Dimerization of ADARs Expands The Range of Substrates That Can Undergo A‐to‐I RNA Editing

Abstract

RNA editing alters genomically encoded information to generate the transcriptomic diversity required for normal development and proper neuronal function. The adenosine deaminase that act on RNA (ADAR) family of enzymes catalyze adenosine (A)‐to‐inosine (I) RNA editing at millions of sites in the human transcriptome. However, the molecular mechanisms that regulate editing specificity and efficiency are not understood. Using recombinant proteins, we reveal, that unlike all other A‐to‐I editing enzymes, Caenorhabditis elegans ADR‐2 has a low affinity for double‐stranded RNAs (dsRNAs). Using both in vivo and in vitro approaches, our data indicates that ADR‐2 can physically interact with the dsRNA binding protein, ADR‐1, which is also a deaminase‐deficient member of the ADAR family. Our data from RNA‐immunoprecipitation studies of ADR‐2 indicate that ADR‐1 is required for ADR‐2 to stably interact with some target mRNAs in vivo. Furthermore, biochemical editing assays from lysates expressing ADR‐1 mutant proteins indicate that both RNA binding by ADR‐1 and the protein‐protein interaction between ADR‐1 and ADR‐2 promotes RNA editing efficiency. In sum, we have identified a molecular mechanism for regulating the ability of ADAR to both bind target mRNAs and edit. As human ADARs are known to have some overlapping substrate specificities, these results raise the possibility that dimerization between ADAR family members, and perhaps protein‐protein interactions of ADARs with other dsRNA binding proteins, provides the A‐to‐I editing enzymes with a molecular mechanism to specifically recognize editing targets over the thousands of RNAs present in a cell.Support or Funding InformationAmerican Cancer Society Research Scholar Grant (15‐051‐RMC) to H.A.H. Indiana University School of Medicine Start‐up Funds to H.A.H.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.