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For other uses, see Adar (disambiguation).

Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene (which stands for adenosine deaminase acting on RNA).[1][2]

Adenosine deaminase, RNA-specific
Protein ADAR PDB 1qbj.png
PDB rendering based on 1qbj.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols ADAR ; ADAR1; AGS6; DRADA; DSH; DSRAD; G1P1; IFI-4; IFI4; K88DSRBP; P136
External IDs OMIM146920 MGI1889575 HomoloGene9281 GeneCards: ADAR Gene
EC number
RNA expression pattern
PBB GE ADAR 201786 s at tn.png
More reference expression data
Species Human Mouse
Entrez 103 56417
Ensembl ENSG00000160710 ENSMUSG00000027951
UniProt P55265 Q99MU3
RefSeq (mRNA) NM_001025107 NM_001038587
RefSeq (protein) NP_001020278 NP_001033676
Location (UCSC) Chr 1:
154.58 – 154.63 Mb
Chr 3:
89.72 – 89.75 Mb
PubMed search [1] [2]

Adenosine deaminases acting on RNA (ADAR) are enzymes responsible for binding to double stranded RNA (dsRNA) and converting adenosine (A) to inosine (I) by deamination.[3] ADAR protein is a RNA-binding protein, which functions in RNA-editing through post-transcriptional modification of mRNA transcripts by changing the nucleotide content of the RNA.[4] The conversion from A to I in the RNA disrupt the normal A:U pairing which makes the RNA unstable. Inosine is structurally similar to that of guanine (G) which leads to I to cytosine (C) binding. In RNA I functions the same as G in both translation and replication. Codon changes can arise from editing which may lead to changes in the coding sequences for proteins and their functions.[5] Most editing site are found in noncoding regions of RNA such as untranslated regions (UTRs), Alu elements and long interspersed nuclear element (LINEs). Mutations in this gene have been associated with dyschromatosis symmetrica hereditaria, as well as Aicardi–Goutières syndrome.[6] Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[4]


Adenosine Deaminase Acting on RNA (ADAR) and its gene were first discovered accidentally in 1987 as a result of research by Brenda Bass and Harold Weintraub.[7] These researchers were using antisense RNA inhibition to determine which genes play a key role in the development of Xenopus leavis embryos. Previous research on Xenopus oocytes had been successful. However, when Bass and Weintraub applied identical protocols to Xenopus embryos, they were unable to determine the embryo’s developmental genes. In an attempt to understand why the method was unsuccessful, they began comparing duplex RNA in both oocytes and embryos. This lead them to discover that a developmentally regulated activity denatures RNA:RNA hybrids in embryos.

In 1988, Richard Wagner et al. further studied the activity occurring on Xenopus embryos.[8] They determined that a protein was responsible for the unwinding of RNA due to the absence of activity after proteinase treatment. It was also shown that this protein is specific for double stranded RNA, or dsRNA, and does not require ATP. Additionally, it became evident that the protein’s activity on dsRNA modifies it beyond a point of rehybridization, but does not fully denature it. Finally, the researchers determined that this unwinding is due to the deamination of adenosine residues to inosine. This modification results in mismatched base-pairing between inosine and uridine, leading to the destabilization and unwinding of dsRNA.

Function and origin[edit]

Adenosine Deaminase Acting on RNA is one of the most common forms of RNA editing, and has both selective and non-selective activity.[9] ADAR is able to both modify and regulate the output of gene product, as inosine is interpreted by the cell to be guanosine. ADAR has also been determined to change the functionality of small RNA molecules. Its is believed that ADAR evolved from ADAT (Adenosine Deaminase Acting on tRNA), a critical protein present in all eukaryotes, early in the metazoan period through the addition of a dsRNA binding domain. This likely occurred in the lineage which leads to the crown Metazoa when a duplicate ADAT gene was coupled to a gene encoding at least one double stranded RNA binding. The ADAR family of genes has been largely conserved over the history of its existence. This, along with its presence in the majority of modern phyla, indicates that RNA editing is an essential regulatory gene for metazoan organisms. ADAR has not been discovered in a variety of non-metazoan eukaryotes, such as plants, fungi and choanoflagellates.


In mammals, there are three types of ADARs, 1, 2 and 3.[10] ADAR1 and ADAR2 are found in many tissues in the body while ADAR3 is only found in the brain.[5] ADAR1 and ADAR2 are known to be catalytically active while ADAR3 is thought to be inactive.[5] ADAR1 has two known isoforms known as ADAR1p150 and ADAR1p110. ADAR1p110 is only found in the nucleus and ADAR1p150 goes from the nucleus to the cytoplasm.[10]

Catalytic activity[edit]

Biochemical reaction[edit]

ADARs catalyze the reaction from A to I by hydrolytic deamination.[3] It does this by the use of an activated water molecule for a nucelophilic attack. It is done by the addition of water to carbon 6 and removal of ammonia with a hydrated intermediate.

ADAR1 mechanism.png

Active site[edit]

In humans, the enzyme's active site has 2-3 amino-terminal dsRNA binding domains (dsRBDs) and one carboxy terminal catalytic deaminase domain.[10] In the dsRBD domain there is a conserved α-β-β-β-α configuration present.[5] ADAR1 contains two areas for binding Z-DNA known as Zα and Zβ. ADAR2 and ADAR3 have an arginine rich single stranded RNA (ssRNA) binding domain. A crystal structure of ADAR2 has been solved.[10] In the enzyme active site, there is a glutamic acid residue(E396) that hydrogen bonds to a water. There is a histidine (H394) and two cysteine restudies (C451 and C516) that coordinates a zinc ion. The zinc activates the water molecule for the nucelophilic hydrolytic deamination. Within the catalytic core there is an inositol hexakisphosphate (IP6), which stabilizes arginine and lysine residues.

ADAR1 active site


It has been found in mammals that the conversion from A to I requires homodimerization of ADAR1 and ADAR2, but not ADAR3.[5] In vivo studies have not yet been conclusive if RNA binding is required for dimerization. A study with ADAR1 and 2 mutants which were not able to bind to dsRNA were still able to dimerize, showing they may bind based on protein-protein interactions [5][11]

Model organisms[edit]

Model organisms have been used in the study of ADAR function. A conditional knockout mouse line, called Adartm1a(EUCOMM)Wtsi[12][13] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists[14][15][16] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[17][18] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[6] Few homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no abnormalities were observed in these animals.[17]

Role in disease[edit]

Aicardi-Goutières Syndrome[edit]

ADAR1 is one of multiple genes which can contribute to Aicardi-Goutières syndrome when mutated.[19] This is a genetic inflammatory disease primarily affecting the skin and the brain. The inflammation is caused by incorrect activation of interferon inducible genes such as those activated to fight off viral infections. Mutation and loss of function of ADAR1 prevents destabilization of double stranded RNA (dsRNA) and the body mistakes this for viral RNA resulting in an autoimmune response.[20]


Research has shown that ADAR1 can be both beneficial and a hindrance in a cells ability to fight off HIV infection. Expression levels of the ADAR1 protein have shown to be elevated during HIV infection and it has been suggested that it is responsible for A to G mutations in the HIV genome, inhibiting replication.[21] The authors of this study also suggest that mutation of the HIV genome by ADAR1 might in some cases lead to beneficial viral mutations which could contribute to drug resistance.

Hepatocellular carcinoma[edit]

Studies of samples from patients with hepatocellular carcinoma (HCC) have shown that ADAR1 is frequently upregulated and ADAR2 is frequently downregulated in the disease. It has been suggested that this is responsible for the disrupted A to I editing pattern seen in HCC and that ADAR1 acts as an oncogene in this context whilst ADAR2 has tumor suppressor activities.[22] The imbalance of ADAR expression could change the frequency of A to I transitions in the protein coding region of genes, resulting in mutated proteins which drive the disease. The dysregulation of ADAR1 and ADAR2 could be used as a possible poor prognostic marker.


In contrast to hepatocellular carcinoma, several research studies have indicated that loss of ADAR1 contributes to melanoma growth and metastasis. It is known that ADAR can act on microRNA and affect it’s biogenesis, stability and/or it’s binding target.[23] It has been suggested that ADAR1 is downregulated by cAMP- response element binding protein (CREB), limiting its ability to act on miRNA.[24] One such example is miR-455-5p which is edited by ADAR1. When ADAR is downregulated by CREB the unedited miR-455-5p downregulates a tumor suppressor protein called CPEB1, contributing to melanoma progression in an in vivo model.[24]

Dyschromatosis Symmetrica Hereditaria (DSH1)[edit]

A Gly1007Arg mutation in ADAR1, as well as other truncated versions, have been implicated as a cause in some cases of DSH1.[25] This is a disease characterized by hyperpigmentation in the hands and feet and can occur in Japanese and Chinese families.

Viral activity[edit]


ADAR1 is an interferon ( IFN )-inducible protein (one released by a cell in response to a pathogen or virus), so it would make sense that it would assist with a cell’s immune pathway. This seems to be true for the HCV replicon, Lymphocytic choriomeningitis LCMV, and polyomavirus [26]


ADAR1 is known to be proviral in other circumstances. ADAR1’s A to I editing has been found in many viruses including measles virus,[27][28] influenza virus,[29] lymphocytic choriomeningitis virus,[30] polyomavirus,[31] hepatitis delta virus,[32] and hepatitis C virus.[33] Although ADAR1 has been seen in other viruses, it has only been studied extensively in a few. One of those is ‘‘‘measles virus (MV)’’’. Research done on MV has shown that ADAR1 enhances viral replication. This is done through two different mechanisms: RNA editing and inhibition of dsRNA-activated protein kinase ( PKR ).[26] Specifically, viruses are thought to use ADAR1 as a positive replication factor by selectively suppressing dsRNA-dependent and antiviral pathways.[34]


See also[edit]


  1. ^ Kim U, Wang Y, Sanford T, Zeng Y, Nishikura K (Dec 1994). "Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing". Proc Natl Acad Sci USA 91 (24): 11457–61. doi:10.1073/pnas.91.24.11457. PMC 45250. PMID 7972084. 
  2. ^ "Entrez Gene: ADAR Adenosine Deaminase Acting on RNA". 
  3. ^ a b editor, Charles E. Samuel, (2012). Adenosine deaminases acting on RNA (ADARs) and A-to-I editing. Heidelberg: Springer. ISBN 978-3-642-22800-1. 
  4. ^ a b "ADAR". NBCI. U.S. National Library of Medicine. 
  5. ^ a b c d e f Nishikura, Kazuko (7 June 2010). "Functions and Regulation of RNA Editing by ADAR Deaminases". Annual Review of Biochemistry 79 (1): 321–349. doi:10.1146/annurev-biochem-060208-105251. 
  6. ^ Rice, Gillian I; Kasher, Paul R; Forte, Gabriella M A; Mannion, Niamh M; Greenwood, Sam M; Szynkiewicz, Marcin; Dickerson, Jonathan E; Bhaskar, Sanjeev S; Zampini, Massimiliano; Briggs, Tracy A; Jenkinson, Emma M; Bacino, Carlos A; Battini, Roberta; Bertini, Enrico; Brogan, Paul A; Brueton, Louise A; Carpanelli, Marialuisa; De Laet, Corinne; de Lonlay, Pascale; del Toro, Mireia; Desguerre, Isabelle; Fazzi, Elisa; Garcia-Cazorla, Àngels; Heiberg, Arvid; Kawaguchi, Masakazu; Kumar, Ram; Lin, Jean-Pierre S-M; Lourenco, Charles M; Male, Alison M; Marques, Wilson; Mignot, Cyril; Olivieri, Ivana; Orcesi, Simona; Prabhakar, Prab; Rasmussen, Magnhild; Robinson, Robert A; Rozenberg, Flore; Schmidt, Johanna L; Steindl, Katharina; Tan, Tiong Y; van der Merwe, William G; Vanderver, Adeline; Vassallo, Grace; Wakeling, Emma L; Wassmer, Evangeline; Whittaker, Elizabeth; Livingston, John H; Lebon, Pierre; Suzuki, Tamio; McLaughlin, Paul J; Keegan, Liam P; O'Connell, Mary A; Lovell, Simon C; Crow, Yanick J (23 September 2012). "Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature". Nature Genetics 44 (11): 1243–1248. doi:10.1038/ng.2414. 
  7. ^ Samuel, Charles E. (2011-03-15). "Adenosine Deaminases Acting on RNA (ADARs) are both Antiviral and Proviral Dependent upon the Virus". Virology 411 (2): 180–193. doi:10.1016/j.virol.2010.12.004. ISSN 0042-6822. PMC 3057271. PMID 21211811. 
  8. ^ Wagner, Richard (January 24, 1989). "A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells and Xenopus eggs" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 
  9. ^ Grice, Laura F.; Degnan, Bernard M. (2015-01-29). "The origin of the ADAR gene family and animal RNA editing". BMC Evolutionary Biology 15 (1): 4. doi:10.1186/s12862-015-0279-3. ISSN 1471-2148. PMC 4323055. PMID 25630791. 
  10. ^ a b c d Savva, Yiannis A; Rieder, Leila E; Reenan, Robert A (2012). "The ADAR protein family". Genome Biology 13 (12): 252. doi:10.1186/gb-2012-13-12-252. 
  11. ^ Cho, D.-S. C.; Yang, W.; Lee, J. T.; Shiekhattar, R.; Murray, J. M.; Nishikura, K. (4 March 2003). "Requirement of Dimerization for RNA Editing Activity of Adenosine Deaminases Acting on RNA". Journal of Biological Chemistry 278 (19): 17093–17102. doi:10.1074/jbc.M213127200. 
  12. ^ "International Knockout Mouse Consortium". 
  13. ^ "Mouse Genome Informatics". 
  14. ^ Skarnes, William C.; Rosen, Barry; West, Anthony P.; Koutsourakis, Manousos; Bushell, Wendy; Iyer, Vivek; Mujica, Alejandro O.; Thomas, Mark; Harrow, Jennifer; Cox, Tony; Jackson, David; Severin, Jessica; Biggs, Patrick; Fu, Jun; Nefedov, Michael; de Jong, Pieter J.; Stewart, A. Francis; Bradley, Allan (15 June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750. 
  15. ^ Dolgin, Elie (15 June 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–263. doi:10.1038/474262a. PMID 21677718. 
  16. ^ Collins, FS; Rossant, J; Wurst, W (2007). "A Mouse for All Reasons". Cell 128: 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  17. ^ a b GERDIN, AK (September 2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 0–0. doi:10.1111/j.1755-3768.2010.4142.x. 
  18. ^ van der Weyden, Louise; White, Jacqueline K; Adams, David J; Logan, Darren W (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353. 
  19. ^ Rice (2012). "Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature". Nature Genetics 44 (11): 1243–1248. doi:10.1038/ng.2414. 
  20. ^ Liddicoat (2015). "RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself". Science 349 (6252): 1115–1120. doi:10.1126/science.aac7049. 
  21. ^ Weiden (2014). "Adenosine Deaminase Acting on RNA-1 (ADAR1) Inhibits HIV-1 Replication in Human Alveolar Macrophages". PLoS ONE 9 (10): e108476. doi:10.1371/journal.pone.0108476. 
  22. ^ Chan (2014). "A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma". Gut 63 (5): 832–843. doi:10.1136/gutjnl-2012-304037. 
  23. ^ Heale (2009). "Editing independent effects of ADARs on the miRNA/siRNA pathways". The EMBO Journal 28 (20): 345–3156. doi:10.1038/emboj.2009.244. 
  24. ^ a b Shoshan (2015). "Hypo Adenosine-to-Inosine miR-455-5p Editing Promotes Melanoma Growth and Metastasis". Nature Cell Biology 17 (3): 311–321. doi:10.1038/ncb3110. 
  25. ^ Tojo (2006). "Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation". Movement Disorders 21 (9): 1510–1513. doi:10.1002/mds.21011. 
  26. ^ a b Gelinas, J.-F.; Clerzius, G.; Shaw, E.; Gatignol, A. (13 April 2011). "Enhancement of Replication of RNA Viruses by ADAR1 via RNA Editing and Inhibition of RNA-Activated Protein Kinase". Journal of Virology 85 (17): 8460–8466. doi:10.1128/JVI.00240-11. 
  27. ^ Baczko (November 1993). "Clonal expansion of hypermutated measles virus in a SSPE brain". Virology 197 (1): 188–95. doi:10.1006/viro.1993.1579. 
  28. ^ Cattaneo (21 October 1988). "Biased hypermutation and other genetic changes in defective measles viruses in human brain infections". Cell 55 (2): 255–65. doi:10.1016/0092-8674(88)90048-7. 
  29. ^ Tenoever (2 March 2007). "Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity". Science 315 (5816): 1274–8. doi:10.1126/science.1136567. 
  30. ^ Zahn (January 2007). "A-to-G hypermutation in the genome of lymphocytic choriomeningitis virus". Virology 81 (2): 457–64. doi:10.1128/jvi.00067-06. 
  31. ^ Kumar (15 April 1997). "Nuclear antisense RNA induces extensive adenosine modifications and nuclear retention of target transcripts". Proc Natl Acad Sci USA 94 (8): 3542–7. doi:10.1073/pnas.94.8.3542. 
  32. ^ Luo (March 1990). "A specific base transition occurs on replicating hepatitis delta virus RNA". Virology 64 (3): 1021–7. 
  33. ^ Taylor (May 2007). "New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1". Virology 79 (10): 6291–8. 
  34. ^ Toth (23 October 2009). "RNA-specific Adenosine Deaminase ADAR1 Suppresses Measles Virus-induced Apoptosis and Activation of Protein Kinase PKR". Biological Chemistry 284 (43): 29350–29356. doi:10.1074/jbc.M109.045146. 

Further reading[edit]

External links[edit]