Competition between ADAR and RNAi pathways for an extensive class of RNA targets

Adenosine deaminases that act on RNAs (ADARs) interact with double-stranded RNAs, deaminating adenosines to inosines. Previous studies of Caenorhabditis elegans suggested an antagonistic interaction between ADAR and RNAi machineries, with ADAR defects suppressed upon additional knockout of RNAi. These results suggest a pool of common RNA substrates capable of engaging both pathways. To define and characterize such substrates, we examined small RNA and mRNA populations of ADAR mutants and identified a distinct set of loci from which RNAi-dependent short RNAs are dramatically upregulated. At these same loci, we observe populations of multiply edited transcripts, supporting a specific role for ADARs in preventing access to the RNAi pathway for an extensive population of dsRNAs. Characterization of these loci reveal an extensive overlap with non-coding and intergenic regions, suggesting that the landscape of ADAR targets may extend beyond previously annotated classes of transcripts.