ADAR: Difference between revisions - Wikipedia

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The '''double-stranded RNA-specific adenosine deaminase''' [[enzyme]] family are encoded by the ''ADAR'' family [[Gene|genes]].<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.

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[[Codon]] changes may arise from RNA editing leading to changes in the coding sequences for proteins and their functions.<ref name="Nishikura" /> Most editing sites are found in noncoding regions of RNA such as [[untranslated regions]] (UTRs), [[Alu elements]], and [[Long interspersed nuclear element|long interspersed nuclear elements]] (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==

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== 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" />

== Enzyme classification ==

In mammals, there are three types of ADAR enzymes, ADAR (ADAR1), [[ADARB1]] (ADAR2) and [[ADARB2]] (ADAR3).<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> ADAR and ADARB1 are found in many tissues in the body while ADARB2 is only found in the brain.<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> ADAR and ADARB1 are known to be catalytically active while evidence suggests ADARB2 is inactive.<ref name="Nishikura" /> ADAR has two known [[Protein isoform|isoforms]], ADAR1p150 and ADAR1p110. ADAR1p110 is typically found in the nucleus while ADAR1p150 shuffles between the nucleus and the cytoplasm, mostly present in the cytoplasm.<ref name="Savva" /> ADAR and ADARB1 share functional domains and have similar expression patterns, structure of proteins, and require substrate double stranded RNA structures. However, they differ in their editing activity.<ref>{{Cite journal |display-authors=6 |vauthors=Higuchi M, Maas S, Single FN, Hartner J, Rozov A, Burnashev N, Feldmeyer D, Sprengel R, Seeburg PH |date=July 2000 |title=Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2 |journal=Nature |volume=406 |issue=6791 |pages=78–81 |bibcode=2000Natur.406...78H |doi=10.1038/35017558 |pmid=10894545 |s2cid=4412160}}</ref>

==Catalytic activity==

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== Model organisms ==

Model organisms have been used in the study of ADAR function. A conditional knockout mouse line, called Adartm1a(EUCOMM)Wtsi<ref name="mouse model 8">{{Cite web |title=International Knockout Mouse Consortium |url=http://www.mousephenotype.org/?query=Adar}}</ref><ref name="mouse model 9">{{Cite web |title=Mouse Genome Informatics |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4432463}}</ref> 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.<ref name="mouse model 10">{{Cite journal |display-authors=6 |vauthors=Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A |date=June 2011 |title=A conditional knockout resource for the genome-wide study of mouse gene function |journal=Nature |volume=474 |issue=7351 |pages=337–342 |doi=10.1038/nature10163 |pmc=3572410 |pmid=21677750}}</ref><ref name="mouse model 11">{{Cite journal |vauthors=Dolgin E |date=June 2011 |title=Mouse library set to be knockout |journal=Nature |volume=474 |issue=7351 |pages=262–263 |doi=10.1038/474262a |pmid=21677718 |doi-access=free}}</ref><ref name="mouse model 12">{{Cite journal |vauthors=Collins FS, Rossant J, Wurst W |date=January 2007 |title=A mouse for all reasons |journal=Cell |volume=128 |issue=1 |pages=9–13 |doi=10.1016/j.cell.2006.12.018 |pmid=17218247 |s2cid=18872015 |doi-access=free}}</ref> Male and female mice underwent a standardized [[Phenotype|phenotypic]] screen to determine the effects of deletion.<ref name="mouse model 6">{{Cite journal |vauthors=Gardin A, White J |date=September 2010 |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice |journal=Acta Ophthalmologica |volume=88 |pages=0 |doi=10.1111/j.1755-3768.2010.4142.x |s2cid=85911512}}</ref><ref name="mouse model 13">{{Cite journal |vauthors=van der Weyden L, White JK, Adams DJ, Logan DW |date=June 2011 |title=The mouse genetics toolkit: revealing function and mechanism |journal=Genome Biology |volume=12 |issue=6 |pages=224 |doi=10.1186/gb-2011-12-6-224 |pmc=3218837 |pmid=21722353 |doi-access=free }}</ref> Twenty five tests were carried out on the mutants 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.<ref name="mouse model 6" />

==Role in disease==

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== Further reading ==

* {{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 ~~|chapter=HIV-1 envelope gp120 and viral particles block adenosine deaminase binding to human CD26~~ |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}}