Regulation of alternative splicing by RNA editing

The enzyme ADAR2 is a double-stranded RNA-specific adenosine deaminase whic h is involved in the editing of mammalian messenger RNAs by the site-specif ic conversion of adenosine to inosine(1-3) Here we identify several rat ADA R2 mRNAs produced as a result of two distinct alternative splicing events. One such splicing event uses a proximal 3' acceptor site, adding 47 nucleot ides to the ADAR2 coding region, changing the predicted reading frame of th e mature ADAR2 transcript. Nucleotide-sequence analysis of ADAR2 genomic DN A revealed the presence of adenosine-adenosine (AA) and adenosine-guanosine (AG) dinucleotides at these proximal and distal alternative 3' acceptor si tes, 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 adenos ine-inosine (Al) dinucleotide which effectively mimics the highly conserved AG sequence normally found at 3' splice junctions. Our observations indica te that RNA editing can serve as a mechanism for regulating alternative spl icing and they suggest a novel strategy by which ADAR2 can modulate its own expression.