CELLULAR SIGNALING BY DOUBLE STRANDED RNA

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Cellular signaling by double-stranded (ds) RNA will be investigated in this project. DsRNA is an important regulator of gene transcription, protein synthesis and cell growth. The multiple cellular functions of dsRNA have been discovered in the contexts of the interferon system, different aspects of which will be studied in the other projects of this program. Transcriptional signaling by dsRNA will be analyzed using defective cell mutants. One such mutant has been already isolated and more will be generated during the course of the proposed investigation. The mutant cells will be examined for defects in candidate proteins which might be involved in dsRNA signaling. If no such defect is found, the cells will be complemented with cDNA expression libraries made from wild-type cells and the mutated protein will be cloned. In two other aims, cellular functions of two dsRNA-binding proteins, which were cloned during the last funding period, will be investigated. One protein, PACT interacts with PKR and activates it. The mechanism of the activation process and its consequence on transcriptional signaling, protein synthesis and cell growth regulation will be studied. P9O, the other dsRNA-binding protein, is a nuclear phosphoprotein. Its possible involvement in cell cycle regulation and nuclear RNA metabolism will be investigated. The proposed studies will provide important mechanistic information about the cellular functions of dsRNA, a major regulator in virus-infected cells.