Retroviral Genomic RNA Dimer Structure and Function

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DESCRIPTION (provided by applicant): A unique feature of all retroviruses studied to date is that they encapsidate a dimer of identical positive-strand genomic RNAs. The dimerization of retroviral genomic RNA plays a critical role in viral replication; mutations that interfere with the ability of the viral RNA to form dimers have a dramatic effect on infectivity. Despite the invariant nature of this highly specific phenomenon across all retroviral systems, important biological and structural questions remain unanswered. First, the precise role(s) played by dimerization in the viral life cycle is obscure. The region of the viral genome that encompasses the dimer linkage structure contains cis-acting signals that are indispensable for splicing, translation and packaging of the full length viral RNA. Studies performed in our laboratories as well as those reported by other groups suggest that the ability of the RNA to form dimers may impact on any or all of these steps in viral replication. Second, neither the mechanism by which dimers form nor the structure of the final dimer has been elucidated. Although several groups have suggested that dimerization is a dynamic process involving several determinants, there is significant disagreement regarding the nature of the RNA determinants themselves, the order in which these determinants interact, as well as the structure of the mature dimer. Finally, given these gaps in our knowledge, there is a very limited understanding of the interaction between the process by which dimers arise, the final structure they achieve and the ultimate impact of dimer formation on biological function. We believe our studies will provide important insights into RNA structure and retroviral biology. Specifically, we will: I. Characterize the role played by dimerization of the viral genomic RNA in viral replication. II. Establish a detailed molecular understanding of the RNA structures required for dimerization of the Moloney murine sarcoma virus (MuSV) genomic RNA and the mechanism by which these structures assemble into an active dimer. III. Define the interaction between the structure of the dimer and its function in the viral life cycle.