Abstract
Alu elements are repetitive short interspersed elements prevalent in the primate genome. These repeats account for over 10% of the genome with more than a million highly similar copies. A direct outcome of this is an enrichment in long structures of stable dsRNA, which are the target of adenosine deaminases acting on RNAs (ADARs), the enzymes catalyzing A-to-I RNA editing. Indeed, A-to-I editing by ADARs is extremely abundant in primates: over a hundred million editing sites exist in their genomes. However, despite the radical increase in ADAR targets brought on by the introduction of Alu elements, the few evolutionary conserved editing sites manage to retain their editing levels. Here, we review and discuss the cost of having an unusual amount of dsRNA and editing in the transcriptome, as well as the opportunities it presents, which possibly contributed to accelerating primate evolution.
Key words
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Li JB, Church GM (2013) Deciphering the functions and regulation of brain-enriched A-to-I RNA editing. Nat Neurosci 16:1518–1522
Savva YA, Rieder LE, Reenan RA (2012) The ADAR protein family. Genome Biol 13:252
Nishikura K (2010) Functions and regulation of RNA editing by ADAR Deaminases. Annu Rev Biochem 79:321–349
Chen CX, Cho DS, 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 (New York, NY) 6:755–767
Oakes E, Anderson A, Cohen-Gadol A et al (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
Bass BL (2002) RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 71:817–846
Ramaswami G, Zhang R, Piskol R et al (2013) Identifying RNA editing sites using RNA sequencing data alone. Nat Methods 10:128–132
St Laurent G, Tackett MR, Nechkin S et al (2013) Genome-wide analysis of A-to-I RNA editing by single-molecule sequencing in Drosophila. Nat Struct Mol Biol 20:1333–1339
Pinto Y, Cohen HY, Levanon EY (2014) Mammalian conserved ADAR targets comprise only a small fragment of the human editosome. Genome Biol 15:R5
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
Hoopengardner B (2003) Nervous system targets of RNA editing identified by comparative genomics. Science 301:832–836
Yang W, Chendrimada TP, Wang Q et al (2005) Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol 13:13–21
Kawahara Y, Zinshteyn B, Sethupathy P et al (2007) Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315:1137–1140
Paul D, Sinha AN, Ray A et al (2017) A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoedited in glioblastoma multiforme. Sci Rep 7:2466
Pinto Y, Buchumenski I, Levanon EY et al (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
Blow M, Grocock R, van Dongen S et al (2006) RNA editing of human microRNAs. Genome Biol 7:R27
Alon S, Mor E, Vigneault F et al (2012) Systematic identification of edited microRNAs in the human brain. Genome Res 22:1533–1540
Warnefors M, Liechti A, Halbert J et al (2014) Conserved microRNA editing in mammalian evolution, development and disease. Genome Biol 15:R83
Wahlstedt H, Daniel C, Ensterö M et al (2009) Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res 19(6):978–986. https://doi.org/10.1101/gr.089409.108
Greenberger S, Levanon EY, Paz-Yaacov N et al (2010) Consistent levels of A-to-I RNA editing across individuals in coding sequences and non-conserved Alu repeats. BMC Genomics 11:608
Slotkin W, Nishikura K (2013) Adenosine-to-inosine RNA editing and human disease. Genome Med 5:105
Gallo A, Locatelli F (2011) ADARs: allies or enemies? The importance of A-to-I RNA editing in human disease: from cancer to HIV-1. Biol Rev 87:95–110
Levanon EY (2005) Evolutionarily conserved human targets of adenosine to inosine RNA editing. Nucleic Acids Res 33:1162–1168
Ohlson J, Pedersen JS, Haussler D et al (2007) Editing modifies the GABAA receptor subunit 3. RNA 13:698–703
Eisenberg E, Levanon EY (2018) A-to-I RNA editing—immune protector and transcriptome diversifier. Nat Rev Genet 19:473–490
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
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
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
Blow M (2004) A survey of RNA editing in human brain. Genome Res 14:2379–2387
Bazak L, Haviv A, Barak M et al (2013) 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
Ullu E and Tschudi C Alu sequences are processed 7SL RNA genes. Nature 312:171–2
Batzer MA, Deininger PL (2002) Alu repeats and human genomic diversity. Nat Rev Genet 3:370–379
Neeman Y, Levanon EY, Jantsch MF, et al (2006) RNA editing level in the mouse is determined by the genomic repeat repertoire. RNA (New York, NY) 12:1802–9
Eisenberg E, Li JB, Levanon EY (2010) Sequence based identification of RNA editing sites. RNA Biol 7:248–252
Lin W, Piskol R, Tan MH et al (2012) Comment on “widespread RNA and DNA sequence differences in the human transcriptome”. Science 335:1302–1302
Pickrell JK, Gilad Y, Pritchard JK (2012) Comment on “widespread RNA and DNA sequence differences in the human transcriptome”. Science (New York, NY) 335:1302; author reply 1302
Kleinman CL, Majewski J (2012) Comment on “widespread RNA and DNA sequence differences in the human transcriptome”. Science 335:1302; author reply 1302
Bahn JH, Lee J-H, Li G et al (2011) Accurate identification of A-to-I RNA editing in human by transcriptome sequencing. Genome Res 22:142–150
Park E, Williams B, Wold BJ et al (2012) RNA editing in the human ENCODE RNA-seq data. Genome Res 22:1626–1633
Peng Z, Cheng Y, Tan BC-M et al (2012) Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat Biotechnol 30:253–260
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
Porath HT, Carmi S, Levanon EY (2014) A genome-wide map of hyper-edited RNA reveals numerous new sites. Nat Commun 5:4726
Cattenoz PB, Taft RJ, Westhof E et al (2012) Transcriptome-wide identification of A > I RNA editing sites by inosine specific cleavage. RNA 19:257–270
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
Ramaswami G and Li JB (2013) RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic acids research gkt996
Djebali S, Davis CA, Merkel A et al (2012) Landscape of transcription in human cells. Nature 489:101–108
Hishiki T, Kawamoto S, Morishita S et al (2000) BodyMap: a human and mouse gene expression database. Nucleic Acids Res 28:136–138
Nishikura K (2006) Editor meets silencer: crosstalk between RNA editing and RNA interference. Nat Rev Mol Cell Biol 7:919–931
George CX, John L, Samuel CE (2014) An RNA editor, adenosine deaminase acting on double-stranded RNA (ADAR1). J Interf Cytokine Res 34:437–446
Saunders LR, Barber GN (2003) The dsRNA binding protein family: critical roles, diverse cellular functions. FASEB J 17:961–983
Barak M, Porath HT, Finkelstein G et al (2020) Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity. Genome Biology 21:26
Neeman Y, Dahary D, Levanon EY et al (2005) Is there any sense in antisense editing? Trends Genet 21(10):544–547
Bass BL, Weintraub H (1987) A developmentally regulated activity that unwinds RNA duplexes. Cell 48:607–613
Bass BL, Weintraub H (1988) An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell 55:1089–1098
Eisenberg E, Nemzer S, Kinar Y et al (2005) Is abundant A-to-I RNA editing primate-specific? Trends Genet 21:77–81
Wang IX, So E, Devlin JL et al (2013) ADAR regulates RNA editing, transcript stability, and gene expression. Cell Rep 5:849–860
Melcher T, Maas S, Herb A et al (1996) A mammalian RNA editing enzyme. Nature 379:460–464
Riedmann EM, Schopoff S, Hartner JC et al (2008) Specificity of ADAR-mediated RNA editing in newly identified targets. RNA 14:1110–1118
Kwak S, Nishimoto Y, Yamashita T (2008) Newly identified ADAR-mediated A-to-I editing positions as a tool for ALS research. RNA Biol 5:193–197
Burns CM, Chu H, Rueter SM et al (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387:303–308
Nishimoto Y, Yamashita T, Hideyama T et al (2008) Determination of editors at the novel A-to-I editing positions. Neurosci Res 61:201–206
Bazak L, Levanon EY, Eisenberg E (2014) Genome-wide analysis of Alu editability. Nucleic Acids Res 42:6876–6884
Bhalla T, Rosenthal JJC, Holmgren M et al (2004) Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nat Struct Mol Biol 11:950–956
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
Freund EC, Sapiro AL, Li Q et al (2019) Unbiased identification of trans regulators of ADAR and A-to-I RNA editing. bioRxiv:631200
Quinones-Valdez G, Tran SS, Jun H-I et al (2019) Regulation of RNA editing by RNA-binding proteins in human cells. Comm Biol 2:19
Roth SH, Levanon EY, Eisenberg E. (2019) Genome-wide quantification of ADAR adenosine-to-inosine RNA editing activity. Nat Methods 16:1131–1138
Schaffer AA, Kopel E, Hendel A et al (2020) The cell line A-to-I RNA editing catalogue. Nucleic Acids Res https://doi.org/10.1093/nar/gkaa305
Hulme AE, Bogerd HP, Cullen BR et al (2007) Selective inhibition of Alu retrotransposition by APOBEC3G. Gene 390:199
Koito A, Ikeda T (2013) Intrinsic immunity against retrotransposons by APOBEC cytidine deaminases. Front Microbiol 4:28
Cordaux R, Hedges DJ, Herke SW et al (2006) Estimating the retrotransposition rate of human Alu elements. Gene 373:134–137
Smalheiser NR, Torvik VI (2006) Alu elements within human mRNAs are probable microRNA targets. Trends Genet 22:532–536
Liang H, Landweber LF (2007) Hypothesis: RNA editing of microRNA target sites in humans? RNA (New York, NY) 13:463–467
Hoffman Y, Dahary D, Bublik DR et al (2013) The majority of endogenous microRNA targets within Alu elements avoid the microRNA machinery. Bioinformatics 29:894–902
Zhang Z, Carmichael GG (2001) The fate of dsRNA in the nucleus: a p54(nrb)-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell 106:465–475
Scadden ADJ, Smith CW (2001) Specific cleavage of hyper-edited dsRNAs. EMBO J 20:4243–4252
Savva YA, JEC J, Chang Y-J et al (2013) RNA editing regulates transposon-mediated heterochromatic gene silencing. Nat Commun 4:2745
Schmitz J, Brosius J (2011) Exonization of transposed elements: a challenge and opportunity for evolution. Biochimie 93:1928–1934
Lev-Maor G (2003) The birth of an alternatively spliced exon: 3′ splice-site selection in Alu exons. Science 300:1288–1291
Sela N, Mersch B, Gal-Mark N et al (2007) Comparative analysis of transposed element insertion within human and mouse genomes reveals Alu’s unique role in shaping the human transcriptome. Genome Biol 8:R127
Lev-Maor G, Sorek R, Levanon EY et al (2007) RNA-editing-mediated exon evolution. Genome Biol 8:R29
Daniel C, Silberberg G, Behm M et al (2014) Alu elements shape the primate transcriptome by cis-regulation of RNA editing. Genome Biol 15:R28
Barak M, Levanon EY, Eisenberg E et al (2009) Evidence for large diversity in the human transcriptome created by Alu RNA editing. Nucleic Acids Res 37:6905–6915
Schmucker D, Clemens JC, Shu H et al (2000) Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101:671–684
Paz-Yaacov N, Levanon EY, Nevo E et al (2010) Adenosine-to-inosine RNA editing shapes transcriptome diversity in primates. Proc Natl Acad Sci U S A 107:12174–12179
Mattick JS, Mehler MF (2008) RNA editing, DNA recoding and the evolution of human cognition. Trends Neurosci 31:227–233
Acknowledgments
EYL was supported by the International Collaboration Grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, a partnership of the Israel Cancer Research Fund and City of Hope, as supported by The Harvey L. Miller Family Foundation [grant number 205467].
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Schaffer, A.A., Levanon, E.Y. (2021). ALU A-to-I RNA Editing: Millions of Sites and Many Open Questions. In: Picardi, E., Pesole, G. (eds) RNA Editing. Methods in Molecular Biology, vol 2181. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0787-9_9
Download citation
DOI: https://doi.org/10.1007/978-1-0716-0787-9_9
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-0786-2
Online ISBN: 978-1-0716-0787-9
eBook Packages: Springer Protocols