Disease relevance of ADAR

• Adenovirus VAI RNA antagonizes the RNA-editing activity of the ADAR adenosine deaminase [1].
• Two Z-DNA binding motifs (Zalpha and Zbeta) present in ADAR correspond to repeated regions homologous to the N-terminal region of the vaccinia virus E3L protein [2].
• Regulation of glutamate receptor RNA editing and ADAR mRNA expression in developing human normal and Down's syndrome brains [3].
• Hepatitis delta virus minimal substrates competent for editing by ADAR1 and ADAR2 [4].
• They have been found previously in two other IFN-inducible proteins, the dsRNA editing enzyme, ADAR1, and Z-DNA binding protein 1 (ZBP1), as well as in the poxvirus virulence factor, E3L [5].
• There is low experssion level of ADAR1 and ADAR2 in cancers. In addition low level of A-to-I RNA editing was found in glioblastoma multiforme [6].

Psychiatry related information on ADAR

• Conclusions: Multi-targeted interventions are needed to reduce the risk of psychopathology and associated DSH repetition [7].
• BACKGROUND: Deliberate self-harm (DSH, attempted suicide) is one of the most common reasons for emergency hospital admission in Great Britain. Approximately 20 % of patients repeat self-harm in the 12 months after admission [8].

High impact information on ADAR

• The enzyme ADAR2 is a double-stranded RNA-specific adenosine deaminase which is involved in the editing of mammalian messenger RNAs by the site-specific conversion of adenosine to inosine [9].
• The A-to-I editing observed in RNAs encoding non-NMDA glutamate receptor subunits may be due to the actions of a double-stranded RNA-specific adenosine deaminase that is widespread in higher organisms [10].
• This activity is consistent with that of a double-stranded RNA-specific adenosine deaminase previously described in Xenopus oocytes and widely distributed in mammalian tissues [11].
• 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 [12].
• 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 [12].

Biological context of ADAR

• We demonstrate the association of ADAR RNA editing enzymes with physiological supramolecular complexes, the lnRNP particles [13].
• The hADAT1 cDNA predicts a protein of 502 aa whose sequence displays strongest overall homology to a Drosophila melanogaster ORF (50% similarity, 32% identity), and the catalytic domain is closely related to the other ADAR proteins [14].
• RNA editing of specific residues by adenosine deamination is a nuclear process catalyzed by adenosine deaminases acting on RNA (ADAR) [15].
• Our results indicate that HDV requires highly regulated and selective editing and that the level of ADAR expression can play an important role: overexpression of ADARs inhibits HDV RNA replication and compromises virus viability [16].
• Protein phosphorylation by PKR, RNA editing by the ADAR adenosine deaminase, and RNA degradation by the 2',5'-oligoA pathway all involve dsRNA either as an effector or as a substrate [17].

Anatomical context of ADAR

• This inhibition can be observed in extracts prepared from interferon-treated human cells and from monkey COS cells in which wild-type recombinant ADAR was expressed [1].
• In cultured cells, we observed that both human ADAR1 (hADAR1) and hADAR2 were capable of editing the amber/W site with comparable efficiencies [4].
• ADAR1 mRNA content was 3.5 times higher in SLE cells than in control T cells (p=0.001) [18].
• In agreement with this observation, endogenous ADAR1 was identified in the cytoplasm and nucleolus of mouse splenocytes and HeLa cells [19].
• Direct sequencing of cDNA fragments produced by reverse transcription-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR were used to examine the expression of ADAR in peripheral lymphocytes isolated from affected individuals [20].

Associations of ADAR with chemical compounds

• Multiple members of the ADAR (adenosine deaminases acting on RNA) gene family are involved in A-to-I RNA editing [13].
• RNA editing by members of the ADAR (adenosine deaminase that acts on RNA) enzyme family involves hydrolytic deamination of adenosine to inosine within the context of a double-stranded pre-mRNA substrate [21].
• However, with natural substrates, substitution of the first two dsRBMs of ADAR1 with those from PKR dramatically reduced site-selective editing activity at the R/G and (+)60 sites of the glutamate receptor B subunit pre-RNA and completely abolished editing of the serotonin 2C receptor (5-HT(2C)R) pre-RNA at the A site [22].
• 2,6-Diaminopurine ribonucleoside in RNA is not a substrate for ADAR, in contrast to adenosine deaminase (ADA), which catalyzes a similar reaction on nucleosides [23].
• Here, we report the purification of a 90-kDa double-stranded RNA-specific adenosine deaminase from HeLa cell nuclear extract that specifically edits the glutamine codon at position 586 in the pre-mRNA of the glutamate receptor B subunit [24].

Physical interactions of ADAR

• The PKR KCS element selectively bound nuclear proteins more efficiently than did the ADAR1 KCS-l element [25].
• We have examined the effects of equivalent site-directed mutations in each of the three R-motif copies of dsRAD on RNA-binding activity and adenosine deaminase enzyme activity [26].

Co-localisations of ADAR

• We show that ADAR1 colocalizes with SUMO-1 in a subnucleolar region that is distinct from the fibrillar center, the dense fibrillar component, and the granular component [27].

Regulatory relationships of ADAR

• ADAR3 inhibited in vitro the activities of RNA editing enzymes of the ADAR gene family, raising the possibility of a regulatory role in RNA editing [28].
• The promoter-proximal KCS element of the PKR kinase gene enhances transcription irrespective of orientation and position relative to the ISRE element and is functionally distinct from the KCS-like element of the ADAR deaminase Promoter [25].

Other interactions of ADAR

• We also defined the minimal HDV substrate required for hADAR1- and hADAR2-mediated editing [4].
• We report here the identification and characterization of a human ADAR protein, hADAT1, that specifically deaminates adenosine 37 to inosine in eukaryotic tRNA(Ala) [14].
• The sequences of the KCS and KCS-l elements and their positions relative to the cognate ISRE element are similar between the PKR and ADAR1 promoters [25].
• Identification and characterization of a human tRNA-specific adenosine deaminase related to the ADAR family of pre-mRNA editing enzymes [14].
• Furthermore, nuclear accumulation of human (hs) ADAR1 is transcription dependent and can be stimulated by LMB, an inhibitor of Crm1-dependent nuclear export, indicating that hsADAR1 can move between the nucleus and cytoplasm [29].

Analytical, diagnostic and therapeutic context of ADAR

• Gel shift analysis revealed that two complexes are formed on the RNA as protein concentration is increased; the ADAR monomers can be cross-linked to one another in an RNA-dependent fashion [21].
• This study should be useful for genetic counseling and prenatal diagnosis for affected families and in expanding the database on ADAR gene mutations in DSH [30].
• Because transcript editing is regulated by adenosine deaminases that act on RNA (ADAR), we quantified expression of ADAR1 transcripts in SLE and control T cells by competitive PCR [18].
• Crystallization of the Zalpha domain of the human editing enzyme ADAR1 complexed with a DNA-RNA chimeric oligonucleotide in the left-handed Z-conformation [31].
• Interaction of the Zalpha domain of human ADAR1 with a negatively supercoiled plasmid visualized by atomic force microscopy [32].

References