RNA rewriting, recoding, and rewiring in human disease.

ADAR (adenosine deAminase acting on RNA) editases catalyze the deamination of adenosine to inosine (A-to-I), a post-transcriptional modification that alters coding and non-coding RNA stability and function. ADAR editases such as ADAR1 have recently been shown to play a key role in normal stem cell maintenance. While ADAR mutations are associated with hereditary autoimmune diseases such as Aicardi-Goutières syndrome, ADAR copy-number alterations and editase activation have been associated with progression of a broad array of malignancies. In this review we discuss evidence linking aberrant A-to-I editing to cancer and other degenerative diseases, and the mechanisms that may be targeted by novel therapeutic strategies.

[1]  Gideon Rechavi,et al.  MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth. , 2013, The Journal of clinical investigation.

[2]  François Major,et al.  Recognition and coupling of A-to-I edited sites are determined by the tertiary structure of the RNA , 2009, Nucleic acids research.

[3]  C. Samuel,et al.  Mechanism of interferon action: double-stranded RNA-specific adenosine deaminase from human cells is inducible by alpha and gamma interferons. , 1995, Virology.

[4]  R. Benne,et al.  Major transcript of the frameshifted coxll gene from trypanosome mitochondria contains four nucleotides that are not encoded in the DNA , 1986, Cell.

[5]  Yi Xing,et al.  Adenosine deamination in human transcripts generates novel microRNA binding sites , 2009, Human molecular genetics.

[6]  K. Nishikura,et al.  Genomic organization and chromosomal location of the human dsRNA adenosine deaminase gene: the enzyme for glutamate-activated ion channel RNA editing. , 1995, Journal of molecular biology.

[7]  S. Orkin,et al.  ADAR1 is essential for maintenance of hematopoiesis and suppression of interferon signaling , 2008, Nature Immunology.

[8]  D. Feldmeyer,et al.  Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2 , 2000, Nature.

[9]  F. Nielsen,et al.  Dimerization of ADAR2 is mediated by the double-stranded RNA binding domain. , 2006, RNA.

[10]  Jessica M. Rusert,et al.  ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia , 2012, Proceedings of the National Academy of Sciences.

[11]  John M. Murray,et al.  Requirement of Dimerization for RNA Editing Activity of Adenosine Deaminases Acting on RNA* , 2003, The Journal of Biological Chemistry.

[12]  K. Wells,et al.  Modulation of RNA editing by functional nucleolar sequestration of ADAR2 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  I. Mian,et al.  A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Jin Billy Li,et al.  Accurate identification of human Alu and non-Alu RNA editing sites , 2012, Nature Methods.

[15]  A. Hatzigeorgiou,et al.  Redirection of Silencing Targets by Adenosine-to-Inosine Editing of miRNAs , 2007, Science.

[16]  M. Weiss,et al.  Stress-induced Apoptosis Associated with Null Mutation of ADAR1 RNA Editing Deaminase Gene* , 2004, Journal of Biological Chemistry.

[17]  John H Livingston,et al.  Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature , 2012, Nature Genetics.

[18]  M. Carmo-Fonseca,et al.  Dynamic association of RNA-editing enzymes with the nucleolus , 2003, Journal of Cell Science.

[19]  S. Sato,et al.  Substrate recognition by ADAR1 and ADAR2. , 2001, RNA.

[20]  Joshua J C Rosenthal,et al.  Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing , 2013, Proceedings of the National Academy of Sciences.

[21]  P. Seeburg,et al.  RNA editing in brain controls a determinant of ion flow in glutamate-gated channels , 1991, Cell.

[22]  B. Bass,et al.  RNA hairpins in noncoding regions of human brain and Caenorhabditis elegans mRNA are edited by adenosine deaminases that act on RNA , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Fritz J Sedlazeck,et al.  Adenosine deaminases that act on RNA induce reproducible changes in abundance and sequence of embryonic miRNAs , 2012, Genome research.

[24]  P. Seeburg,et al.  Cloning of a human RNA editing deaminase (ADARB1) of glutamate receptors that maps to chromosome 21q22.3. , 1997, Genomics.

[25]  K. Nishikura,et al.  RNA Binding-independent Dimerization of Adenosine Deaminases Acting on RNA and Dominant Negative Effects of Nonfunctional Subunits on Dimer Functions* , 2007, Journal of Biological Chemistry.

[26]  A. Cedazo-Mínguez,et al.  Apolipoprotein E and Alzheimer's disease: molecular mechanisms and therapeutic opportunities , 2007, Journal of cellular and molecular medicine.

[27]  Dirk Feldmeyer,et al.  Early-Onset Epilepsy and Postnatal Lethality Associated with an Editing-Deficient GluR-B Allele in Mice , 1995, Science.

[28]  Leilei Chen,et al.  Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma , 2013, Nature Medicine.

[29]  Yongfeng Jin,et al.  A structural determinant required for RNA editing , 2011, Nucleic acids research.

[30]  R. Reenan,et al.  Tertiary structural elements determine the extent and specificity of messenger RNA editing , 2013, Nature Communications.

[31]  Christian L. Barrett,et al.  An RNA editing fingerprint of cancer stem cell reprogramming , 2015, Journal of Translational Medicine.

[32]  Reuben S Harris,et al.  RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. , 2002, Molecular cell.

[33]  K. Nishikura,et al.  Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. , 2000, Science.

[34]  Shahar Alon,et al.  Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma , 2014, Genome Biology.

[35]  C. Samuel,et al.  The interferon-inducible, double-stranded RNA-specific adenosine deaminase gene (DSRAD) maps to human chromosome 1q21.1-21.2. , 1995, Genomics.

[36]  T. Innerarity,et al.  A novel translational repressor mRNA is edited extensively in livers containing tumors caused by the transgene expression of the apoB mRNA-editing enzyme. , 1997, Genes & development.

[37]  C. Burant,et al.  Molecular cloning of an apolipoprotein B messenger RNA editing protein. , 1993, Science.

[38]  W. H. Lo,et al.  Two novel mutations and evidence for haploinsufficiency of the ADAR gene in dyschromatosis symmetrica hereditaria , 2006, The British journal of dermatology.

[39]  Thorsten Stafforst,et al.  An RNA-deaminase conjugate selectively repairs point mutations. , 2012, Angewandte Chemie.

[40]  S. Tsuji,et al.  Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons , 2012, Neurobiology of Disease.

[41]  G. Kammer,et al.  Transcript mutations of the α regulatory subunit of protein kinase A and up-regulation of the RNA-editing gene transcript in lupus T lymphocytes , 2002, The Lancet.

[42]  T Kuner,et al.  Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. , 1994, Science.

[43]  R. Benne.  The long and the short of it , 1996, Nature.

[44]  D. Speicher,et al.  Purification and characterization of double-stranded RNA adenosine deaminase from bovine nuclear extracts. , 1994, The Journal of biological chemistry.

[45]  M Schrey,et al.  Underediting of glutamate receptor GluR-B mRNA in malignant gliomas , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Yan Li,et al.  Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma. , 2014, Cancer research.

[47]  K. Nishikura,et al.  A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. , 2000, RNA.

[48]  S. Maas,et al.  Novel Exon of Mammalian ADAR2 Extends Open Reading Frame , 2009, PloS one.

[49]  S. Akbarian,et al.  Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer's disease, Huntington's disease and schizophrenia , 1995, Brain Research.

[50]  J. Taylor,et al.  Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[51]  W. Keller,et al.  Purification and properties of double-stranded RNA-specific adenosine deaminase from calf thymus. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Dawson,et al.  Regulation of alternative splicing by RNA editing , 1999, Nature.

[53]  Ramana V. Davuluri,et al.  ADAR1 Forms a Complex with Dicer to Promote MicroRNA Processing and RNA-Induced Gene Silencing , 2013, Cell.

[54]  M. Jantsch,et al.  The human but not the Xenopus RNA-editing enzyme ADAR1 has an atypical nuclear localization signal and displays the characteristics of a shuttling protein. , 2001, Molecular biology of the cell.

[55]  Zuo Zhang,et al.  The Fate of dsRNA in the Nucleus A p54nrb-Containing Complex Mediates the Nuclear Retention of Promiscuously A-to-I Edited RNAs , 2001, Cell.

[56]  P. Seeburg,et al.  Liver Disintegration in the Mouse Embryo Caused by Deficiency in the RNA-editing Enzyme ADAR1* , 2004, Journal of Biological Chemistry.

[57]  Biochemical analysis and scanning force microscopy reveal productive and nonproductive ADAR2 binding to RNA substrates. , 2003, RNA.

[58]  C. Samuel,et al.  Expression of Interferon-inducible RNA Adenosine Deaminase ADAR1 during Pathogen Infection and Mouse Embryo Development Involves Tissue-selective Promoter Utilization and Alternative Splicing* , 2005, Journal of Biological Chemistry.

[59]  Paul Vogel,et al.  Improving site-directed RNA editing in vitro and in cell culture by chemical modification of the guideRNA. , 2014, Angewandte Chemie.

[60]  M. O’Connell,et al.  Down-regulation of RNA Editing in Pediatric Astrocytomas , 2008, Journal of Biological Chemistry.

[61]  Jacek Majewski,et al.  Comment on “Widespread RNA and DNA Sequence Differences in the Human Transcriptome” , 2012, Science.

[62]  Kimihiro Hino,et al.  A-to-I editing in the miRNA seed region regulates target mRNA selection and silencing efficiency , 2014, Nucleic acids research.

[63]  Edwin Sandanaraj,et al.  Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. , 2012, The Journal of clinical investigation.

[64]  P. Seeburg,et al.  Modulation of microRNA processing and expression through RNA editing by ADAR deaminases , 2006, Nature Structural &Molecular Biology.

[65]  Z W Gu,et al.  Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. , 1987, Science.

[66]  Steven J. M. Jones,et al.  Hypo Adenosine-to-Inosine miR-455-5p Editing Promotes Melanoma Growth and Metastasis , 2015, Nature Cell Biology.

[67]  T. Cheng,et al.  ADAR1 is required for hematopoietic progenitor cell survival via RNA editing , 2009, Proceedings of the National Academy of Sciences.

[68]  P. Seeburg,et al.  RNA editing of AMPA receptor subunit GluR-B: A base-paired intron-exon structure determines position and efficiency , 1993, Cell.

[69]  T. Mikkelsen,et al.  Altered adenosine-to-inosine RNA editing in human cancer. , 2007, Genome research.

[70]  R. Pease,et al.  A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine , 1987, Cell.

[71]  L. Zhang,et al.  ADAR1 is essential for intestinal homeostasis and stem cell maintenance , 2013, Cell Death and Disease.

[72]  Yukio Kawahara,et al.  RNA editing of the microRNA‐151 precursor blocks cleavage by the Dicer–TRBP complex , 2007, EMBO reports.

[73]  D. Viskochil,et al.  C-->U editing of neurofibromatosis 1 mRNA occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRNA-editing enzyme. , 2002, American journal of human genetics.

[74]  A. Scadden.  The RISC subunit Tudor-SN binds to hyper-edited double-stranded RNA and promotes its cleavage , 2005, Nature Structural &Molecular Biology.

[75]  M. Jantsch,et al.  RNA-Regulated Interaction of Transportin-1 and Exportin-5 with the Double-Stranded RNA-Binding Domain Regulates Nucleocytoplasmic Shuttling of ADAR1 , 2009, Molecular and Cellular Biology.

[76]  Seung-Yong Jeong,et al.  RNA editing in RHOQ promotes invasion potential in colorectal cancer , 2014, The Journal of experimental medicine.

[77]  Henry Mirsky,et al.  RNA editing of a miRNA precursor. , 2004, RNA.

[78]  M. O’Connell,et al.  Editing independent effects of ADARs on the miRNA/siRNA pathways , 2009, The EMBO journal.

[79]  V. Kim,et al.  MicroRNA maturation: stepwise processing and subcellular localization , 2002, The EMBO journal.

[80]  Zhen Wang,et al.  Five novel mutations in the ADAR1 gene associated with dyschromatosis symmetrica hereditaria , 2014, BMC Medical Genetics.

[81]  A. Herbert,et al.  The role of binding domains for dsRNA and Z-DNA in the in vivo editing of minimal substrates by ADAR1 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[82]  Joseph K. Pickrell,et al.  Comment on “Widespread RNA and DNA Sequence Differences in the Human Transcriptome” , 2012, Science.

[83]  N. Sherman,et al.  Molecular Cloning of Apobec-1 Complementation Factor, a Novel RNA-Binding Protein Involved in the Editing of Apolipoprotein B mRNA , 2000, Molecular and Cellular Biology.

[84]  Brenda L Bass,et al.  RNA editing by adenosine deaminases that act on RNA. , 2002, Annual review of biochemistry.

[85]  Jin Billy Li,et al.  Comment on “Widespread RNA and DNA Sequence Differences in the Human Transcriptome” , 2012, Science.

[86]  Jens Lagergren,et al.  A-to-I editing of microRNAs in the mammalian brain increases during development , 2012, Genome research.

[87]  P. Seeburg,et al.  A standardized nomenclature for adenosine deaminases that act on RNA. , 1997, RNA.

[88]  Shahar Alon,et al.  Systematic identification of edited microRNAs in the human brain , 2012, Genome research.

[89]  Xinshu Xiao,et al.  Genomic Analysis of ADAR1 Binding and its Involvement in Multiple RNA Processing Pathways , 2015, Nature Communications.

[90]  Michael M. Mwangi,et al.  Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA editing targets in transcript 3′ UTRs , 2010, Nature Structural &Molecular Biology.

[91]  Manolis Kellis,et al.  Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo , 2013, Nature.

[92]  P. Peterlongo,et al.  RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. , 2000, Human molecular genetics.

[93]  Ryan D. Morin,et al.  Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution , 2009, Nature.

[94]  Gideon Rechavi,et al.  Hippocampus-specific deficiency in RNA editing of GluA2 in Alzheimer's disease , 2014, Neurobiology of Aging.

[95]  P. Seeburg,et al.  Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2 , 2010, The Journal of Neuroscience.

[96]  G. Silberberg,et al.  Alu elements shape the primate transcriptome by cis-regulation of RNA editing , 2014, Genome Biology.

[97]  W. Keller,et al.  Two forms of human double-stranded RNA-specific editase 1 (hRED1) generated by the insertion of an Alu cassette. , 1997, RNA.

[98]  I. Kanazawa,et al.  Regulation of glutamate receptor RNA editing and ADAR mRNA expression in developing human normal and Down's syndrome brains. , 2004, Brain research. Developmental brain research.

[99]  Eli Eisenberg,et al.  A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes , 2014, Genome research.

[100]  J. Wettengel,et al.  Optimal guideRNAs for re-directing deaminase activity of hADAR1 and hADAR2 in trans , 2014, Nucleic acids research.

[101]  Lauren V. Alpert,et al.  Auto-regulatory RNA editing fine-tunes mRNA re-coding and complex behaviour in Drosophila , 2012, Nature Communications.

[102]  C. Samuel,et al.  Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase , 1995, Molecular and cellular biology.

[103]  Mingyao Li,et al.  Widespread RNA and DNA Sequence Differences in the Human Transcriptome , 2011, Science.

[104]  M. Akiyama,et al.  Novel ADAR1 mutations including a single amino acid deletion in the deaminase domain underlie dyschromatosis symmetrica hereditaria in Japanese families , 2014, International journal of dermatology.