Disease relevance of Adar

• In human hepatitis virus infection, ADAR1 has been shown to target viral RNA and to suppress viral replication through dsRNA editing [1].
• Here, we report a proviral effect of ADAR1 that enhances replication of vesicular stomatitis virus (VSV) through a mechanism independent of dsRNA editing [1].
• The catalytic domain of all three ADAR gene family members is very similar to that of Escherichia coli cytidine deaminase and APOBEC-1 [2].
• These events preceded the development of pulmonary edema and leukocyte accumulation in lung tissue and followed the local production of interferon-gamma, a known inducer of ADAR1 in other cell systems [3].

High impact information on Adar

• The members of the ADAR (adenosine deaminase acting on RNA) gene family are involved in site-selective RNA editing that changes adenosine residues of target substrate RNAs to inosine [4].
• Our results suggest the importance of regulated levels of ADAR1 expression, which is critical for embryonic erythropoiesis in the liver [4].
• Analysis of staged chimeric mouse embryos with a high contribution from embryonic stem cells with a functional null allele for ADAR1 revealed a heterozygous embryonic-lethal phenotype [4].
• Most ADAR1+/- chimeric embryos died before embryonic day 14 with defects in the hematopoietic system [4].
• This deaminase, like DRADA, is expressed in many tissues and the search is now on for more substrates of these RNA-editing enzymes [5].

Biological context of Adar

• Assignment of the RNA-specific adenosine deaminase gene (Adar) to mouse chromosome 3F2 by in situ hybridization [6].
• Two regions within ADAR1 are defined that act independently of each other to induce translation: the first includes the double-stranded RNA binding domains (DRBMs) of ADAR1 while the second maps to the C-terminal portion of the catalytic domain [7].
• Here we report that the inflammation-induced up-regulation of ADAR1 involves differential production and intracellular localization of several isoforms with distinct RNA-binding domains and localization signals [8].
• Although live ADAR1-/- embryos with normal gross appearance could be recovered up to E11.5, widespread apoptosis was detected in many tissues [9].
• Our results demonstrate an essential requirement for ADAR1 in embryogenesis and suggest that it functions to promote survival of numerous tissues by editing one or more double-stranded RNAs required for protection against stress-induced apoptosis [9].

Anatomical context of Adar

• Induction of protein translation by ADAR1 within living cell nuclei is not dependent on RNA editing [7].
• In agreement with this observation, endogenous ADAR1 was identified in the cytoplasm and nucleolus of mouse splenocytes and HeLa cells [8].
• Fibroblasts derived from ADAR1-/- embryos were also prone to apoptosis induced by serum deprivation [9].
• Probably as a consequence of these developmental impairments, ADAR1-deficient embryonic stem cells failed to contribute to liver, bone marrow, spleen, thymus, and blood in adult chimeric mice [10].
• In contrast to ADAR1, ADAR2 transcripts in the pancreatic islets exhibit a nearly 2-fold increase in insulin-resistant mice chronically fed a high fat diet [11].

Associations of Adar with chemical compounds

• ADAR2 is a double-stranded-RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-selective conversion of adenosine to inosine [12].
• We show here by gene targeting that ADAR1 selectively edits in vivo two of five closely spaced adenosines in the serotonin 5-hydroxytryptamine subtype 2C receptor pre-mRNA of nervous tissue; and hence, site-selective adenosine-to-inosine editing is indeed a function of ADAR1 [10].

Regulatory relationships of Adar

• Up-regulation of ADAR1 was confirmed in vitro in T lymphocytes and macrophages stimulated with a variety of inflammatory mediators including tumour necrosis factor-alpha and interferon-gamma [13].

Other interactions of Adar

• Through the subcellular targeting of minigenes that contain natural editing sites, we show that ADAR2- but not ADAR1-mediated RNA editing occurs in the nucleolus [14].
• Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene [9].

Analytical, diagnostic and therapeutic context of Adar

• In this study, we investigated the formation of complexes between differentially epitope-tagged ADAR monomers by sequential affinity chromatography and size exclusion column chromatography [2].

References