The RNA editing enzymes ADARs: mechanism of action and human disease

A-to-I RNA editing is a ubiquitous and crucial molecular mechanism able to convert adenosines into inosines (then read as guanosines by several intracellular proteins/enzymes) within RNA molecules, changing the genomic information. The A-to-I deaminase enzymes (ADARs), which modify the adenosine, can alter the splicing and translation machineries, the double-stranded RNA structures and the binding affinity between RNA and RNA-binding proteins. ADAR activity is an essential mechanism in mammals and altered editing has been associated with several human diseases. Many efforts are now being concentrated on modifying ADAR activity in vivo in an attempt to correct RNA editing dysfunction. Concomitantly, ongoing studies aim to show the way that the ADAR deaminase domain can be used as a possible new tool, an intracellular Trojan horse, for the correction of heritage diseases not related to RNA editing events.

[1]  Zipora Y. Fligelman,et al.  Systematic identification of abundant A-to-I editing sites in the human transcriptome , 2004, Nature Biotechnology.

[2]  C. Norbury,et al.  The Long and Short of MicroRNA , 2013, Cell.

[3]  Jin Billy Li,et al.  Edinburgh Research Explorer Identifying Rna Editing Sites Using Rna Sequencing Data Alone , 2022 .

[4]  B. Bass,et al.  Most How Does Rna Editing Affect Dsrna-mediated Gene Silencing? , 2022 .

[5]  J. Brosius,et al.  Beyond DNA: RNA editing and steps toward Alu exonization in primates. , 2008, Journal of molecular biology.

[6]  Yishay Pinto,et al.  Mammalian conserved ADAR targets comprise only a small fragment of the human editosome , 2014, Genome Biology.

[7]  Alexander Rich,et al.  Widespread A-to-I RNA Editing of Alu-Containing mRNAs in the Human Transcriptome , 2004, PLoS biology.

[8]  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.

[9]  Yukio Kawahara,et al.  A-to-I RNA Editing and Human Disease , 2006, RNA biology.

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

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

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

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

[14]  I. Greger,et al.  AMPA Receptor Tetramerization Is Mediated by Q/R Editing , 2003, Neuron.

[15]  I. Greger,et al.  RNA Editing at Arg607 Controls AMPA Receptor Exit from the Endoplasmic Reticulum , 2002, Neuron.

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

[17]  K. Nishikura,et al.  Editor meets silencer: crosstalk between RNA editing and RNA interference , 2006, Nature Reviews Molecular Cell Biology.

[18]  K. Nishikura Functions and regulation of RNA editing by ADAR deaminases. , 2010, Annual review of biochemistry.

[19]  T. Jenuwein,et al.  Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component , 2002, Nature Genetics.

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

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

[22]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[23]  A. Dejean,et al.  Coordinated methyl and RNA binding is required for heterochromatin localization of mammalian HP1α , 2002, EMBO reports.

[24]  Yiannis A. Savva,et al.  RNA editing regulates transposon-mediated heterochromatic gene silencing , 2013, Nature Communications.

[25]  Jin Billy Li,et al.  RADAR: a rigorously annotated database of A-to-I RNA editing , 2013, Nucleic Acids Res..

[26]  Angela Gallo,et al.  ADARs: allies or enemies? The importance of A‐to‐I RNA editing in human disease: from cancer to HIV‐1 , 2012, Biological reviews of the Cambridge Philosophical Society.

[27]  Molly Megraw,et al.  Frequency and fate of microRNA editing in human brain , 2008, Nucleic acids research.

[28]  Y. Yoshida,et al.  Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. , 2002, Nature medicine.

[29]  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.

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

[31]  G. Carmichael,et al.  Effects of Length and Location on the Cellular Response to Double-Stranded RNA , 2004, Microbiology and Molecular Biology Reviews.

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

[33]  N. Hasebe,et al.  TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2 , 2010, Acta Neuropathologica.

[34]  Ichiro Kanazawa,et al.  Glutamate receptors: RNA editing and death of motor neurons , 2004, Nature.

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

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

[37]  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.

[38]  M. O’Connell,et al.  The Effect of RNA Editing and ADARs on miRNA Biogenesis and Function. , 2011, Advances in experimental medicine and biology.

[39]  S. Kwak,et al.  AMPA receptor‐mediated neuronal death in sporadic ALS , 2010, Neuropathology : official journal of the Japanese Society of Neuropathology.

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

[41]  N. Schirle,et al.  Selective inhibition of ADAR2-catalyzed editing of the serotonin 2c receptor pre-mRNA by a helix-threading peptide. , 2010, Organic & biomolecular chemistry.

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

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

[44]  Eli Eisenberg,et al.  RNA-editing-mediated exon evolution , 2007, Genome Biology.

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

[46]  R. Boldrini,et al.  ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis , 2012, Oncogene.

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

[48]  F. Locatelli,et al.  ADAR Enzyme and miRNA Story: A Nucleotide that Can Make the Difference , 2013, International journal of molecular sciences.

[49]  Kol Jia Yong,et al.  A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma , 2013, Gut.

[50]  P. Seeburg,et al.  RNA editing of brain glutamate receptor channels: mechanism and physiology 1 Published on the World Wide Web on 5 February 1998. 1 , 1998, Brain Research Reviews.

[51]  R. Emeson,et al.  Functions and mechanisms of RNA editing. , 2000, Annual review of genetics.

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

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

[54]  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.

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

[56]  Zuo Zhang,et al.  Vigilins Bind to Promiscuously A-to-I-Edited RNAs and Are Involved in the Formation of Heterochromatin , 2005, Current Biology.

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

[58]  Angela Gallo,et al.  A-to-I RNA editing: the "ADAR" side of human cancer. , 2012, Seminars in cell & developmental biology.

[59]  S. Tsuji,et al.  Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons , 2013, EMBO molecular medicine.

[60]  R. Shiekhattar,et al.  The Microprocessor complex mediates the genesis of microRNAs , 2004, Nature.

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