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Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While many clinical hepatitis C virus (HCV) infections are resistant to alpha interferon (IFN-alpha) therapy, subgenomic in vitro self-replicating HCV RNAs (HCV replicons) are characterized by marked IFN-alpha sensitivity. IFN-alpha treatment of replicon-containing cells results in a rapid loss of viral RNA via translation inhibition through double-stranded RNA-activated protein kinase (PKR) and also through a new pathway involving RNA editing by an adenosine deaminase that acts on double-stranded RNA (ADAR1). More than 200 genes are induced by IFN-alpha, and yet only a few are attributed with an antiviral role. We show that inhibition of both PKR and ADAR1 by the addition of adenovirus-associated RNA stimulates replicon expression and reduces the amount of inosine recovered from RNA in replicon cells. Small inhibitory RNA, specific for ADAR1, stimulated the replicon 40-fold, indicating that ADAR1 has a role in limiting replication of the viral RNA. This is the first report of ADAR's involvement in a potent antiviral pathway and its action to specifically eliminate HCV RNA through adenosine to inosine editing. These results may explain successful HCV replicon clearance by IFN-alpha in vitro and may provide a promising new therapeutic strategy for HCV as well as other viral infections.
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PMID:New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. 1585 13

RNA editing increases during development in more than 20 transcripts encoding proteins involved in rapid synaptic neurotransmission in Drosophila central nervous system and muscle. Adar (adenosine deaminase acting on RNA) mutant flies expressing only genome-encoded, unedited isoforms of ion-channel subunits are viable but show severe locomotion defects. The Adar transcript itself is edited in adult wild-type flies to generate an isoform with a serine to glycine substitution close to the ADAR active site. We show that editing restricts ADAR function since the edited isoform of ADAR is less active in vitro and in vivo than the genome-encoded, unedited isoform. Ubiquitous expression in embryos and larvae of an Adar transcript that is resistant to editing is lethal. Expression of this transcript in embryonic muscle is also lethal, with above-normal, adult-like levels of editing at sites in a transcript encoding a muscle voltage-gated calcium channel.
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PMID:Tuning of RNA editing by ADAR is required in Drosophila. 1592 Apr 80

The carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (pol II) is essential for several co-transcriptional pre-messenger RNA processing events, including capping, 3'-end processing and splicing. We investigated the role of the CTD of RNA pol II in the coordination of A to I editing and splicing of the ADAR2 (ADAR: adenosine deaminases that act on RNA) pre-mRNA. The auto-editing of Adar2 intron 4 by the ADAR2 adenosine deaminase is tightly coupled to splicing, as the modification of the dinucleotide AA to AI creates a new 3' splice site. Unlike other introns, the CTD is not required for efficient splicing of intron 4 at either the normal 3' splice site or the alternative site created by editing. However, the CTD is required for efficient co-transcriptional auto-editing of ADAR2 intron 4. Our results implicate the CTD in site-selective RNA editing by ADAR2 and in coordination of editing with alternative splicing.
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PMID:RNA editing and alternative splicing: the importance of co-transcriptional coordination. 1660 95

Members of the ADAR (adenosine deaminase that acts on RNA) enzyme family catalyze the hydrolytic deamination of adenosine to inosine within double-stranded RNAs, a poorly understood process that is critical to mammalian development. We have performed fluorescence resonance energy transfer experiments in mammalian cells transfected with fluorophore-bearing ADAR1 and ADAR2 fusion proteins to investigate the relationship between these proteins. These studies conclusively demonstrate the homodimerization of ADAR1 and ADAR2 and also show that ADAR1 and ADAR2 form heterodimers in human cells. RNase treatment of cells expressing these fusion proteins changes their localization but does not affect dimerization. Taken together these results suggest that homo- and heterodimerization are important for the activity of ADAR family members in vivo and that these associations are RNA independent.
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PMID:FRET analysis of in vivo dimerization by RNA-editing enzymes. 1661 4

The most prevalent type of RNA editing is mediated by ADAR (adenosine deaminase acting on RNA) enzymes, which convert adenosines to inosines (a process known as A-->I RNA editing) in double-stranded (ds)RNA substrates. A-->I RNA editing was long thought to affect only selected transcripts by altering the proteins they encode. However, genome-wide screening has revealed numerous editing sites within inverted Alu repeats in introns and untranslated regions. Also, recent evidence indicates that A-->I RNA editing crosstalks with RNA-interference pathways, which, like A-->I RNA editing, involve dsRNAs. A-->I RNA editing therefore seems to have additional functions, including the regulation of retrotransposons and gene silencing, which adds a new urgency to the challenges of fully understanding ADAR functions.
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PMID:Editor meets silencer: crosstalk between RNA editing and RNA interference. 1738 55

Dyschromatosis symmetrica hereditaria (OMIM127400) is a rare autosomal dominant pigmentary genodermatosis caused by mutations in the RNA-specific adenosine deaminase (ADAR) gene. This study investigated 5 families and 3 sporadic patients with dyschromatosis symmetrica hereditaria in the Chinese Han population from Anhui province, China. By direct sequencing, 5 novel ADAR gene mutations (c.982C>T, c.1491insA, c.2568_2571delTAAC, c.2969C>G and c.3040G>T) and 3 mutations described previously (c.3203-2A>G, c.3247C>T and c.3286C>T) were identified, all of which were heterozygous. We reviewed a total of 48 mutations in the ADAR gene in patients with dyschromatosis symmetrica hereditaria by previous reports and speculated that the mutation hotspots on the ADAR gene might be located in exons 9-15. The tRNA-specific and double-stranded RNA adenosine deaminase domain is essential for the deaminase activity of the ADAR encoded protein.
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PMID:Five novel mutations of RNA-specific adenosine deaminase gene with dyschromatosis symmetrica hereditaria. 1722 10

Adenosine to inosine (A-to-I) modification by the ADAR (adenosine deaminase that acts on RNA) enzymes perform the most common type of RNA editing in metazoans. ADARs use double stranded RNA as substrates but allow interruptions of bulges and loops in the structure. It is well known that these enzymes can use messenger RNA as targets for A-to-I editing and thereby recode the transcript. Both ADAR1 and ADAR2 have been proven to be able to also target short double stranded RNA molecules of the same size as a microRNA. However, it is not until recently shown that A-to-I editing occurs in microRNAs and its precursors. Since the editing activity is found both in the nucleus and the cytoplasm there are several steps during the microRNA maturation pathway that can be targeted for modification. This review will give an overview of what is known today about the interactions between the endogenous RNA interference process and RNA editing. It will also give some insight into the power of A-to-I modification in its ability to increase the variety of microRNA gene silencing.
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PMID:A-to-I editing challenger or ally to the microRNA process. 1762 90

Adenosine-to-inosine (A-to-I) RNA editing is the enzymatic deamination of A-to-I catalyzed by ADAR (adenosine deaminase acting on RNA). Adenosine is read by ribosomes as guanosine causing a codon change and potentially protein recoding. A-to-I RNA editing can be either promiscuous, where the editing is nonspecific, or site specific, which requires a complex target RNA secondary structure formed by intramolecular base pairings between editing sequences and intronic or exonic editing site complementary sequences (ECSs). The most numerous editing sites have been found in noncoding regions containing Alu repeats, such as 3' untranslated regions, while specific editing sites are mostly found in transcripts involved in the transmission of neuronal signals. Previously A-to-I RNA editing sites were discovered by chance, but recently investigators have used comparative genomic and bioinformatics methods to identify novel sites. In this chapter, we discuss these approaches to identifying new editing sites.
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PMID:Comparative genomic and bioinformatic approaches for the identification of new adenosine-to-inosine substrates. 1766 44

Increasing proteomic diversity via the hydrolytic deamination of adenosine to inosine (A-to-I) in select mRNA templates appears crucial to the correct functioning of the nervous system in several model organisms, including Drosophila, Caenorabditis elegans, and mice. The genome of the fruitfly, Drosophila melanogaster, contains a single gene encoding the enzyme responsible for deamination, termed ADAR (for adenosine deaminase acting on RNA). The mRNAs that form the substrates for ADAR primarily function in neuronal signaling, and, correspondingly, deletion of ADAR leads to severe nervous system defects. While several ADAR enzymes are present in mice, the presence of a single ADAR in Drosophila, combined with the diverse genetic toolkit available to researchers and the wide range of ADAR target mRNAs identified to date, make Drosophila an ideal organism to study the genetic basis of A-to-I RNA editing. This chapter describes a variety of methods for genetically manipulating Drosophila A-to-I editing both in time and space, as well as techniques to study the molecular basis of ADAR-mRNA interactions. A prerequisite for experiments in this field is the ability to quantify the levels of editing in a given mRNA. Therefore, several commonly used methods for the quantification of editing levels will also be described.
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PMID:Genetic approaches to studying adenosine-to-inosine RNA editing. 1766 45

We and other investigators have demonstrated up-regulation of the expression of the RNA-editing gene 150-kDa adenosine deaminase that acts on RNA (ADAR1) in systemic lupus erythematosus (SLE) T cells and B cells, peripheral blood mononuclear cells (PBMC), natural killer (NK) cells. The presence of a small proportion of activated T cells is the hallmark of SLE. Therefore, it was hypothesized that 150-kDa ADAR1 gene expression is induced by the physiological activation of T cells. To examine this hypothesis, normal T cells were activated by anti-CD3-epsilon plus anti-CD28 for various time periods from 0 to 48 hr. The expression of 110-kDa and 150-kDa ADAR1, and interleukin (IL)-2 and beta-actin gene transcripts was analysed. An approximately fourfold increase in 150-kDa ADAR1 gene expression was observed in activated T cells. ADAR2 gene transcripts are substrates for ADAR1 and ADAR2 enzymes. Therefore, we assessed the role of the 150-kDa ADAR enzyme in editing of ADAR2 gene transcripts. In activated T cells, site-selective editing of the -2 site was observed. Previous studies indicate that this site is predominantly edited by ADAR1. In addition to this, novel editing sites at base positions -56, -48, -45, -28, -19, -15, +46 and +69 were identified in activated T cells. On the basis of these results, it is proposed that 150-kDa ADAR1 gene expression is selectively induced in T cells by anti-CD3-epsilon and anti-CD28 stimulation and that it may play a role in site-selective editing of gene transcripts and in altering the functions of several gene products of T cells during activation and proliferation.
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PMID:Induction of 150-kDa adenosine deaminase that acts on RNA (ADAR)-1 gene expression in normal T lymphocytes by anti-CD3-epsilon and anti-CD28. 1789 25


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