Department of Biochemistry and Molecular Biology - Indiana University School of Medicine

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Host:  Dipali Sashital

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"Rewiring the Genome: Molecular Mechanisms that Regulate RNA Editing"

Sequence alterations that change the genome-encoded information present in RNAs provide a powerful way to diversify the transcripts expressed in an organism’s tissues over time.  The ADAR family of RNA editing enzymes catalyze millions of adenosine (A) to inosine (I) modifications in eukaryotic transcriptomes to create proteomic and phenotypic diversity. Loss of these modifications results in lethality in mice and behavioral phenotypes in worm and fly model systems.  Consistent with an important role in both normal development and proper neuronal function, aberrant RNA editing has been linked over 35 human pathologies, including several neurological disorders, metabolic diseases, and cancer.

Our recent work has focused on understanding the regulation of A-to-I editing and demonstrated that editing-deficient members of the ADAR family, C. elegans ADR-1 and human ADAR3, play important roles in regulating A-to-I editing in neural cells.  Our initial characterization revealed that ADR-1 functions primarily to promote editing by ADR-2 at specific adenosines across the C. elegans transcriptome.  This work was the first to demonstrate that RNA binding by a cellular factor could promote RNA editing at specific adenosines in vivo. Importantly, we recently demonstrated that ADR-1 and ADR-2 function together to regulate neural expression of a mRNA that is required for proper neuronal function in worms; indicating the biological importance of the ADR-1/ADR-2 interaction.