View source for ADAR

{{Short description|Mammalian protein found in Homo sapiens}}
{{cs1 config|name-list-style=vanc}}{{other uses|Adar (disambiguation)}}
{{Infobox_gene}}

The '''double-stranded RNA-specific adenosine deaminase''' [[enzyme]] family are encoded by the ''ADAR'' family [[gene]]s.<ref name=":0">{{cite journal |vauthors=Savva YA, Rieder LE, Reenan RA |date=December 2012 |title=The ADAR protein family |journal=Genome Biology |volume=13 |issue=12 |pages=252 |doi=10.1186/gb-2012-13-12-252 |pmc=3580408 |pmid=23273215 |doi-access=free }}</ref> ADAR stands for ''adenosine deaminase acting on [[RNA]]''.<ref name="entrez">{{cite web |title=Entrez Gene: ADAR Adenosine Deaminase Acting on RNA |url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=103}}</ref><ref name="pmid7972084">{{cite journal |vauthors=Kim U, Wang Y, Sanford T, Zeng Y, Nishikura K |date=November 1994 |title=Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=91 |issue=24 |pages=11457–11461 |bibcode=1994PNAS...9111457K |doi=10.1073/pnas.91.24.11457 |pmc=45250 |pmid=7972084 |doi-access=free}}</ref> This article focuses on the ADAR proteins; This article details the evolutionary history, structure, function, mechanisms and importance of all proteins within this family.<ref name=":0" />

ADAR enzymes bind to double-stranded RNA ([[dsRNA]]) and convert [[adenosine]] to [[inosine]] ([[hypoxanthine]]) by [[deamination]].<ref name="Samuel">{{cite book |title=Adenosine deaminases acting on RNA (ADARs) and A-to-I editing |vauthors=Samuel CE |date=2012 |publisher=Springer |isbn=978-3-642-22800-1 |location=Heidelberg}}</ref> ADAR proteins act post-transcriptionally, changing the [[nucleotide]] content of RNA.<ref name="NCBI" /> The conversion from adenosine to inosine (A to I) in the RNA disrupts the normal A:U pairing, destabilizing the RNA. Inosine is structurally similar to [[guanine]] (G) which leads to inosine to [[cytosine]] (I:C) binding.<ref>{{cite journal |vauthors=Licht K, Hartl M, Amman F, Anrather D, Janisiw MP, Jantsch MF |date=January 2019 |title=Inosine induces context-dependent recoding and translational stalling |journal=Nucleic Acids Research |volume=47 |issue=1 |pages=3–14 |doi=10.1093/nar/gky1163 |pmc=6326813 |pmid=30462291}}</ref> Inosine typically mimics guanosine during translation but can also bind to uracil, cytosine, and adenosine, though it is not favored.

[[Codon]] changes may arise from RNA editing leading to changes in the coding sequences for proteins and their functions.<ref name="Nishikura">{{cite journal |vauthors=Nishikura K |date=7 June 2010 |title=Functions and regulation of RNA editing by ADAR deaminases |journal=Annual Review of Biochemistry |volume=79 |issue=1 |pages=321–349 |doi=10.1146/annurev-biochem-060208-105251 |pmc=2953425 |pmid=20192758}}</ref> Most editing sites are found in noncoding regions of RNA such as [[untranslated regions]] (UTRs), [[Alu elements]], and [[long interspersed nuclear element]]s (LINEs).<ref>{{cite journal |vauthors=Tajaddod M, Jantsch MF, Licht K |date=March 2016 |title=The dynamic epitranscriptome: A to I editing modulates genetic information |journal=Chromosoma |volume=125 |issue=1 |pages=51–63 |doi=10.1007/s00412-015-0526-9 |pmc=4761006 |pmid=26148686}}</ref>  Codon changes can give rise to alternate transcriptional splice variants. ADAR impacts the [[transcriptome]] in editing-independent ways, likely by interfering with other RNA-binding proteins.<ref name="NCBI">{{cite web |title=ADAR |url=https://www.ncbi.nlm.nih.gov/gene/10 |website=NCBI |publisher=U.S. National Library of Medicine}}</ref> 

Mutations in this gene are associated with several diseases including HIV, measles, and melanoma. Recent research supports a linkage between RNA-editing and nervous system disorders such as amyotrophic lateral sclerosis (ALS). Atypical RNA editing linked to ADAR may also correlate to mental disorders such as schizophrenia, epilepsy, and suicidal depression.<ref>{{cite journal |vauthors=Savva YA, Rieder LE, Reenan RA |date=December 2012 |title=The ADAR protein family |journal=Genome Biology |volume=13 |issue=12 |pages=252 |doi=10.1186/gb-2012-13-12-252 |pmc=3580408 |pmid=23273215 |doi-access=free }}</ref>

==Discovery==
The ADAR enzyme and its associated [[gene]] were discovered accidentally in 1987 as a result of research by [[Brenda Bass]] and [[Harold Weintraub]].<ref>{{cite journal |vauthors=Samuel CE |date=March 2011 |title=Adenosine deaminases acting on RNA (ADARs) are both antiviral and proviral |journal=Virology |volume=411 |issue=2 |pages=180–193 |doi=10.1016/j.virol.2010.12.004 |pmc=3057271 |pmid=21211811}}</ref> 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]] was successful. However, when Bass and Weintraub applied identical protocols to ''Xenopus'' embryos, they were unable to determine the embryo's developmental genes. To understand why the method was unsuccessful, they began comparing duplex RNA in both oocytes and embryos. This led them to discover a developmentally regulated activity that denatures RNA:RNA hybrids in embryos.

In 1988, Richard Wagner et al. further studied the activity occurring on ''Xenopus'' embryos.<ref name="pmid2704740">{{cite journal |vauthors=Wagner RW, Smith JE, Cooperman BS, Nishikura K |date=April 1989 |title=A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells and Xenopus eggs |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=86 |issue=8 |pages=2647–2651 |bibcode=1989PNAS...86.2647W |doi=10.1073/pnas.86.8.2647 |pmc=286974 |pmid=2704740 |doi-access=free}}</ref> They determined a [[protein]] was responsible for unwinding of RNA due to the absence of activity after [[proteinase]] treatment. This protein is specific for dsRNA and does not require [[Adenosine triphosphate|ATP]]. It became evident this protein's activity on dsRNA modifies it beyond a point of rehybridization but does not fully denature it. Finally, the researchers determined 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.

== Evolution and function ==

ADARs are one of the most common forms of RNA editing, and have both selective and non-selective activity.<ref>{{cite journal |vauthors=Grice LF, Degnan BM |date=January 2015 |title=The origin of the ADAR gene family and animal RNA editing |journal=BMC Evolutionary Biology |volume=15 |issue=1 |pages=4 |doi=10.1186/s12862-015-0279-3 |pmc=4323055 |pmid=25630791 |bibcode=2015BMCEE..15....4G |doi-access=free }}</ref> ADAR is able to modify and regulate the output of gene product, as inosine is interpreted by the [[Cell (biology)|cell]] to be [[guanosine]]. ADAR can change the functionality of small RNA molecules. Recently, ADARs have also been discovered as a regulator on splicing and [[Circular RNA|circRNA]] biogenesis with their editing capability or RNA binding function.<ref>{{cite journal |display-authors=6 |vauthors=Tang SJ, Shen H, An O, Hong H, Li J, Song Y, Han J, Tay DJ, Ng VH, Bellido Molias F, Leong KW, Pitcheshwar P, Yang H, Chen L |date=February 2020 |title=Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development |journal=Nature Communications |volume=11 |issue=1 |pages=799 |bibcode=2020NatCo..11..799T |doi=10.1038/s41467-020-14621-5 |pmc=7005744 |pmid=32034135}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Hsiao YE, Bahn JH, Yang Y, Lin X, Tran S, Yang EW, Quinones-Valdez G, Xiao X |date=June 2018 |title=RNA editing in nascent RNA affects pre-mRNA splicing |journal=Genome Research |volume=28 |issue=6 |pages=812–823 |doi=10.1101/gr.231209.117 |pmc=5991522 |pmid=29724793}}</ref><ref>{{cite journal |display-authors=6 |vauthors=Shen H, An O, Ren X, Song Y, Tang SJ, Ke XY, Han J, Tay DJ, Ng VH, Molias FB, Pitcheshwar P, Leong KW, Tan KK, Yang H, Chen L |date=March 2022 |title=ADARs act as potent regulators of circular transcriptome in cancer |journal=Nature Communications |volume=13 |issue=1 |pages=1508 |bibcode=2022NatCo..13.1508S |doi=10.1038/s41467-022-29138-2 |pmc=8938519 |pmid=35314703}}</ref> 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 another gene which encoded 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 [[Phylum|phyla]], indicates that RNA editing is essential in regulating genes for metazoan organisms. ADAR has not been discovered in a variety of non-metazoan eukaryotes, such as [[plants]], [[fungi]] and [[choanoflagellates]].

ADARs are suggested to have two functions: to increase diversity of the proteome by inducing creation of harmless non-genomically encoded proteins, and protecting crucial translational sites. The conventional belief is their primary role is to increase the diversity of transcripts and expand the protein variation, promoting evolution of proteins.<ref name=":0" />

== Forms of ADAR Enzymes ==
In mammals, there are three types of ADAR enzymes: ADAR (ADAR1), [[ADARB1]] (ADAR2), and [[ADARB2]] (ADAR3).<ref name=":0" /> 

'''ADAR (ADAR1) and ADAR2 (ADARB1)'''

ADAR one and two are both found within various tissues of the body. These two forms of ADAR are also found to be catalytically active, meaning they can be used as a catalyst in a reaction. Both forms also have similar expression pattern structures of proteins and require substrate double-stranded RNA structures.<ref name="Nishikura" />  However, they differ in their editing activity in that both ADAR one and two can edit GluR-B pre-mRNA at the R/G site and only ADAR2 can alter the Q/R site.<ref>{{Cite journal |last1=Källman |first1=Annika M. |last2=Sahlin |first2=Margareta |last3=Ohman |first3=Marie |date=2003-08-15 |title=ADAR2 A-->I editing: site selectivity and editing efficiency are separate events |journal=Nucleic Acids Research |volume=31 |issue=16 |pages=4874–4881 |doi=10.1093/nar/gkg681 |issn=1362-4962 |pmid=12907730|pmc=169957 }}</ref> ADAR1 has been found two have two isoforms, ADAR1p150 and ADARp110. ADAR1p110 is typically found in the nucleus, while ADAR1p150 shuffles between the nucleus and the cytoplasm, mostly present in the cytoplasm.

'''ADAR3 (ADARB2)'''

ADAR 3 varies from the other two forms of ADAR in that it is only found within brain tissue. It also is considered to be inactive when it comes to catalytic activity.<ref name="Nishikura" /> ADAR3 has been found to be linked to memory and learning in mice, showing that it plays a crucial role in the nervous system. In vitro studies have also shown that ADAR3 might play a role in the regulation of ADAR one and two.<ref>{{Cite journal |last1=Wang |first1=Yuru |last2=Chung |first2=Dong Hee |last3=Monteleone |first3=Leanna R. |last4=Li |first4=Jie |last5=Chiang |first5=Yao |last6=Toney |first6=Michael D. |last7=Beal |first7=Peter A. |date=2019-11-18 |title=RNA binding candidates for human ADAR3 from substrates of a gain of function mutant expressed in neuronal cells |journal=Nucleic Acids Research |volume=47 |issue=20 |pages=10801–10814 |doi=10.1093/nar/gkz815 |issn=1362-4962 |pmc=6846710 |pmid=31552420}}</ref>

==Catalytic activity==

===Biochemical reaction===
ADARs [[Catalysis|catalyze]] the hydrolytic deamination reaction from adenosine to inosine.<ref name="Samuel" /> An activated water molecule will react with adenosine in a nucleophilic substitution reaction with the carbon-6 amine group. A hydrated intermediate will exist for a short period of time, then the amine group will leave as an ammonia ion.

<span class="mw-default-size" role="presentation">[[File:ADAR1_mechanism.png|link=|354x354px]]</span> 
 
<gallery>
File:ADAR reaction.jpg|Adenosine conversion to Inosine via ADAR
</gallery>

===Active site===
In humans, ADAR enzymes have two to three amino-terminal dsRNA binding domains (dsRBDs), and one carboxy terminal catalytic deaminase domain.<ref name="Savva">{{cite journal |vauthors=Savva YA, Rieder LE, Reenan RA |date=December 2012 |title=The ADAR protein family |journal=Genome Biology |volume=13 |issue=12 |pages=252 |doi=10.1186/gb-2012-13-12-252 |pmc=3580408 |pmid=23273215 |doi-access=free}}</ref> In the dsRBD there is a conserved α-β-β-β-α configuration.<ref name="Nishikura" /> ADAR1 contains two areas for binding [[Z-DNA]] known as Zα and Zβ.<ref>{{cite journal |vauthors=Srinivasan B, Kuś K, Athanasiadis A |date=August 2022 |title=Thermodynamic analysis of Zα domain-nucleic acid interactions |journal=The Biochemical Journal |volume=479 |issue=16 |pages=1727–1741 |doi=10.1042/BCJ20220200 |pmid=35969150 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Gabriel L, Srinivasan B, Kuś K, Mata JF, João Amorim M, Jansen LE, Athanasiadis A |date=May 2021 |title=Enrichment of Zα domains at cytoplasmic stress granules is due to their innate ability to bind to nucleic acids |journal=Journal of Cell Science |volume=134 |issue=10 |pages=jcs258446 |doi=10.1242/jcs.258446 |pmid=34037233 |s2cid=235202242|doi-access=free }}</ref> ADAR2 and ADAR3 have an arginine rich [[single stranded]] RNA (ssRNA) binding domain. A crystal structure of ADAR2 has been solved.<ref name="Savva" /> In the enzyme active site, there is a [[glutamic acid]] residue(E396) that hydrogen bonds to a water. A [[histidine]] (H394) and two [[cysteine]] residues (C451 and C516) coordinate with a [[zinc]] ion. The zinc activates the water molecule for the nucleophilic hydrolytic deamination. Within the catalytic core there is an [[inositol hexakisphosphate]] (IP6), which stabilizes [[arginine]] and [[lysine]] residues.

[[File:ADAR1 active site.png|ADAR1 active site|304x304px]]

===Dimerization===
ADAR1 and ADAR2 have been shown to form homodimers in mammals, while ADAR3 does not.<ref name="Nishikura" /> Earlier studies suggested that dimerization might be necessary for enzymatic activity and could occur independently of RNA binding, based on experiments with ADAR mutants that failed to bind double-stranded RNA (dsRNA) but could still dimerize, indicating protein-protein interactions were sufficient.<ref name="Nishikura" /><ref name="Cho">{{cite journal |vauthors=Cho DS, Yang W, Lee JT, Shiekhattar R, Murray JM, Nishikura K |date=May 2003 |title=Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA |journal=The Journal of Biological Chemistry |volume=278 |issue=19 |pages=17093–17102 |doi=10.1074/jbc.M213127200 |pmid=12618436 |doi-access=free}}</ref> However, more recent research has clarified that dimerization is not strictly required for ADAR1 enzymatic activity. A recent study demonstrated that ADAR1 dimerization occurs specifically through its third double-stranded RNA-binding domain (dsRBD3), and importantly, this dimerization is RNA-independent.<ref name="Mboukou">{{cite journal |vauthors=Mboukou A, Rajendra V, Messmer S, Mandl TC, Catala M, Tisné C, Jantsch MF, Barraud P  |date=November 2024 |title=Dimerization of ADAR1 modulates site-specificity of RNA editing |journal=Nature Communications |volume=15 |pages=10051 |doi=10.1038/s41467-024-53777-2 |pmid=39572551 |doi-access=free|pmc=11582362 }}</ref> This shows that ADAR1 can form dimers via a defined protein-protein interface without involving RNA. In addition, dimerization disruption do not completely abrogate ADAR1 editing activity, but affects editing efficiency differently depending on the selected editing site.<ref name="Mboukou" />

==Role in disease==

===Aicardi–Goutières Syndrome and bilateral striatal necrosis/dystonia===

ADAR1 is one of multiple genes which often contribute to [[Aicardi–Goutières syndrome]] when mutated.<ref name="Rice_2012">{{cite journal |display-authors=6 |vauthors=Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, Dickerson JE, Bhaskar SS, Zampini M, Briggs TA, Jenkinson EM, Bacino CA, Battini R, Bertini E, Brogan PA, Brueton LA, Carpanelli M, De Laet C, de Lonlay P, del Toro M, Desguerre I, Fazzi E, Garcia-Cazorla A, Heiberg A, Kawaguchi M, Kumar R, Lin JP, Lourenco CM, Male AM, Marques W, Mignot C, Olivieri I, Orcesi S, Prabhakar P, Rasmussen M, Robinson RA, Rozenberg F, Schmidt JL, Steindl K, Tan TY, van der Merwe WG, Vanderver A, Vassallo G, Wakeling EL, Wassmer E, Whittaker E, Livingston JH, Lebon P, Suzuki T, McLaughlin PJ, Keegan LP, O'Connell MA, Lovell SC, Crow YJ |date=November 2012 |title=Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature |journal=Nature Genetics |volume=44 |issue=11 |pages=1243–1248 |doi=10.1038/ng.2414 |pmc=4154508 |pmid=23001123}}</ref> [[Aicardi–Goutières syndrome]] 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.<ref>{{cite journal |display-authors=6 |vauthors=Yang S, Deng P, Zhu Z, Zhu J, Wang G, Zhang L, Chen AF, Wang T, Sarkar SN, Billiar TR, Wang Q |date=October 2014 |title=Adenosine deaminase acting on RNA 1 limits RIG-I RNA detection and suppresses IFN production responding to viral and endogenous RNAs |journal=Journal of Immunology |volume=193 |issue=7 |pages=3436–3445 |doi=10.4049/jimmunol.1401136 |pmc=4169998 |pmid=25172485}}</ref> 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).<ref>{{cite journal |vauthors=Gallo A, Vukic D, Michalík D, O'Connell MA, Keegan LP |date=September 2017 |title=ADAR RNA editing in human disease; more to it than meets the I |journal=Human Genetics |volume=136 |issue=9 |pages=1265–1278 |doi=10.1007/s00439-017-1837-0 |pmid=28913566 |s2cid=3754471}}</ref> This buildup of dsRNA stimulates IFN production without a viral infection, causing an inflammatory reaction and autoimmune response.<ref>{{cite journal |display-authors=6 |vauthors=Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, Li JB, Seeburg PH, Walkley CR |date=September 2015 |title=RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself |journal=Science |volume=349 |issue=6252 |pages=1115–1120 |bibcode=2015Sci...349.1115L |doi=10.1126/science.aac7049 |pmc=5444807 |pmid=26275108}}</ref> The phenotype in the 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 lacking this domain.<ref>{{cite journal |display-authors=6 |vauthors=Ward SV, George CX, Welch MJ, Liou LY, Hahm B, Lewicki H, de la Torre JC, Samuel CE, Oldstone MB |date=January 2011 |title=RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=108 |issue=1 |pages=331–336 |bibcode=2011PNAS..108..331W |doi=10.1073/pnas.1017241108 |pmc=3017198 |pmid=21173229 |doi-access=free}}</ref> In humans, the P193A mutation in the Zα domain is causal for [[Aicardi–Goutières syndrome]]<ref name="Rice_2012" /> and for the more severe phenotype found in Bilateral Striatal Necrosis/Dystonia.<ref>{{cite journal |display-authors=6 |vauthors=Livingston JH, Lin JP, Dale RC, Gill D, Brogan P, Munnich A, Kurian MA, Gonzalez-Martinez V, De Goede CG, Falconer A, Forte G, Jenkinson EM, Kasher PR, Szynkiewicz M, Rice GI, Crow YJ |date=February 2014 |title=A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1 |journal=Journal of Medical Genetics |volume=51 |issue=2 |pages=76–82 |doi=10.1136/jmedgenet-2013-102038 |pmid=24262145 |s2cid=8716360}}</ref> The findings establish a biological role for the left-handed Z-DNA conformation.<ref>{{cite journal |vauthors=Herbert A |date=January 2020 |title=Mendelian disease caused by variants affecting recognition of Z-DNA and Z-RNA by the Zα domain of the double-stranded RNA editing enzyme ADAR |journal=European Journal of Human Genetics |volume=28 |issue=1 |pages=114–117 |doi=10.1038/s41431-019-0458-6 |pmc=6906422 |pmid=31320745}}</ref>

=== Amyotrophic Lateral Sclerosis (ALS) ===
In motor neurons, the most well-grounded marker of [[amyotrophic lateral sclerosis]] (ALS) is the [[TAR DNA-binding protein 43|TAR DNA-binding protein (TDP-43)]]. When there is failure of RNA-editing due to downregulation of TDP-43, motor neurons devoid of ADAR2 enzymes express unregulated, leading to abnormally permeable Ca<sup>2+</sup> channels. ADAR2 knockout mice show signs of ALS phenotype similarity. Current researchers are developing a molecular targeting therapy by normalizing expression of ADAR2.<ref>{{cite journal |vauthors=Yamashita T, Kwak S |date=July 2019 |title=Cell death cascade and molecular therapy in ADAR2-deficient motor neurons of ALS |journal=Neuroscience Research |volume=144 |pages=4–13 |doi=10.1016/j.neures.2018.06.004 |pmid=29944911 |s2cid=49433496}}</ref>

=== Cancer ===
(ADAR)-induced A-to-I RNA editing may elicit dangerous [[amino acid]] mutations. Editing mRNA typically imparts [[missense mutation]]s leading to alterations in the beginning and terminating regions of translation. However, crucial amino acid changes can occur, resulting in change of function of several cellular processes. Amino acid changes can result in protein structural changes at secondary, tertiary, and quaternary structures. Researchers observed high levels of oncogenetic A-to-I editing in circular RNA precursors, directly confirming ADAR's relationship to cancer. A list of tumor related RNA editing sites can be found [https://www.frontiersin.org/articles/10.3389/fonc.2020.632187/full here].<ref>{{cite journal |vauthors=Wang H, Chen S, Wei J, Song G, Zhao Y |date=2021 |title=A-to-I RNA Editing in Cancer: From Evaluating the Editing Level to Exploring the Editing Effects |journal=Frontiers in Oncology |volume=10 |pages=632187 |doi=10.3389/fonc.2020.632187 |pmc=7905090 |pmid=33643923 |doi-access=free}}</ref>

==== Hepatocellular carcinoma ====
Studies of patients with [[hepatocellular carcinoma]] (HCC) have shown trends of upregulated ADAR1 and downregulated ADAR2. Results suggest the irregular regulation 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.<ref>{{cite journal |display-authors=6 |vauthors=Chan TH, Lin CH, Qi L, Fei J, Li Y, Yong KJ, Liu M, Song Y, Chow RK, Ng VH, Yuan YF, Tenen DG, Guan XY, Chen L |date=May 2014 |title=A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma |journal=Gut |volume=63 |issue=5 |pages=832–843 |doi=10.1136/gutjnl-2012-304037 |pmc=3995272 |pmid=23766440}}</ref> The imbalance in 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 prognostic marker.

==== Melanoma ====
Studies have indicated that loss of ADAR1 contributes to melanoma growth and metastasis. ADAR enzymes can act on microRNA and affect its biogenesis, stability and/or its binding target.<ref>{{cite journal |display-authors=6 |vauthors=Heale BS, Keegan LP, McGurk L, Michlewski G, Brindle J, Stanton CM, Caceres JF, O'Connell MA |date=October 2009 |title=Editing independent effects of ADARs on the miRNA/siRNA pathways |journal=The EMBO Journal |volume=28 |issue=20 |pages=3145–3156 |doi=10.1038/emboj.2009.244 |pmc=2735678 |pmid=19713932}}</ref> ADAR1 may be downregulated by cAMP- response element binding protein (CREB), limiting its ability to act on miRNA.<ref name="Melanoma Ref">{{cite journal |display-authors=6 |vauthors=Shoshan E, Mobley AK, Braeuer RR, Kamiya T, Huang L, Vasquez ME, Salameh A, Lee HJ, Kim SJ, Ivan C, Velazquez-Torres G, Nip KM, Zhu K, Brooks D, Jones SJ, Birol I, Mosqueda M, Wen YY, Eterovic AK, Sood AK, Hwu P, Gershenwald JE, Robertson AG, Calin GA, Markel G, Fidler IJ, Bar-Eli M |date=March 2015 |title=Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis |journal=Nature Cell Biology |volume=17 |issue=3 |pages=311–321 |doi=10.1038/ncb3110 |pmc=4344852 |pmid=25686251}}</ref> 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.

===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.<ref>{{cite journal |display-authors=6 |vauthors=Tojo K, Sekijima Y, Suzuki T, Suzuki N, Tomita Y, Yoshida K, Hashimoto T, Ikeda S |date=September 2006 |title=Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation |journal=Movement Disorders |volume=21 |issue=9 |pages=1510–1513 |doi=10.1002/mds.21011 |pmid=16817193 |s2cid=38374943}}</ref> This is a disease characterized by hyperpigmentation in the hands and feet and can occur in Japanese and Chinese families.

===HIV===
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.<ref>{{cite journal |display-authors=6 |vauthors=Weiden MD, Hoshino S, Levy DN, Li Y, Kumar R, Burke SA, Dawson R, Hioe CE, Borkowsky W, Rom WN, Hoshino Y |date=2014 |title=Adenosine deaminase acting on RNA-1 (ADAR1) inhibits HIV-1 replication in human alveolar macrophages |journal=PLOS ONE |volume=9 |issue=10 |pages=e108476 |bibcode=2014PLoSO...9j8476W |doi=10.1371/journal.pone.0108476 |pmc=4182706 |pmid=25272020 |doi-access=free}}</ref> The mutation in the HIV genome by ADAR1 might in some cases lead to beneficial viral mutations which could contribute to drug resistance.

<ref name="Melanoma Ref" />

==Viral activity==

===Antiviral===
ADAR1 is an interferon ( [[Interferon|IFN]] )-inducible protein (one released by a cell in response to a pathogen or virus), able to assist in a cell's immune pathway. Evidence shows elimination of [[Hepatitis C virus|HCV]] replicon, Lymphocytic choriomeningitis [[Lymphocytic choriomeningitis|LCMV]], and [[Polyomaviridae|polyomavirus]].<ref name="Enhancement">{{cite journal |vauthors=Gélinas JF, Clerzius G, Shaw E, Gatignol A |date=September 2011 |title=Enhancement of replication of RNA viruses by ADAR1 via RNA editing and inhibition of RNA-activated protein kinase |journal=Journal of Virology |volume=85 |issue=17 |pages=8460–8466 |doi=10.1128/JVI.00240-11 |pmc=3165853 |pmid=21490091}}</ref><ref name="Pfaller">{{cite journal |vauthors=Pfaller CK, George CX, Samuel CE |date=September 2021 |title=Adenosine Deaminases Acting on RNA (ADARs) and Viral Infections |journal=Annual Review of Virology |volume=8 |issue=1 |pages=239–264 |doi=10.1146/annurev-virology-091919-065320 |pmid=33882257 |doi-access=free}}</ref>

===Proviral===
ADAR1 is proviral in other circumstances. ADAR1’s A to I editing has been found in many viruses including measles virus,<ref>{{cite journal |display-authors=6 |vauthors=Baczko K, Lampe J, Liebert UG, Brinckmann U, ter Meulen V, Pardowitz I, Budka H, Cosby SL, Isserte S, Rima BK |date=November 1993 |title=Clonal expansion of hypermutated measles virus in a SSPE brain |journal=Virology |volume=197 |issue=1 |pages=188–195 |doi=10.1006/viro.1993.1579 |pmid=8212553}}</ref><ref name="Pfaller" /><ref>{{cite journal |vauthors=Cattaneo R, Schmid A, Eschle D, Baczko K, ter Meulen V, Billeter MA |date=October 1988 |title=Biased hypermutation and other genetic changes in defective measles viruses in human brain infections |journal=Cell |volume=55 |issue=2 |pages=255–265 |doi=10.1016/0092-8674(88)90048-7 |pmc=7126660 |pmid=3167982}}</ref> influenza virus,<ref>{{cite journal |vauthors=Tenoever BR, Ng SL, Chua MA, McWhirter SM, García-Sastre A, Maniatis T |date=March 2007 |title=Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity |journal=Science |volume=315 |issue=5816 |pages=1274–1278 |doi=10.1126/science.1136567 |pmid=17332413 |s2cid=86636484}}</ref> lymphocytic choriomeningitis virus,<ref>{{cite journal |vauthors=Zahn RC, Schelp I, Utermöhlen O, von Laer D |date=January 2007 |title=A-to-G hypermutation in the genome of lymphocytic choriomeningitis virus |journal=Journal of Virology |volume=81 |issue=2 |pages=457–464 |doi=10.1128/jvi.00067-06 |pmc=1797460 |pmid=17020943}}</ref> polyomavirus,<ref>{{cite journal |vauthors=Kumar M, Carmichael GG |date=April 1997 |title=Nuclear antisense RNA induces extensive adenosine modifications and nuclear retention of target transcripts |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=94 |issue=8 |pages=3542–3547 |bibcode=1997PNAS...94.3542K |doi=10.1073/pnas.94.8.3542 |pmc=20475 |pmid=9108012 |doi-access=free}}</ref> hepatitis delta virus,<ref name="pmid2304136">{{cite journal |vauthors=Luo GX, Chao M, Hsieh SY, Sureau C, Nishikura K, Taylor J |date=March 1990 |title=A specific base transition occurs on replicating hepatitis delta virus RNA |journal=Journal of Virology |volume=64 |issue=3 |pages=1021–1027 |doi=10.1128/JVI.64.3.1021-1027.1990 |pmc=249212 |pmid=2304136}}</ref> and hepatitis C virus.<ref name="pmid15858013">{{cite journal |vauthors=Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM |date=May 2005 |title=New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1 |journal=Journal of Virology |volume=79 |issue=10 |pages=6291–6298 |doi=10.1128/JVI.79.10.6291-6298.2005 |pmc=1091666 |pmid=15858013}}</ref> Although ADAR1 has been seen in other viruses, it has only been studied extensively in a few. Research on measles virus shows ADAR1 enhancing viral replication through two different mechanisms: RNA editing and inhibition of dsRNA-activated protein kinase ([[Protein kinase R|PKR]]).<ref name="Enhancement" /><ref name="Pfaller" /> Specifically, viruses are thought to use ADAR1 as a positive replication factor by selectively suppressing dsRNA-dependent and antiviral pathways.<ref>{{cite journal |vauthors=Toth AM, Li Z, Cattaneo R, Samuel CE |date=October 2009 |title=RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR |journal=The Journal of Biological Chemistry |volume=284 |issue=43 |pages=29350–29356 |doi=10.1074/jbc.M109.045146 |pmc=2785566 |pmid=19710021 |doi-access=free}}</ref>

== See also ==
*[[RNA editing]]
*[[Potassium channel RNA editing signal]]
*[[ADARB1]]
*[[Z-DNA]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite book |title=Cellular Peptidases in Immune Functions and Diseases |vauthors=Valenzuela A, Blanco J, Callebaut C, Jacotot E, Lluis C, Hovanessian AG, Franco R |chapter=HIV-1 Envelope gp120 and Viral Particles Block Adenosine Deaminase Binding to Human CD26 |year=1997 |isbn=978-1-4757-9615-5 |volume=421 |pages=185–92 |series=Advances in Experimental Medicine and Biology |doi=10.1007/978-1-4757-9613-1_24 |pmid=9330696}}
* {{cite journal |display-authors=6 |vauthors=Wathelet MG, Szpirer J, Nols CB, Clauss IM, De Wit L, Islam MQ, Levan G, Horisberger MA, Content J, Szpirer C |date=September 1988 |title=Cloning and chromosomal location of human genes inducible by type I interferon |journal=Somatic Cell and Molecular Genetics |volume=14 |issue=5 |pages=415–426 |doi=10.1007/BF01534709 |pmid=3175763 |s2cid=42406993}}
* {{cite journal |vauthors=Wang Y, Zeng Y, Murray JM, Nishikura K |date=November 1995 |title=Genomic organization and chromosomal location of the human dsRNA adenosine deaminase gene: the enzyme for glutamate-activated ion channel RNA editing |journal=Journal of Molecular Biology |volume=254 |issue=2 |pages=184–195 |doi=10.1006/jmbi.1995.0610 |pmid=7490742 |doi-access=free}}
* {{cite journal |vauthors=Patterson JB, Samuel CE |date=October 1995 |title=Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase |journal=Molecular and Cellular Biology |volume=15 |issue=10 |pages=5376–5388 |doi=10.1128/mcb.15.10.5376 |pmc=230787 |pmid=7565688}}
* {{cite journal |vauthors=Patterson JB, Thomis DC, Hans SL, Samuel CE |date=July 1995 |title=Mechanism of interferon action: double-stranded RNA-specific adenosine deaminase from human cells is inducible by alpha and gamma interferons |journal=Virology |volume=210 |issue=2 |pages=508–511 |doi=10.1006/viro.1995.1370 |pmid=7618288 |doi-access=free}}
* {{cite journal |vauthors=O'Connell MA, Krause S, Higuchi M, Hsuan JJ, Totty NF, Jenny A, Keller W |date=March 1995 |title=Cloning of cDNAs encoding mammalian double-stranded RNA-specific adenosine deaminase |journal=Molecular and Cellular Biology |volume=15 |issue=3 |pages=1389–1397 |doi=10.1128/mcb.15.3.1389 |pmc=230363 |pmid=7862132}}
* {{cite journal |vauthors=Weier HU, George CX, Greulich KM, Samuel CE |date=November 1995 |title=The interferon-inducible, double-stranded RNA-specific adenosine deaminase gene (DSRAD) maps to human chromosome 1q21.1-21.2 |journal=Genomics |volume=30 |issue=2 |pages=372–375 |doi=10.1006/geno.1995.0034 |pmid=8586444}}
* {{cite journal |vauthors=Liu Y, George CX, Patterson JB, Samuel CE |date=February 1997 |title=Functionally distinct double-stranded RNA-binding domains associated with alternative splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase |journal=The Journal of Biological Chemistry |volume=272 |issue=7 |pages=4419–4428 |doi=10.1074/jbc.272.7.4419 |pmid=9020165 |doi-access=free}}
* {{cite journal |vauthors=Valenzuela A, Blanco J, Callebaut C, Jacotot E, Lluis C, Hovanessian AG, Franco R |date=April 1997 |title=Adenosine deaminase binding to human CD26 is inhibited by HIV-1 envelope glycoprotein gp120 and viral particles |journal=Journal of Immunology |volume=158 |issue=8 |pages=3721–3729 |doi=10.4049/jimmunol.158.8.3721 |pmid=9103436 |s2cid=22609553|doi-access=free }}
* {{cite journal |vauthors=Herbert A, Alfken J, Kim YG, Mian IS, Nishikura K, Rich A |date=August 1997 |title=A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=94 |issue=16 |pages=8421–8426 |bibcode=1997PNAS...94.8421H |doi=10.1073/pnas.94.16.8421 |pmc=22942 |pmid=9237992 |doi-access=free}}
* {{cite journal |vauthors=Liu Y, Herbert A, Rich A, Samuel CE |date=July 1998 |title=Double-stranded RNA-specific adenosine deaminase: nucleic acid binding properties |journal=Methods |volume=15 |issue=3 |pages=199–205 |doi=10.1006/meth.1998.0624 |pmid=9735305}}
* {{cite journal |vauthors=George CX, Samuel CE |date=April 1999 |title=Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=96 |issue=8 |pages=4621–4626 |bibcode=1999PNAS...96.4621G |doi=10.1073/pnas.96.8.4621 |pmc=16382 |pmid=10200312 |doi-access=free}}
* {{cite journal |vauthors=Schwartz T, Rould MA, Lowenhaupt K, Herbert A, Rich A |date=June 1999 |title=Crystal structure of the Zalpha domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA |journal=Science |volume=284 |issue=5421 |pages=1841–1845 |doi=10.1126/science.284.5421.1841 |pmid=10364558}}
* {{cite journal |display-authors=6 |vauthors=Schade M, Turner CJ, Kühne R, Schmieder P, Lowenhaupt K, Herbert A, Rich A, Oschkinat H |date=October 1999 |title=The solution structure of the Zalpha domain of the human RNA editing enzyme ADAR1 reveals a prepositioned binding surface for Z-DNA |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=96 |issue=22 |pages=12465–12470 |bibcode=1999PNAS...9612465S |doi=10.1073/pnas.96.22.12465 |pmc=22950 |pmid=10535945 |doi-access=free}}
* {{cite journal |vauthors=Blanco J, Valenzuela A, Herrera C, Lluís C, Hovanessian AG, Franco R |date=July 2000 |title=The HIV-1 gp120 inhibits the binding of adenosine deaminase to CD26 by a mechanism modulated by CD4 and CXCR4 expression |journal=FEBS Letters |volume=477 |issue=1–2 |pages=123–128 |doi=10.1016/S0014-5793(00)01751-8 |pmid=10899322 |s2cid=22229481 |doi-access=|bibcode=2000FEBSL.477..123B }}
* {{cite journal |vauthors=Herrera C, Morimoto C, Blanco J, Mallol J, Arenzana F, Lluis C, Franco R |date=June 2001 |title=Comodulation of CXCR4 and CD26 in human lymphocytes |journal=The Journal of Biological Chemistry |volume=276 |issue=22 |pages=19532–19539 |doi=10.1074/jbc.M004586200 |pmid=11278278 |doi-access=free}}
* {{cite journal |vauthors=Wong SK, Sato S, Lazinski DW |date=June 2001 |title=Substrate recognition by ADAR1 and ADAR2 |journal=RNA |volume=7 |issue=6 |pages=846–858 |doi=10.1017/S135583820101007X |pmc=1370134 |pmid=11421361}}
* {{cite journal |vauthors=Eckmann CR, Neunteufl A, Pfaffstetter L, Jantsch MF |date=July 2001 |title=The human but not the Xenopus RNA-editing enzyme ADAR1 has an atypical nuclear localization signal and displays the characteristics of a shuttling protein |journal=Molecular Biology of the Cell |volume=12 |issue=7 |pages=1911–1924 |doi=10.1091/mbc.12.7.1911 |pmc=55639 |pmid=11451992}}
{{refend}}
* {{cite journal |display-authors=6 |vauthors=Yang S, Deng P, Zhu Z, Zhu J, Wang G, Zhang L, Chen AF, Wang T, Sarkar SN, Billiar TR, Wang Q |date=October 2014 |title=Adenosine deaminase acting on RNA 1 limits RIG-I RNA detection and suppresses IFN production responding to viral and endogenous RNAs |journal=Journal of Immunology |volume=193 |issue=7 |pages=3436–3445 |doi=10.4049/jimmunol.1401136 |pmc=4169998 |pmid=25172485}}

== External links ==
* [https://archive.today/20130415185107/http://www.omim.org/search?index=entry&start=1&limit=10&sort=score+desc&search=number:(127400+OR+146920)  OMIM entries on Dyschromatosis Symmetrica Hereditaria 1]
* {{UCSC genome browser|ADAR}}
* {{UCSC gene details|ADAR}}

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