Disease relevance of ADARB1

• Hepatitis delta virus minimal substrates competent for editing by ADAR1 and ADAR2 [1].
• Inhibition of hepatitis delta virus RNA editing by short inhibitory RNA-mediated knockdown of ADAR1 but not ADAR2 expression [2].
• Potential relevance of overexpression of RED1 to the development of the Down Syndrome phenotype is discussed [3].
• Here, we show that forebrain ischemia in adult rats selectively reduces expression of ADAR2 enzyme and, hence, disrupts RNA Q/R site editing of GluR2 subunit in vulnerable neurons [4].
• By using a human teratocarcinoma cell line, NT2, we investigated the change of the RNA editing of GluR subunits in conjunction with the expression of two DRADA members, DRADA1 and DRADA2 genes, during neuronal differentiation [5].
• We reintroduced either ADAR2 or the inactive version of ADAR2 in three astrocytoma cell lines (U118, A172, U87) [6].

Psychiatry related information on ADARB1

• ADARB1 maps to human chromosome 21q22.3, a region to which several genetic disorders map, including one form of bipolar affective disorder [7].
• Sequence analysis of ADARB1 gene in patients with familial bipolar disorder [8].

High impact information on ADARB1

• Particularly exciting has been the discovery of a putative RNA editing enzyme, the activation-induced cytidine deaminase (AID), that is required for all immunoglobulin gene-specific modification reactions (somatic hypermutation, class switch recombination, and gene conversion) [9].
• 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 [10].
• Use of the proximal 3' acceptor depends upon the ability of ADAR2 to edit its own pre-mRNA, converting the intronic AA to an adenosine-inosine (AI) dinucleotide which effectively mimics the highly conserved AG sequence normally found at 3' splice junctions [10].
• Here we identify several rat ADAR2 mRNAs produced as a result of two distinct alternative splicing events [10].
• Nucleotide-sequence analysis of ADAR2 genomic DNA revealed the presence of adenosine-adenosine (AA) and adenosine-guanosine (AG) dinucleotides at these proximal and distal alternative 3' acceptor sites, respectively [10].

Chemical compound and disease context of ADARB1

• Since glutamate receptor channels are essential elements in synaptic function and plasticity and mediate pathology in many neurological disorders, and since RED1 is central in glutamate receptor channel control, ADARB1 is a candidate gene for diseases with neurological symptoms, such as bipolar affective disorder and epilepsy [7].

Biological context of ADARB1

• Our search for DRADA1-like genes through expressed sequence tag databases led to the cloning of the second member of this class of enzyme, DRADA2, which has a high degree of sequence homology to DRADA1 yet exhibits a distinctive RNA editing site selectivity [11].
• Recently, a gene encoding a double-stranded-specific editase (RED1) was cloned from a rat brain cDNA library [12].
• We examined the effects of increased ADAR1 and ADAR2 expression on HDV RNA editing and replication in transfected Huh7 cells [13].
• These data suggest that both sequence and structural elements are required to define adenosine moieties targeted for specific ADAR2-mediated deamination [14].
• Alternative splicing to this proximal acceptor shifts the reading frame of the mature mRNA transcript, resulting in the loss of functional ADAR2 expression [14].

Anatomical context of ADARB1

• In cultured cells, we observed that both human ADAR1 (hADAR1) and hADAR2 were capable of editing the amber/W site with comparable efficiencies [1].
• We conclude that the GluR-B editing activity present in HeLa cell extracts and the recombinant hRED1 protein are indistinguishable [15].
• Recovery of GluR2 Q/R site editing by expression of exogenous ADAR2b gene or a constitutively active CREB, VP16-CREB, which induces expression of endogenous ADAR2, protects vulnerable neurons in the rat hippocampus from forebrain ischemic insult [4].
• Furthermore, the antibodies can immunodeplete a calf thymus extract of dsRNA adenosine deaminase activity, and the activity can be restored by addition of pure bovine deaminase [16].
• Chromosomal storage of the RNA-editing enzyme ADAR1 in Xenopus oocytes [17].

Associations of ADARB1 with chemical compounds

• Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases [11].
• Adenosine to inosine editing by ADAR2 requires formation of a ternary complex on the GluR-B R/G site [18].
• Purification of human double-stranded RNA-specific editase 1 (hRED1) involved in editing of brain glutamate receptor B pre-mRNA [12].
• Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing [19].
• Nucleocytoplasmic distribution of human RNA-editing enzyme ADAR1 is modulated by double-stranded RNA-binding domains, a leucine-rich export signal, and a putative dimerization domain [20].

Physical interactions of ADARB1

• DLM-1 contains an N-terminal Z-DNA binding domain homologous to the Zalpha domain in the RNA editing enzyme ADAR1 [21].

Enzymatic interactions of ADARB1

• Editing of the human GluR-B transcript is catalyzed by the enzyme ADAR2 at the Q/R and R/G sites [18].

Regulatory relationships of ADARB1

• These results suggest that Q/R site of GluRs editing is regulated in a regional, and hence presumably cell-specific, manner and that the GluR2 Q/R site editing is critically regulated by ADAR2 in human brain [22].

Other interactions of ADARB1

• These changes correlate with a decrease in enzymatic activity of the editing enzyme adenosine deaminase acting on RNA (ADAR) 2, as deduced from analysis of ADAR2 self-editing [23].
• As originally reported for rat RED1, the DRADA2a and -2b isoforms edit GluR-B RNA efficiently at the so-called Q/R site, whereas DRADA1 barely edits this site [11].
• Adenosine deaminase that acts on RNA (ADAR)1 and ADAR2 are enzymes that catalyze such reactions, and each, when overexpressed, are capable of editing HDV RNA in vivo [24].
• 3. This locus contains two genes expressed in the brain - ADARB1 and TRPM2 - involved in regulating intracellular Ca(2+) concentrations [25].
• The founder member APOBEC1, which has been used as a paradigm, is an RNA-editing enzyme with proposed antecedents in yeast [26].

Analytical, diagnostic and therapeutic context of ADARB1

• This variant accounts for between 13% and 20% of the total ADAR2 mRNA in each developmental stage and brain region examined, even though its translated product is not expressed at levels that are detectable by Western blot analysis [27].
• Fluorescent in situ hybridization localized the DRADA gene on the long arm chromosome 1, region q21 [28].
• In the presence of methyl-coenzyme M the red1 signal showed a more resolved 14N-superhyperfine splitting than in the presence of coenzyme M indicating a possible axial ligation of the substrate to the Ni(I) [29].
• Targeted disruption of DEC1 drastically reduced both T-toxin production and virulence of race T to T-cytoplasm maize, whereas specific inactivation of RED1 had no apparent effect on T-toxin production (as determined by bioassay) or on virulence [30].
• Homology modelling studies and site directed mutagenesis showed remarkable differences in three-dimensional structures and catalytic mechanisms between RED1 and RED2 [31].

References