The proposed research builds on our findings that the EBNA1 protein of Epstein-Barr Virus (EBV) is pivotal to the proliferation and survival of normal and tumor-derived EBV-positive cells. It builds on our and other researchers' findings that there are multiple cis-acting elements within EBV's genome that can contribute to extrachromosomal replication. It also encompasses collaborative studies with Drs. Compton and Lambert to examine extrachromosomal replication of Kaposi's sarcoma virus (KSHV) and human papillomavirus type 16 (HPV-16). We shall identify and characterize cis-acting elements of EBV DNA other than its dyad symmetry element (DS) that can support initiation of DNA synthesis and study similar elements in KSHV DNA. We are particularly interested in elucidating the mechanisms by which viral replicons are maintained in proliferating cells and shall study the maintenance of EBV-derived plasmids by EBNA1 and the possible contributions of the E2 protein to the maintenance of HPV16-derived plasmids. These studies are driven by the hypothesis that the inhibition of maintenance functions of human tumor viruses should permit the development of rational, effective therapies for their associated tumors. Both EBNA1 of EBV and LANA1 of KSHV inhibit apoptosis. We propose to identify the mechanisms by which they do so. It is possible that blocking this inhibition would also be therapeutically beneficial for treating EBV- and KSHV-associated tumors.
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