Regulation of alternative splicing by RNA editing

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Abstract
The enzyme ADAR2 is a double-stranded RNA-specific adenosine deaminase which is involved in the editing of mammalian messenger RNAs by the site-specific conversion of adenosine to inosine1,2,3. Here we identify several rat ADAR2 mRNAs produced as a result of two distinct alternative splicing events. One such splicing event uses a proximal 3′ acceptor site, adding 47 nucleotides to the ADAR2 coding region, changing the predicted reading frame of the mature ADAR2 transcript. Nucleotide-sequence analysis of ADAR2 genomic DNA revealed the presence of adenosine–adenosine (AA) and adenosine–guanosine (AG) dinucleotides at these proximal and distal alternative 3′ acceptor sites, respectively. Use of the proximal 3′ acceptor depends upon the ability of ADAR2 to edit its own pre-mRNA, converting the intronic AA to an adenosine–inosine (Al) dinucleotide which effectively mimics the highly conserved AG sequence normally found at 3′ splice junctions. Our observations indicate that RNA editing can serve as a mechanism for regulating alternative splicing and they suggest a novel strategy by which ADAR2 can modulate its own expression.