ADAR

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).[5][6]

ADAR
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1QBJ, 1QGP, 1XMK, 2ACJ, 2GXB, 2L54, 2MDR, 3F21, 3F22, 3F23, 3IRQ, 3IRR
Identifiers
Aliases	ADAR, ADAR1, AGS6, DRADA, DSH, DSRAD, G1P1, IFI-4, IFI4, K88DSRBP, P136, adenosine deaminase, RNA-specific, adenosine deaminase, RNA specific, adenosine deaminase RNA specific
External IDs	OMIM: 146920 MGI: 1889575 HomoloGene: 9281 GeneCards: ADAR
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q21.3 Start 154,582,057 bp[1] End 154,628,013 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 F1 Start 89,715,022 bp[2] End 89,753,446 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • metal ion binding • double-stranded RNA adenosine deaminase activity • adenosine deaminase activity • GO:0001948 protein binding • hydrolase activity • RNA binding • double-stranded RNA binding • tRNA-specific adenosine deaminase activity Cellular component • cytoplasm • membrane • supraspliceosomal complex • nucleoplasm • nucleolus • cell nucleus Biological process • hematopoietic stem cell homeostasis • cellular response to virus • miRNA loading onto RISC involved in gene silencing by miRNA • RNA processing • protein import into nucleus • immune system process • negative regulation of type I interferon-mediated signaling pathway • mRNA processing • response to virus • base conversion or substitution editing • negative regulation of apoptotic process • in utero embryonic development • pre-miRNA processing • negative regulation of viral genome replication • defense response to virus • type I interferon signaling pathway • osteoblast differentiation • hematopoietic progenitor cell differentiation • protein export from nucleus • response to interferon-alpha • negative regulation of protein kinase activity by regulation of protein phosphorylation • erythrocyte differentiation • somatic diversification of immune receptors via somatic mutation • definitive hemopoiesis • positive regulation of viral genome replication • negative regulation of RNA interference • gene silencing by RNA • innate immune system • adenosine to inosine editing • production of miRNAs involved in gene silencing by miRNA Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	103	56417
Ensembl	ENSG00000160710	ENSMUSG00000027951
UniProt	P55265	Q99MU3
RefSeq (mRNA)	NM_001025107 NM_001111 NM_001193495 NM_015840 NM_015841 NM_001365045 NM_001365046 NM_001365047 NM_001365048 NM_001365049	NM_001038587 NM_001146296 NM_019655 NM_001357958
RefSeq (protein)	NP_001020278 NP_001102 NP_001180424 NP_056655 NP_056656	NP_001033676 NP_001139768 NP_062629 NP_001344887
Location (UCSC)	Chr 1: 154.58 – 154.63 Mb	Chr 3: 89.72 – 89.75 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[7] 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.[8] 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. Inosine typically mimicks guanosine during translation.[9] Codon changes can arise from editing which may lead to changes in the coding sequences for proteins and their functions.[10] Most editing sites are found in noncoding regions of RNA such as untranslated regions (UTRs), Alu elements, and long interspersed nuclear element (LINEs).[11] Mutations in this gene have been associated with dyschromatosis symmetrica hereditaria, as well as Aicardi–Goutières syndrome.[12] Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[8] ADAR also impacts the transcriptome in editing-independent ways, likely by interfering with other RNA-binding proteins.[13]

Discovery

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.[14] These researchers were using antisense RNA inhibition to determine which genes play a key role in the development of Xenopus laevis 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 led 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.[15] 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

ADARs acting on RNA is one of the most common forms of RNA editing, and has both selective and non-selective activity.[16] 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. Recently, ADARs have also been discovered as a splicing regulator with their editing capability or RNA binding function.[17][18] It 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.

Types

In mammals, there are three types of ADARs, ADAR (ADAR1), ADARB1 (ADAR2) and ADARB2 (ADAR3).[19] ADAR and ADARB1 are found in many tissues in the body while ADARB2 is only found in the brain.[10] ADAR and ADARB1 are known to be catalytically active while ADARB2 is thought to be inactive.[10] ADAR has two known isoforms known as ADAR1p150 and ADAR1p110. ADAR1p110 is usually only found in the nucleus while ADAR1p150 shuffles between the nucleus to the cytoplasm and is mostly present in the cytoplasm.[19] Although ADAR and ADARB1 share many common functional domains as well as commonality in terms of expression pattern, structure of protein and requirements of substrates having double stranded RNA structures, they differ in their editing activity.[20]

Catalytic activity

Biochemical reaction

ADARs catalyze the reaction from A to I by hydrolytic deamination.[7] 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.

• 
  scheme of adenosine conversion to inosine via ADAR

Active site

In humans, the enzyme's active site has 2-3 amino-terminal dsRNA binding domains (dsRBDs) and one carboxy terminal catalytic deaminase domain.[19] In the dsRBD domain there is a conserved α-β-β-β-α configuration present.[10] 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.[19] 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.

Dimerization

It has been found in mammals that the conversion from A to I requires homodimerization of ADAR1 and ADAR2, but not ADAR3.[10] 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[10][21]

Model organisms

Model organisms have been used in the study of ADAR function. A conditional knockout mouse line, called Adartm1a(EUCOMM)Wtsi[22][23] 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[24][25][26] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[27][28] 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.[27]

Role in disease

Aicardi–Goutières syndrome and Bilateral Striatal Necrosis/Dystonia

ADAR1 is one of multiple genes which can contribute to Aicardi–Goutières syndrome when mutated.[12] This is a genetic inflammatory disease primarily affecting the skin and the brain and it is characterized by high levels of IFN-α in cerebral spinal fluid.[29] 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). This build up of dsRNA stimulates IFN production without a viral infection, causing an inflammatory reaction and autoimmune response.[30] The phenotype in Adar knock-out mice is rescued by the p150 form of ADAR1 containing the Zα domain that binds specifically to the left-handed double-stranded conformation found in Z-DNA and Z-RNA, but not by the p110 isoform that lacks this domain.[31] In humans, the P193A mutation in the Zα domain is causal for Aicardi–Goutières syndrome [12] and for the more severe phenotype found in Bilateral Striatal Necrosis/Dystonia.[32] The findings establish a biological role for the left-handed Z-DNA conformation.[33]

HIV

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.[34] 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

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.[35] 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.

Melanoma

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 its biogenesis, stability and/or its binding target.[36] It has been suggested that ADAR1 is downregulated by cAMP- response element binding protein (CREB), limiting its ability to act on miRNA.[37] 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.[37]

Dyschromatosis symmetrica hereditaria (DSH1)

A Gly1007Arg mutation in ADAR1, as well as other truncated versions, have been implicated as a cause in some cases of DSH1.[38] This is a disease characterized by hyperpigmentation in the hands and feet and can occur in Japanese and Chinese families.

Viral activity

Antiviral

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[39]

Proviral

ADAR1 is known to be proviral in other circumstances. ADAR1’s A to I editing has been found in many viruses including measles virus,[40][41] influenza virus,[42] lymphocytic choriomeningitis virus,[43] polyomavirus,[44] hepatitis delta virus,[45] and hepatitis C virus.[46] 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).[39] Specifically, viruses are thought to use ADAR1 as a positive replication factor by selectively suppressing dsRNA-dependent and antiviral pathways.[47]

See also

• RNA editing
• Potassium channel RNA editing signal
• ADARB1
• Z-DNA

References

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Further reading

• Valenzuela A, Blanco J, Callebaut C, Jacotot E, Lluis C, Hovanessian AG, Franco R (1997). HIV-1 envelope gp120 and viral particles block adenosine deaminase binding to human CD26. Advances in Experimental Medicine and Biology. 421. pp. 185–92. doi:10.1007/978-1-4757-9613-1_24. ISBN 978-1-4757-9615-5. PMID 9330696.
• Wathelet MG, Szpirer J, Nols CB, Clauss IM, De Wit L, Islam MQ, Levan G, Horisberger MA, Content J, Szpirer C (September 1988). "Cloning and chromosomal location of human genes inducible by type I interferon". Somatic Cell and Molecular Genetics. 14 (5): 415–26. doi:10.1007/BF01534709. PMID 3175763.
• Wang Y, Zeng Y, Murray JM, Nishikura K (November 1995). "Genomic organization and chromosomal location of the human dsRNA adenosine deaminase gene: the enzyme for glutamate-activated ion channel RNA editing". Journal of Molecular Biology. 254 (2): 184–95. doi:10.1006/jmbi.1995.0610. PMID 7490742.
• Patterson JB, Samuel CE (October 1995). "Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase". Molecular and Cellular Biology. 15 (10): 5376–88. doi:10.1128/mcb.15.10.5376. PMC 230787. PMID 7565688.
• Patterson JB, Thomis DC, Hans SL, Samuel CE (July 1995). "Mechanism of interferon action: double-stranded RNA-specific adenosine deaminase from human cells is inducible by alpha and gamma interferons". Virology. 210 (2): 508–11. doi:10.1006/viro.1995.1370. PMID 7618288.
• O'Connell MA, Krause S, Higuchi M, Hsuan JJ, Totty NF, Jenny A, Keller W (March 1995). "Cloning of cDNAs encoding mammalian double-stranded RNA-specific adenosine deaminase". Molecular and Cellular Biology. 15 (3): 1389–97. doi:10.1128/mcb.15.3.1389. PMC 230363. PMID 7862132.
• Weier HU, George CX, Greulich KM, Samuel CE (November 1995). "The interferon-inducible, double-stranded RNA-specific adenosine deaminase gene (DSRAD) maps to human chromosome 1q21.1-21.2". Genomics. 30 (2): 372–5. doi:10.1006/geno.1995.0034. PMID 8586444.
• Liu Y, George CX, Patterson JB, Samuel CE (February 1997). "Functionally distinct double-stranded RNA-binding domains associated with alternative splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase". The Journal of Biological Chemistry. 272 (7): 4419–28. doi:10.1074/jbc.272.7.4419. PMID 9020165.
• Valenzuela A, Blanco J, Callebaut C, Jacotot E, Lluis C, Hovanessian AG, Franco R (April 1997). "Adenosine deaminase binding to human CD26 is inhibited by HIV-1 envelope glycoprotein gp120 and viral particles". Journal of Immunology. 158 (8): 3721–9. PMID 9103436.
• Herbert A, Alfken J, Kim YG, Mian IS, Nishikura K, Rich A (August 1997). "A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase". Proceedings of the National Academy of Sciences of the United States of America. 94 (16): 8421–6. doi:10.1073/pnas.94.16.8421. PMC 22942. PMID 9237992.
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• Yang A, Deng P, Zhu J, Wang G, Zhang L, Chen AF, Wang T, Sarkar SN, Billiar TR, Wang Q (October 2014). "Adenosine Deaminase Acting on RNA1 Limits RIG-I RNA Detection and Suppresses IFN Production Responding to Viral and Endogenous RNAs". The Journal of Immunology. 193 (7): 3436–3445. doi:10.4049/jimmunol.1401136. PMC 4169998. PMID 25172485.

External links

• OMIM entries on Dyschromatosis Symmetrica Hereditaria 1
• ADAR human gene location in the UCSC Genome Browser.
• ADAR human gene details in the UCSC Genome Browser.