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Site‐selective versus promiscuous A‐to‐I editing

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Abstract RNA editing by adenosine deamination is acting on polymerase II derived transcripts in all metazoans. Adenosine‐to‐inosine (A‐to‐I) editing is mediated by the adenosine deaminase that acts on RNA (ADAR) enzymes. Two types of adenosine to inosine (A‐to‐I) RNA editing have been defined: site selective and hyper‐editing. Typically, in site selectively edited substrates, one or a few A‐to‐I sites are edited in double‐stranded RNA structures, frequently interrupted by single‐stranded bulges and loops. Hyper‐editing occurs in long stretches of duplex RNA where multiple adenosines are subjected to deamination. In this review, recent findings on editing within noncoding RNA as well as examples of site selective editing within coding regions are presented. We discuss how these two editing events have evolved and the structural differences between a site selective and hyper‐edited substrate. WIREs RNA 2011 2 761–771 DOI: 10.1002/wrna.89 This article is categorized under: RNA Processing > RNA Editing and Modification

The ADAR family members. Three human ADAR proteins are presented showing two isoforms of ADAR1 (p110 and p150), ADAR2, and ADAR3. Xenopus laevis express ADAR1 (Xl ADAR1), while a human ADAR2 homolog is found in squid (Sq ADAR). Two splice variants of SqADAR are known that differ in their number of double‐stranded RNA‐binding domains (RBDs). Drosophila melanogaster express a single ADAR enzyme (Dm ADAR). Common features to all enzymes are two or three dsRBDs (in red), a catalytic deaminase domain (in blue) and a putative nuclear localisation signal (NLS). Certain structural features are specific to particular ADAR members, such as the nulear export signal (NES) found in ADAR1p150 and the single‐stranded RNA‐binding domain in ADAR3 (R‐rich).

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Similar RNA stem loop structures in coding sequence and noncoding microRNAs are subjected to selective A‐to‐I editing. The edited adenosines are in red. Predicted structures derived from coding sequence in human: Gabra‐3 at the I/M editing site; GluA2 at the R/G site of editing. The two structures on the right are derived from the human pri‐miRNA‐376 cluster including miRNA‐368 and miRNA 376a2. The indicated numbers (+4 and +44) refer to the first nucleotide of the mature miRNA sequence.

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Predicted RNA secondary structures of substrates for mammalian ADAR enzymes. The substrates are: (a) Gabra‐3 site I/M; (b) GluA2 site R/G; (c) Kv1.1 site I/V; (d) GluK2 Q/R; (e) GluA2 site Q/R and other; (f) Adar2 intron 4; (g) CTN‐RNA one forward and inverted repeat in 3′UTR; (h) Typical editing in two inversely oriented human Alu repeats. Edited sites are indicated with an A. Exon sequence is in gray while intron sequence is indicated as a black line. Numbers represent nucleotides in the loop.

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A model for multiple A‐to‐I editing of site selectively edited RNA adapted from. Editing is initiated at a principal editing site; a second site is edited at the distance of 10–12 nucleotides (nt) from the initiation site. This site is situated one helical turn from the first site. Consecutive editing can occur not only at the distance of approximately n × 12 nt, but also immediately adjacent to the edited hot‐spots.

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Sequence preference for A‐to‐I editing. The edited adenosine is in black. Preferred nucleotides 5′and 3′of the edited site is in green. Underrepresented neighbor nucleotides are indicated in red. Commonality of the bases is shown by letter height.

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