, Toyoda A, Fujiyama A, Kawabata H, Suzuki T (2014) A biochemical landscape of A-to-I RNA editing in the human brain transcriptome. Genome Res 24(3):522–534. doi:10.1101/gr.162537.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hoopengardner B, Bhalla T, Staber C, Reenan R (2003) Nervous system targets of RNA editing identified by comparative genomics. Science 301(5634):832–836. doi:10.1126/science.1086763

    Article  CAS  PubMed  Google Scholar 

  51. Athanasiadis A, Rich A, Maas S (2004) Widespread A-to-I RNA editing of alu-containing mRNAs in the human transcriptome. PLoS Biol 2(12):2144–2158. doi:10.1371/journal.pbio.0020391

    Article  CAS  Google Scholar 

  52. Blow M, Futreal PA, Wooster R, Stratton MR (2004) A survey of RNA editing in human brain. Genome Res 14(12):2379–2387. doi:10.1101/gr.2951204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kim DD, Kim TT, Walsh T, Kobayashi Y, Matise TC, Buyske S, Gabriel A (2004) Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res 14(9):1719–1725. doi:10.1101/gr.2855504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, Fligelman ZY, Shoshan A, Pollock SR, Sztybel D, Olshansky M, Rechavi G, Jantsch MF (2004) Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol 22(8):1001–1005. doi:10.1038/nbt996

    Article  CAS  PubMed  Google Scholar 

  55. Li JB, Levanon EY, Yoon J-K, Aach J, Xie B, LeProust E, Zhang K, Gao Y, Church GM (2009) Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324(5931):1210–1213. doi:10.1126/science.1170995

    Article  CAS  PubMed  Google Scholar 

  56. Li M, Wang IX, Li Y, Bruzel A, Richards AL, Toung JM, Cheung VG (2011) Widespread RNA and DNA sequence differences in the human transcriptome. Science 333(6038):53–58. doi:10.1126/science.1207018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schrider DR, Gout J-F, Hahn MW (2011) Very few RNA and DNA sequence differences in the human transcriptome. PLoS One 6(10), e25842. doi:10.1371/journal.pone.0025842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Piskol R, Peng Z, Wang J, Li JB (2013) Lack of evidence for existence of noncanonical RNA editing. Nat Biotechnol 31(1):19–20. doi:10.1038/nbt.2472

    Article  CAS  PubMed  Google Scholar 

  59. Lee JH, Ang JK, Xiao X (2013) Analysis and design of RNA sequencing experiments for identifying RNA editing and other single-nucleotide variants. RNA. doi:10.1261/rna.037903.112

    Google Scholar 

  60. Ramaswami G, Lin W, Piskol R, Tan MH, Davis C, Li JB (2012) Accurate identification of human Alu and non-Alu RNA editing sites. Nat Methods 9(6):579–581. doi:10.1038/nmeth.1982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Peng Z, Cheng Y, Tan BC, Kang L, Tian Z, Zhu Y, Zhang W, Liang Y, Hu X, Tan X, Guo J, Dong Z, Bao L, Wang J (2012) Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat Biotechnol 30(3):253–260. doi:10.1038/nbt.2122

    Article  CAS  PubMed  Google Scholar 

  62. Wu D, Lamm AT, Fire AZ (2011) Competition between ADAR and RNAi pathways for an extensive class of RNA targets. Nat Struct Mol Biol 18(10):1094–1101. doi:10.1038/Nsmb.2129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Washburn MC, Kakaradov B, Sundararaman B, Wheeler E, Hoon S, Yeo GW, Hundley HA (2014) The dsRBP and inactive editor ADR-1 utilizes dsRNA-binding to regulate A-to-I RNA editing across the C. elegans transcriptome. Cell Rep 6(4):599–607. doi:10.1016/j.celrep.2014.01.011

    Google Scholar 

  64. Ramaswami G, Zhang R, Piskol R, Keegan LP, Deng P, O’Connell MA, Li JB (2013) Identifying RNA editing sites using RNA sequencing data alone. Nat Methods 10(2):128–132. doi:10.1038/nmeth.2330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Paz N, Levanon EY, Amariglio N, Heimberger AB, Ram Z, Constantini S, Barbash ZS, Adamsky K, Safran M, Hirschberg A, Krupsky M, Ben-Dov I, Cazacu S, Mikkelsen T, Brodie C, Eisenberg E, Rechavi G (2007) Altered adenosine-to-inosine RNA editing in human cancer. Genome Res 17(11):1586–1595. doi:10.1101/gr.6493107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Desterro JMP, 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(9):1805–1818. doi:10.1242/jcs.00371

    Article  CAS  PubMed  Google Scholar 

  67. Sansam CL, Wells KS, Emeson RB (2003) Modulation of RNA editing by functional nucleolar sequestration of ADAR2. Proc Natl Acad Sci 100(24):14018–14023. doi:10.1073/pnas.2336131100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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. doi:10.1128/MCB.01519-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Barraud P, Banerjee S, Mohamed WI, Jantsch MF, Allain FH (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(18):E1852–E1861. doi:10.1073/pnas.1323698111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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 30(20):4211–4222. doi:10.1038/emboj.2011.303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ohta H, Fujiwara M, Ohshima Y, Ishihara T (2008) ADBP-1 regulates an ADAR RNA-editing enzyme to antagonize RNA-interference-mediated gene silencing in Caenorhabditis elegans. Genetics 180(2):785–796. doi:10.1534/genetics.108.093310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lu KP, Zhou XZ (2007) The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol 8(11):904–916. doi:10.1038/nrm2261

    Article  CAS  PubMed  Google Scholar 

  73. Garrncarz W, Tariq A, Handl C, Pusch O, Jantsch MF (2013) A high throughput screen to identify enhancers of ADAR-mediated RNA-editing. RNA Biol 10(2):192–204. doi:10.4161/rna.23208

    Article  CAS  Google Scholar 

  74. Funakoshi M, Li X, Velichutina I, Hochstrasser M, Kobayashi H (2004) Sem1, the yeast ortholog of a human BRCA2-binding protein, is a component of the proteasome regulatory particle that enhances proteasome stability. J Cell Sci 117(26):6447–6454. doi:10.1242/jcs.01575

    Article  CAS  PubMed  Google Scholar 

  75. Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW (2008) Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation. J Mol Biol 383(3):693–712. doi:10.1016/j.jmb.2008.08.044

    Article  CAS  PubMed  Google Scholar 

  76. Ellisdon AM, Dimitrova L, Hurt E, Stewart M (2012) Structural basis for the assembly and nucleic acid binding of the TREX-2 transcription-export complex. Nat Struct Mol Biol 19(3):328–336. doi:10.1038/nsmb.2235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Li J, Zou C, Bai Y, Wazer DE, Band V, Gao Q (2005) DSS1 is required for the stability of BRCA2. Oncogene 25(8):1186–1194

    Article  CAS  Google Scholar 

  78. Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thomä NH, Zheng N, Chen P-L, Lee W-H, Pavletich NP (2002) BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297(5588):1837–1848. doi:10.1126/science.297.5588.1837

    Article  CAS  PubMed  Google Scholar 

  79. 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. doi:10.1091/mbc.E05-06-0536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wilkinson KA, Henley JM (2010) Mechanisms, regulation and consequences of protein SUMOylation. Biochem J 428(2):133–145. doi:10.1042/bj20100158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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. doi:10.1089/jir.2010.0097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yang W, Wang Q, Kanes SJ, Murray JM, Nishikura K (2004) Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy. Brain Res Mol Brain Res 124(1):70–78. doi:10.1016/j.molbrainres.2004.02.010

    Article  CAS  PubMed  Google Scholar 

  83. Yeo J, Goodman RA, Schirle NT, David SS, Beal PA (2010) RNA editing changes the lesion specificity for the DNA repair enzyme NEIL1. Proc Natl Acad Sci 107(48):20715–20719. doi:10.1073/pnas.1009231107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hood JL, Morabito MV, Martinez CR, Gilbert JA, Ferrick EA, Ayers GD, Chappell JD, Dermody TS, Emeson RB (2014) Reovirus-mediated induction of ADAR1 (p150) minimally alters RNA editing patterns in discrete brain regions. Mol Cell Neurosci. doi:10.1016/j.mcn.2014.06.001

    PubMed  PubMed Central  Google Scholar 

  85. Moore MJ (2005) From birth to death: the complex lives of eukaryotic mRNAs. Science 309(5740):1514–1518. doi:10.1126/science.1111443

    Article  CAS  PubMed  Google Scholar 

  86. Anderson P, Kedersha N (2009) RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat Rev Mol Cell Biol 10(6):430–436. doi:10.1038/nrm2694

    Article  CAS  PubMed  Google Scholar 

  87. Bratt E, Ohman M (2003) Coordination of editing and splicing of glutamate receptor pre-mRNA. RNA 9(3):309–318. doi:10.1261/rna.2750803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Palladino MJ, Keegan LP, O’Connell MA, Reenan RA (2000) dADAR, a Drosophila double-stranded RNA-specific adenosine deaminase is highly developmentally regulated and is itself a target for RNA editing. RNA 6(7):1004–1018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  90. Marcucci R, Romano M, Feiguin F, O’Connell MA, Baralle FE (2009) Dissecting the splicing mechanism of the Drosophila editing enzyme; dADAR. Nucleic Acids Res 37(5):1663–1671. doi:10.1093/nar/gkn1080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tariq A, Garncarz W, Handl C, Balik A, Pusch O, Jantsch MF (2013) RNA-interacting proteins act as site-specific repressors of ADAR2-mediated RNA editing and fluctuate upon neuronal stimulation. Nucleic Acids Res 41(4):2581–2593. doi:10.1093/nar/gks1353

    Article  CAS  PubMed  Google Scholar 

  92. Ota H, Sakurai M, Gupta R, Valente L, Wulff B-E, Ariyoshi K, Iizasa H, Davuluri Ramana V, Nishikura K (2013) ADAR1 forms a complex with dicer to promote MicroRNA processing and RNA-induced gene silencing. Cell 153(3):575–589. doi:10.1016/j.cell.2013.03.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bhogal B, Jepson JE, Savva YA, Pepper AS, Reenan RA, Jongens TA (2011) Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein. Nat Neurosci 14(12):1517–1524. doi:10.1038/nn.2950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Reenan RA, Hanrahan CJ, Ganetzky B (2000) The mlenapts RNA helicase mutation in drosophila results in a splicing catastrophe of the para Na + channel transcript in a region of RNA editing. Neuron 25(1):139–149. doi:10.1016/s0896-6273(00)80878-8

    Article  CAS  PubMed  Google Scholar 

  95. de Lucas S, Oliveros JC, Chagoyen M, Ortin J (2014) Functional signature for the recognition of specific target mRNAs by human Staufen1 protein. Nucleic Acids Res. doi:10.1093/nar/gku073

    Google Scholar 

  96. Elbarbary RA, Li W, Tian B, Maquat LE (2013) STAU1 binding 3′ UTR IRAlus complements nuclear retention to protect cells from PKR-mediated translational shutdown. Genes Dev 27(13):1495–1510. doi:10.1101/gad.220962.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Legendre JB, Campbell ZT, Kroll-Conner P, Anderson P, Kimble J, Wickens M (2013) RNA targets and specificity of Staufen, a double-stranded RNA-binding protein in Caenorhabditis elegans. J Biol Chem 288(4):2532–2545. doi:10.1074/jbc.M112.397349

    Article  CAS  PubMed  Google Scholar 

  98. Buratti E, Baralle FE (2004) Influence of RNA secondary structure on the pre-mRNA splicing process. Mol Cell Biol 24(24):10505–10514. doi:10.1128/MCB.24.24.10505-10514.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rieder LE, Staber CJ, Hoopengardner B, Reenan RA (2013) Tertiary structural elements determine the extent and specificity of messenger RNA editing. Nat Commun 4:2232. doi:10.1038/ncomms3232

    Article  PubMed  CAS  Google Scholar 

  100. Laurencikiene J, Kallman AM, Fong N, Bentley DL, Ohman M (2006) RNA editing and alternative splicing: the importance of co-transcriptional coordination. EMBO Rep 7(3):303–307. doi:10.1038/sj.embor.7400621

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Ryman K, Fong N, Bratt E, Bentley DL, Ohman M (2007) The C-terminal domain of RNA Pol II helps ensure that editing precedes splicing of the GluR-B transcript. RNA 13(7):1071–1078. doi:10.1261/rna.404407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Solomon O, Oren S, Safran M, Deshet-Unger N, Akiva P, Jacob-Hirsch J, Cesarkas K, Kabesa R, Amariglio N, Unger R, Rechavi G, Eyal E (2013) Global regulation of alternative splicing by adenosine deaminase acting on RNA (ADAR). RNA 19(5):591–604. doi:10.1261/rna.038042.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Han SP, Tang YH, Smith R (2010) Functional diversity of the hnRNPs: past, present and perspectives. Biochem J 430(3):379–392. doi:10.1042/BJ20100396

    Article  CAS  PubMed  Google Scholar 

  104. Martinez-Contreras R, Cloutier P, Shkreta L, Fisette JF, Revil T, Chabot B (2007) hnRNP proteins and splicing control. Adv Exp Med Biol 623:123–147

    Article  PubMed  Google Scholar 

  105. 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. doi:10.1038/387303a0

    Article  CAS  PubMed  Google Scholar 

  106. Cavaillé J, Buiting K, Kiefmann M, Lalande M, Brannan CI, Horsthemke B, Bachellerie J-P, Brosius J, Hüttenhofer A (2000) Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc Natl Acad Sci 97(26):14311–14316. doi:10.1073/pnas.250426397

    Article  PubMed  PubMed Central  Google Scholar 

  107. Kishore S, Stamm S (2006) The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311(5758):230–232. doi:10.1126/science.1118265

    Article  CAS  PubMed  Google Scholar 

  108. 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. doi:10.1083/jcb.200411129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hughes ME, Grant GR, Paquin C, Qian J, Nitabach MN (2012) Deep sequencing the circadian and diurnal transcriptome of Drosophila brain. Genome Res 22(7):1266–1281. doi:10.1101/gr.128876.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Powell WT, Coulson RL, Crary FK, Wong SS, Ach RA, Tsang P, Alice Yamada N, Yasui DH, Lasalle JM (2013) A Prader-Willi locus lncRNA cloud modulates diurnal genes and energy expenditure. Hum Mol Genet 22(21):4318–4328. doi:10.1093/hmg/ddt281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Keegan LP, Brindle J, Gallo A, Leroy A, Reenan RA, Connell MA (2005) Tuning of RNA editing by ADAR is required in Drosophila. EMBO J 24(12):2183–2193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Feng Y, Sansam CL, Singh M, Emeson RB (2006) Altered RNA editing in mice lacking ADAR2 autoregulation. Mol Cell Biol 26(2):480–488. doi:10.1128/MCB.26.2.480-488.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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. doi:10.1074/jbc.M700265200

    Article  CAS  PubMed  Google Scholar 

  114. 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. doi:10.1261/rna.7920904

    Google Scholar 

  115. Micklem DRAJGSSJD (2000) Distinct roles of two conserved Staufen domains in oskar mRNA localization and translation. EMBO J 19(6):1366–1377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hough RF, Lingam AT, Bass BL (1999) Caenorhabditis elegans mRNAs that encode a protein similar to ADARs derive from an operon containing six genes. Nucleic Acids Res 27(17):3424–3432. doi:10.1093/nar/27.17.3424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wang Z, Hartman E, Roy K, Chanfreau G, Feigon J (2011) Structure of a yeast RNase III dsRBD complex with a noncanonical RNA substrate provides new insights into binding specificity of dsRBDs. Structure 19(7):999–1010. doi:10.1016/j.str.2011.03.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Connolly CM, Dearth AT, Braun RE (2005) Disruption of murine Tenr results in teratospermia and male infertility. Dev Biol 278(1):13–21. doi:10.1016/j.ydbio.2004.10.009

    Article  CAS  PubMed  Google Scholar 

  119. 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. doi:10.1074/jbc.271.50.31795

    Article  CAS  PubMed  Google Scholar 

  120. 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

    Google Scholar 

  121. Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10(2):126–139. doi:10.1038/nrm2632

    Article  CAS  PubMed  Google Scholar 

  122. Nemlich Y, Greenberg E, Ortenberg R, Besser MJ, Barshack I, Jacob-Hirsch J, Jacoby E, Eyal E, Rivkin L, Prieto VG, Chakravarti N, Duncan LM, Kallenberg DM, Galun E, Bennett DC, Amariglio N, Bar-Eli M, Schachter J, Rechavi G, Markel G (2013) MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth. J Clin Invest 123(6):2703–2718. doi:10.1172/jci62980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Heraud-Farlow JE, Kiebler MA (2014) The multifunctional Staufen proteins: conserved roles from neurogenesis to synaptic plasticity. Trends Neurosci. doi:10.1016/j.tins.2014.05.009

    PubMed  PubMed Central  Google Scholar 

  124. Siomi H, Siomi MC, Nussbaum RL, Dreyfuss G (1993) The protein product of the fragile-X gene, Fmr1, has characteristics of an RNA-binding protein. Cell 74(2):291–298. doi:10.1016/0092-8674(93)90420-U

    Article  CAS  PubMed  Google Scholar 

  125. Ascano M Jr, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, Langlois C, Munschauer M, Dewell S, Hafner M, Williams Z, Ohler U, Tuschl T (2012) FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 492(7429):382–386. doi:10.1038/nature11737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. De Boulle K, Verkerk AJMH, Reyniers E, Vits L, Hendrickx J, Van Roy B, Van Den Bos F, de Graaff E, Oostra BA, Willems PJ (1993) A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet 3(1):31–35

    Article  PubMed  Google Scholar 

  127. Siomi H, Choi MY, Siomi MC, Nussbaum RL, Dreyfuss G (1994) Essential role for Kh domains in RNA-binding—impaired RNA-binding by a mutation in the Kh domain of Fmr1 that causes fragile-X syndrome. Cell 77(1):33–39. doi:10.1016/0092-8674(94)90232-1

    Article  CAS  PubMed  Google Scholar 

  128. De Rubeis S, Fernández E, Buzzi A, Di Marino D, Bagni C (2012) Molecular and cellular aspects of mental retardation in the fragile X syndrome: from gene mutation/s to spine dysmorphogenesis. In: Kreutz MR, Sala C (eds) Synaptic plasticity, vol 970, Advances in experimental medicine and biology. Springer, Vienna, pp 517–551. doi:10.1007/978-3-7091-0932-8_23

    Chapter  Google Scholar 

  129. Moritz M, Paulovich AG, Tsay YF, Woolford JL (1990) Depletion of yeast ribosomal proteins L16 or rp59 disrupts ribosome assembly. J Cell Biol 111(6):2261–2274. doi:10.1083/jcb.111.6.2261

    Article  CAS  PubMed  Google Scholar 

  130. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, Raza A, Root DE, Attar E, Ellis SR, Golub TR (2008) Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451(7176):335–339. doi:10.1038/nature06494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hartner JC, Walkley CR, Lu J, Orkin SH (2009) ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol 10(1):109–115. doi:10.1038/ni.1680

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This work was supported by an NIH predoctoral training grant to M.C.W. (T32 GM007757) and start-up funds from the Indiana University School of Medicine.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Heather A. Hundley .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Washburn, M.C., Hundley, H.A. (2016). Controlling the Editor: The Many Roles of RNA-Binding Proteins in Regulating A-to-I RNA Editing. In: Yeo, G. (eds) RNA Processing. Advances in Experimental Medicine and Biology, vol 907. Springer, Cham. https://doi.org/10.1007/978-3-319-29073-7_8

Download citation

Publish with us

Policies and ethics