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Substitutional A‐to‐I RNA editing

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Abstract Adenosine‐to‐inosine (A‐to‐I) editing catalyzed by adenosine deaminases acting on RNA (ADARs) entails the chemical conversion of adenosine residues to inosine residues within double‐stranded RNA (dsRNA) substrates. Inosine base pairs as guanosine and A‐to‐I editing can therefore alter the structure and base pairing properties of the RNA molecule. This has a biological significance in controlling the amount of functional RNA molecules in the cell, in expanding the functionality of a limited set of transcripts, and in defending the cell against certain RNA viruses. A‐to‐I editing is not limited to any specific type of RNA substrate. Instead, it can affect any RNA molecule able to attain the required double‐stranded structure. This includes microRNAs, small interfering RNAs, viral RNAs, and messenger RNAs with potential for recoding events and splice site modifications. Copyright © 2010 John Wiley & Sons, Ltd. This article is categorized under: RNA Processing > RNA Editing and Modification

The domain structures of the human ADAR proteins show that all three proteins have a similar deaminase domain and double‐stranded RNA‐binding domains. The Z‐DNA‐binding domain is unique to ADAR1 and the R‐domain is unique to ADAR3 and the ADAR2 splice variant ADAR2R.

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(a) The hydrolytic deamination of adenosine, as catalyzed by ADARs, converts it to inosine. (b) Whereas adenosine base pairs with uridine, (c) inosine preferentially base pairs with cytidine and the deamination therefore changes the base pairing properties of the RNA molecule.

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(a) In the absence of ADAR editing, long double‐stranded RNAs are efficiently processed by Dicer into duplexes suitable for loading onto RISC. (b) ADAR antagonizes this pathway by editing the double‐stranded RNA41, thereby unwinding it and making it less suitable as a Dicer substrate, and by sequestering the RNA duplexes generated so as to make them unavailable to RISC42.

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The human microRNA pri‐miR‐376a‐2 is an example of an edited microRNA. It forms one of the stem structures of the larger pri‐miRNA and this stem structure allows for the editing by ADAR, which is known to take place at the sites highlighted in yellow. In this case, editing results in the mature miRNA, shown in red, targeting a new set of messenger RNAs.40.

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The microRNA biogenesis pathway begins with the newly transcribed pri‐miRNA and ends in the RISC‐loaded mature microRNA. The loaded microRNA directs RISC to its targets which it degrades. Many instances of editing of pri‐miRNA are known and there is also evidence that editing could take place at the pre‐miRNA stage.

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Summary of splice site modifications possible upon editing of canonical splice site and branch point motifs. The original splice pattern (a) can be modified by the creation of a new 5′ splice site (b), by the creation of a new 3′ splice site (c), by the destruction of a 3′ splice site (d), or by the destruction of the branch point(e).

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Summary of recoding events that can be caused by A‐to‐I editing, including the creation of a Met start codon and the destruction of stop codons.

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Exonic regions of a messenger RNA can be edited cotranscriptionally because they often base pair with downstream intronic regions before splicing takes place. This forms the double‐stranded structure required for editing by ADAR. The complementary intronic regions are termed editing site complementary sequences.

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The hypothesized mechanism underlying catalysis by ADAR, based on an ADAR crystal structure16 and the conservation of the four amino acid residues included in the figure.25.

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