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To edit or not to edit: regulation of ADAR editing specificity and efficiency

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Hundreds to millions of adenosine (A)‐to‐inosine (I) modifications are present in eukaryotic transcriptomes and play an essential role in the creation of proteomic and phenotypic diversity. As adenosine and inosine have different base‐pairing properties, the functional consequences of these modifications or ‘edits’ include altering coding potential, splicing, and miRNA‐mediated gene silencing of transcripts. However, rather than serving as a static control of gene expression, A‐to‐I editing provides a means to dynamically rewire the genetic code during development and in a cell‐type specific manner. Interestingly, during normal development, in specific cells, and in both neuropathological diseases and cancers, the extent of RNA editing does not directly correlate with levels of the substrate mRNA or the adenosine deaminase that act on RNA (ADAR) editing enzymes, implying that cellular factors are required for spatiotemporal regulation of A‐to‐I editing. The factors that affect the specificity and extent of ADAR activity have been thoroughly dissected in vitro. Yet, we still lack a complete understanding of how specific ADAR family members can selectively deaminate certain adenosines while others cannot. Additionally, in the cellular environment, ADAR specificity and editing efficiency is likely to be influenced by cellular factors, which is currently an area of intense investigation. Data from many groups have suggested two main mechanisms for controlling A‐to‐I editing in the cell: (1) regulating ADAR accessibility to target RNAs and (2) protein–protein interactions that directly alter ADAR enzymatic activity. Recent studies suggest cis‐ and trans‐acting RNA elements, heterodimerization and RNA‐binding proteins play important roles in regulating RNA editing levels in vivo. WIREs RNA 2016, 7:113–127. doi: 10.1002/wrna.1319 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > RNA Editing and Modification
Global regulation of adenosine deaminases that act on RNA (ADAR) activity through differential expression and degradation. Many isoforms exist for the different ADAR enzymes and these isoforms are differentially expressed and have different activity levels. Represented here, ADAR2 is expressed as four different isoforms containing different sequences. Each isoform has a putative nuclear localization sequence represented as an orange box and two dsRBDs which are represented by light blue boxes. Also each isoform contains the deaminase domain (dark blue box), although ADAR2b and ADAR2c isoforms have 40 additional amino acids in this region. ADAR2c and ADAR2d have shortened c‐terminal regions (represented as green boxes) as compared to ADAR2a and ADAR2b. ADAR2 activity can also be regulated by subcellular distribution. PIN1 has been shown to phosphorylate ADAR2 and help to maintain its distribution in the nucleus where WWP1 ubiquitination of ADAR2 results in degradation by the proteasome.
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Adenosine deaminases that act on RNA (ADAR) enzymes are prevalent across metazoans. ADARs are defined by their deaminase domain (green). Also present, although in varying quantities, are double‐stranded (ds) RNA‐binding domains (RBDs) (orange). Humans express three ADAR enzymes. Two splice variants of human ADAR1 exist, ADAR1 p150 and ADAR1 p110. Human ADAR1 is unique as it contains Z‐DNA‐binding domains (purple). Human ADAR3 is thought to be catalytically inactive, although it contains the amino acids required for the deaminase domain. Interestingly, ADAR3 also contains an arginine‐rich (R) domain (red). Drosophila (Dm) has one ADAR enzyme containing two dsRBDs. Caenorhabditis elegans (Ce) express two ADAR enzymes, the catalytically inactive ADR‐1 and the enzymatic ADR‐2. Interestingly, unlike the other ADARs shown, Ce ADR‐2 contains only one dsRBD. The squid Loligo pealeii (Sq) expresses one ADAR enzyme, ADAR2, that is alternatively spliced resulting in two isoforms ADAR2a and ADAR2b.
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Adenosine (A)‐to‐inosine (I) RNA editing can affect coding potential, splicing, or small RNA‐binding depending upon where the editing event occurs in the mRNA. (a) Editing within the coding region has the potential to affect the flow of genetic information as a codon is altered changing the amino acid that will be incorporated into the protein. (b) Editing can alter splicing, creating or destroying splice sites. (c) Small RNA binding can also be affected by RNA editing. Editing within 3′ untranslated regions (UTRs) can enhance or disrupt si/miRNA binding. Similarly editing of the si/miRNA itself can affect which targets it binds.
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Deamination of adenosine results in the rare nucleotide inosine. Adenosine deaminases that act on RNA (ADAR) enzymes catalytically deaminate the C6 of adenosine creating inosine. The loss of the amine group results in altered base pairing, with inosine base pairing similar to guanosine. This alteration in binding potential leads to cellular machinery recognizing inosine as guanosine.
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Protein–Protein interactions as well as Protein–RNA interactions regulate adenosine deaminases that act on RNA (ADAR) efficiency. (a) ADAR homodimerization improves editing efficiency. Recently a study determined that the deaminase domain binds a 23‐nt region surrounding the edited adenosine, 18 nt upstream and 5 nt downstream, although currently its not known whether the deaminase domain of both ADARs is required for editing. (b) In Caenorhabditis elegans the RNA‐binding protein (RBP), ADR‐1, has recently been shown to promote editing, perhaps by recruiting ADR‐2, the editing enzyme in C. elegans, to targets. (c) The small nucleolar RNAs (snoRNAs) can bind and promote 2′ O‐methylation of adenosines. ADARs are less capable of editing methylated adenosines. Therefore, snoRNAs can block editing.
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Processing > RNA Editing and Modification
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition

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