Mechanisms of KSHV post-transcriptional gene regulation

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DESCRIPTION (provided by applicant): Viruses use a wide spectrum of molecular mechanisms to favor their own gene expression in the complex environment of an infected host cell. Recent advances suggest that viral regulation of cellular RNA decay pathways is more common than previously appreciated. For example, several factors in the Kaposi's sarcoma-associated herpesvirus (KSHV) have been demonstrated to regulate host or viral RNA turnover rates. In this proposal, a role for the KSHV ORF57 protein in viral transcript stability is examined. ORF57 is a lytic phase protein that is essential for viral replication and has been reported to affect a wide variety of nuclear events in mRNA biogenesis, but its molecular mechanisms remain unknown. The experiments in this proposal are designed to test the hypothesis that ORF57 binds to nuclear RNAs and protects them from cellular RNA decay pathways. Specifically, the studies described here will elucidate the molecular mechanisms of ORF57 nuclear function by examining 1) the effects of ORF57 on nuclear stability of viral mRNAs, 2) the relationship between RNA binding and ORF57 function, and 3) the roles of ORF57 RNA-binding and stability activities in the context of viral lytic infection. Understanding the molecular mechanism of ORF57 is fundamental to understanding the biology of KSHV, the causative agent for Kaposi's sarcoma, primary effusion lymphoma (PEL), and some types of multicentric Castleman's disease (MCD). An appreciation of ORF57 molecular mechanisms may lead to novel therapeutic approaches and bolster knowledge of the pathways important for controlling tumorigenesis. Thus, by revealing the mechanisms of ORF57 function, these studies will provide molecular insights into this important human pathogen and into the biology of its human host cells.