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The role of RNA editing enzyme ADAR1 in human disease

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Abstract Adenosine deaminase acting on RNA (ADAR) catalyzes the posttranscriptional conversion of adenosine to inosine in double‐stranded RNA (dsRNA), which can lead to the creation of missense mutations in coding sequences. Recent studies show that editing‐dependent functions of ADAR1 protect dsRNA from dsRNA‐sensing molecules and inhibit innate immunity and the interferon‐mediated response. Deficiency in these ADAR1 functions underlie the pathogenesis of autoinflammatory diseases such as the type I interferonopathies Aicardi‐Goutieres syndrome and dyschromatosis symmetrica hereditaria. ADAR1‐mediated editing of endogenous coding and noncoding RNA as well as ADAR1 editing‐independent interactions with DICER can also have oncogenic or tumor suppressive effects that affect tumor proliferation, invasion, and response to immunotherapy. The combination of proviral and antiviral roles played by ADAR1 in repressing the interferon response and editing viral RNAs alters viral morphogenesis and cell susceptibility to infection. This review analyzes the structure and function of ADAR1 with a focus on its position in human disease pathways and the mechanisms of its disease‐associated effects. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications
Domain structures of the ADAR family of proteins
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Depiction of the AGS6 mutations of ADAR1. Ten base substitutions and one deletion mutation result in the nine amino acid substitutions, one nonsense (*), and one frameshift (fs) mutation that cause AGS6. Eight of the amino acid substitutions are in the catalytic domain while Pro193Ala as well as the nonsense and frameshift mutations occur in the Z‐DNA binding domains. The Met1034Val mutation is located at the so called “core deaminase domain,” likely to cause significant deficiency in the A‐to‐I deamination function of ADAR1 (Chen et al., 2000)
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(a) ADAR1 can enhance the activity of the microprocessor complex, such as in the case of miR‐21. It may also suppress the microprocessor complex, such as in the case of miR‐302. (b) ADAR1 dimerizes with DICER to form a complex that has an increased rate of pre‐miRNA processing, resulting in increased RNA interference
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(a) A‐to‐I editing by ADAR1 can prevent DROSHA or DICER cleavage of pri‐miRNA or pre‐miRNA, suppressing the target miRNA's maturation and downstream silencing effects. (b) A‐to‐I editing by ADAR1 can lead to altered miRNA seed sequences that can eliminate silencing of the original target (blue) and lead to off‐target silencing (red)
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The role of ADAR1 in regulating the innate immune response to dsRNA. After ADAR1 depletion, unedited dsRNA triggers pattern recognition receptors MDA5, PKR, and OAS, which ultimately lead to the anti‐viral mechanisms of interferon induction, halting translation, and apoptosis
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(a) ADAR1 deaminates at C6 of adenosine to convert it to inosine. (b) A‐to‐I editing in dsRNA results in replacement of A:U base pairs with I:C base pairs, and could create a missense mutation
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Processing > RNA Editing and Modification
RNA in Disease and Development > RNA in Disease

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