STRUCTURE AND FUNCTION OF DSRNA ADENOSINE DEAMINASE

Wistar Institute, Philadelphia PA

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Abstract

DESCRIPTION (From the applicant's abstract): RNA editing plays a critical role in the expression of certain gene products by changing the coding sequences of mRNA's, which results in the synthesis of proteins not directly encoded in the genome. One type of RNA editing involves a conversion of adenosine residues into inosine in transcripts of important mammalian genes such as glutamate receptors (GluR), ion channels and 5-HT serotonin receptors. It is assumed that there are many other target RNAs that are yet to be identified. The overall goal of this project is to elucidate the molecular mechanisms of A to I RNA editing and better understand its biological significance. With the support provided by this grant over the past 7 years, we have cloned for the first time, ADAR I, the first member of the dsRNA adenosine gene family, which led to identification and cloning of the second and third members, ADAR2 and ADAR3. We and others have demonstrated that these recombinantly expressed deaminases can indeed execute or modulate the site selective A-to-I editing of GluR and 5-HT2cR RNAs in vitro. We now propose to: 1) Investigate the mechanism of the editing site selectivity displayed by the different ADAR gene family members. 2) Investigate the possible activation mechanism of ADAR3, the newest member of the gene family and latent form enzyme. 3) Search for new additional members of the ADAR gene family and test their editing site selectivity 4) Identify new target RNAs/genes for A-to-I RNA editing. The information gained from the proposed experiments will allow us to better understand this intriguing RNA editing system and its role in the regulation of target gene expression.