Poster abstracts
Poster number 78 submitted by Suba Rajendren
Molecular Mechanisms to Regulate the Substrate Recognition of an A-to-I RNA Editing Enzyme
Suba Rajendren (Genome, Cell and Developmental Biology Program, Indiana University, Bloomington), Heather A. Hundley (Medical Sciences Program, Indiana University School of Medicine, Bloomington)
Abstract:
RNA editing alters genomically encoded information to generate the transcriptomic diversity required for normal development and proper neuronal function in all animals. Aberrant RNA editing is associated with neurological disorders and cancers in humans. The adenosine deaminase acting on RNA (ADAR) family of enzymes catalyzes adenosine (A) to inosine (I) RNA editing. ADARs act on double stranded RNAs (dsRNAs), however not every adenosine is equally edited. The mechanisms that regulate ADAR specificity and editing efficiency are not well understood. Our lab utilizes Caenorhabditis elegans to study the cellular factors and molecular mechanisms which regulate RNA editing. In C. elegans, RNA editing is catalyzed by ADR-2. However, a dsRNA binding protein, ADR-1, promotes RNA editing at specific sites in vivo. Herein, our studies indicate ADR-2 has low affinity for dsRNA, but interacts with ADR-1, an editing-deficient member of the ADAR family, which has a 100-fold higher affinity for dsRNA. ADR-1 uses one dsRBD to physically interact with ADR-2 and a second dsRBD to bind to dsRNAs, thereby tethering ADR-2 to substrates. ADR-2 interacts with >1200 transcripts in vivo, and ADR-1 is required for 80% of these interactions. Our results identify a novel mode of substrate recognition for ADAR enzymes and indicate that protein-protein interactions can guide substrate recognition for RNA editors. However, in the nervous system, ADR-1 is not required for ADR-2 to edit certain targets, which have one or two highly-edited sites. We hypothesize that protein-protein interactions with other neural RNA binding proteins promote ADR-2 binding to certain transcripts to catalyze editing at specific highly edited sites within the nervous system. Elucidating how ADR-2 binds to substrate mRNAs in specific tissues and determining the tissue specific co-factors of editing will result in identification of molecular mechanisms that regulate RNA editing. This will lead to the development of targeted therapeutics to restore editing in patients with heart and neurological diseases.
Keywords: RNA editing, Celegans, dsRNA binding domains (dsRBDs)