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ADAR Regulates RNA Editing, Transcript Stability, and Gene Expression

Isabel X. Wang, Elizabeth So, James L. Devlin and 3 more

Cell Reports · 2013 · CC BY-NC-ND

doi:10.1016/j.celrep.2013.10.002

Abstract

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine, which is then recognized as guanosine. To study the role of ADAR proteins in RNA editing and gene regulation, we sequenced and compared the DNA and RNA of human B cells. Then, we followed up the findings experimentally with siRNA knockdown and RNA and protein immunoprecipitations. The results uncovered over 60,000 A-to-G editing sites and several thousand genes whose expression levels are influenced by ADARs. Of these ADAR targets, 90% were identified. Our results also reveal that ADAR regulates transcript stability and gene expression through interaction with HuR (ELAVL1). These findings extend the role of ADAR and show that it cooperates with other RNA-processing proteins to regulate the sequence and expression of transcripts in human cells.

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References 53

  1. 1.

    Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al. Gene ontology: tool for the unification of biology. Nat Genet. 2000;25:25-29.

    Not in our library10.1038/75556

  2. 2.
  3. 3.

    Bahn JH, Lee JH, Li G, Greer C, Peng G, Xiao X. Accurate identification of A-to-I RNA editing in human by transcriptome sequencing. Genome Res. 2012;22:142-150.

    Not in our library10.1101/gr.124107.111

  4. 4.

    Bailey TL, Boden M, Buske FA, Frith M, Grant CE, Clementi L, Ren J, Li WW, Noble WS. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 2009;37(Web Server issue):W202-W208.

    Not in our library10.1093/nar/gkp335

  5. 5.

    Bass BL, Weintraub H. An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell. 1988;55:1089-1098.

    Not in our library10.1016/0092-8674(88)90253-x

  6. 6.

    Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, Hall KP, Evers DJ, Barnes CL, Bignell HR, et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008;456:53-59.

    Not in our library10.1038/nature07517

  7. 7.

    Blow M, Futreal PA, Wooster R, Stratton MR. A survey of RNA editing in human brain. Genome Res. 2004;14:2379-2387.

    Not in our library10.1101/gr.2951204

  8. 8.

    Carmi S, Borukhov I, Levanon EY. Identification of widespread ultra-edited human RNAs. PLoS Genet. 2011;7:e1002317.

    Not in our library10.1371/journal.pgen.1002317

  9. 9.

    Chang N, Yi J, Guo G, Liu X, Shang Y, Tong T, Cui Q, Zhan M, Gorospe M, Wang W. HuR uses AUF1 as a cofactor to promote p16INK4 mRNA decay. Mol Cell Biol. 2010;30:3875-3886.

    Not in our library10.1128/mcb.00169-10

  10. 10.

    Chen SH, Habib G, Yang CY, Gu ZW, Lee BR, Weng SA, Silberman SR, Cai SJ, Deslypere JP, Rosseneu M, et al. Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science. 1987;238:363-366.

    Not in our library10.1126/science.3659919

  11. 11.

    Chen CX, Cho DS, Wang Q, Lai F, Carter KC, Nishikura K. A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. RNA. 2000;6:755-767.

    Not in our library10.1017/s1355838200000170

  12. 12.

    Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam HYK, Chen R, Miriami E, Karczewski KJ, Hariharan M, Dewey FE, et al. Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell. 2012;148:1293-1307.

    Not in our library10.1016/j.cell.2012.02.009

  13. 13.
  14. 14.

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

    Not in our library10.1074/jbc.m511831200

  15. 15.

    Clerzius G, Gélinas JF, Daher A, Bonnet M, Meurs EF, Gatignol A. ADAR1 interacts with PKR during human immunodeficiency virus infection of lymphocytes and contributes to viral replication. J Virol. 2009;83:10119-10128.

    Not in our library10.1128/jvi.02457-08

  16. 16.

    Daniel C, Venø MT, Ekdahl Y, Kjems J, Öhman M. A distant cis acting intronic element induces site-selective RNA editing. Nucleic Acids Res. 2012;40:9876-9886.

    Not in our library10.1093/nar/gks691

  17. 17.

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

    Not in our library10.1074/jbc.m310068200

  18. 18.

    Fan XC, Steitz JA. Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. EMBO J. 1998;17:3448-3460.

    Not in our library10.1093/emboj/17.12.3448

  19. 19.

    Grimson A, Farh KKH, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007;27:91-105.

    Not in our library10.1016/j.molcel.2007.06.017

  20. 20.

    Heale BSE, Keegan LP, McGurk L, Michlewski G, Brindle J, Stanton CM, Caceres JF, O’Connell MA. Editing independent effects of ADARs on the miRNA/siRNA pathways. EMBO J. 2009;28:3145-3156.

    Not in our library10.1038/emboj.2009.244

  21. 21.
  22. 22.

    Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009a;4:44-57.

    Not in our library10.1038/nprot.2008.211

  23. 23.

    Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009b;37:1-13.

    Not in our library10.1093/nar/gkn923

  24. 24.

    Ju YS, Kim JI, Kim S, Hong D, Park H, Shin JY, Lee S, Lee WC, Kim S, Yu SB, et al. Extensive genomic and transcriptional diversity identified through massively parallel DNA and RNA sequencing of eighteen Korean individuals. Nat Genet. 2011;43:745-752.

    Not in our library10.1038/ng.872

  25. 25.

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

    Not in our library10.1073/pnas.91.24.11457

  26. 26.

    Kim DDY, Kim TTY, Walsh T, Kobayashi Y, Matise TC, Buyske S, Gabriel A. Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res. 2004;14:1719-1725.

    Not in our library10.1101/gr.2855504

  27. 27.

    Kiran A, Baranov PV. DARNED: a DAtabase of RNa EDiting in humans. Bioinformatics. 2010;26:1772-1776.

    Not in our library10.1093/bioinformatics/btq285

  28. 28.

    Kishore S, Jaskiewicz L, Burger L, Hausser J, Khorshid M, Zavolan M. A quantitative analysis of CLIP methods for identifying binding sites of RNA-binding proteins. Nat Methods. 2011;8:559-564.

    Not in our library10.1038/nmeth.1608

  29. 29.

    Klaue Y, Källman AM, Bonin M, Nellen W, Ohman M. Biochemical analysis and scanning force microscopy reveal productive and nonproductive ADAR2 binding to RNA substrates. RNA. 2003;9:839-846.

    Not in our library10.1261/rna.2167603

  30. 30.

    Kuttan A, Bass BL. Mechanistic insights into editing-site specificity of ADARs. Proc Natl Acad Sci USA. 2012;109:E3295-E3304.

    Not in our library10.1073/pnas.1212548109

  31. 31.

    Lal A, Mazan-Mamczarz K, Kawai T, Yang X, Martindale JL, Gorospe M. Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs. EMBO J. 2004;23:3092-3102.

    Not in our library10.1038/sj.emboj.7600305

  32. 32.

    Lebedeva S, Jens M, Theil K, Schwanhäusser B, Selbach M, Landthaler M, Rajewsky N. Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR. Mol Cell. 2011;43:340-352.

    Not in our library10.1016/j.molcel.2011.06.008

  33. 33.

    Lehmann KA, Bass BL. Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. Biochemistry. 2000;39:12875-12884.

    Not in our library10.1021/bi001383g

  34. 34.

    Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, Fligelman ZY, Shoshan A, Pollock SR, Sztybel D, et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol. 2004;22:1001-1005.

    Not in our library10.1038/nbt996

  35. 35.

    Li JB, Levanon EY, Yoon JK, Aach J, Xie B, Leproust E, Zhang K, Gao Y, Church GM. Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science. 2009;324:1210-1213.

    Not in our library10.1126/science.1170995

  36. 36.

    Li M, Wang IX, Li Y, Bruzel A, Richards AL, Toung JM, Cheung VG. Widespread RNA and DNA sequence differences in the human transcriptome. Science. 2011;333:53-58.

    Not in our library10.1126/science.1207018

  37. 37.

    Licatalosi DD, Darnell RB. RNA processing and its regulation: global insights into biological networks. Nat Rev Genet. 2010;11:75-87.

    Not in our library10.1038/nrg2673

  38. 38.

    Maniatis T, Reed R. An extensive network of coupling among gene expression machines. Nature. 2002;416:499-506.

    Not in our library10.1038/416499a

  39. 39.

    Mukherjee N, Corcoran DL, Nusbaum JD, Reid DW, Georgiev S, Hafner M, Ascano M, Tuschl T, Ohler U, Keene JD. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol Cell. 2011;43:327-339.

    Not in our library10.1016/j.molcel.2011.06.007

  40. 40.

    Myer VE, Fan XC, Steitz JA. Identification of HuR as a protein implicated in AUUUA-mediated mRNA decay. EMBO J. 1997;16:2130-2139.

    Not in our library10.1093/emboj/16.8.2130

All 53 references

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