Genetic and Biochemical Studies of the KSHV LANA Gene

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DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is etiologically linked with KS, primary effusion lymphomas (PELs) and multicentric Castleman's disease. These diseases occur in AIDS and other patients and current therapies are limited. KSHV latently infects the vast majority of tumor cells and viral DNA persists as a multiple copy, extrachromosomal, circular episome. Several lines of evidence support a model in which the latency associated nuclear antigen (LANA) maintains episomes by first mediating replication of KSHV DNA and then tethering episomes to chromosomes for efficient segregation to progeny nuclei. Therefore, effective interventions which interrupt LANA's episome persistence function would be expected to prevent or eliminate KSHV infection and provide effective therapy for KSHV associated malignancies. An understanding of the mechanisms underlying LANA mediated KSHV episome persistence is critical to enable the design of assays that screen small molecules which can inhibit these processes. Further, understanding the structure of the LANA DNA binding domain complexed with cognate DNA would enable rational drug design to interrupt LANA function. This work will investigate the mechanisms central to LANA's episome maintenance function. Proteins mediating LANA's association with chromosomes will be identified. The mechanisms underlying LANA mediated KSHV DNA replication will be investigated. Since the LANA C-terminus specifically binds KSHV DNA, investigations to solve the structure of this domain bound to cognate DNA will begin. Each of these aims investigates an area critical for LANA episome maintenance. Since episome persistence is central to latent infection and most tumor cells are latently infected, this work may lead to new strategies for prevention or treatment of KSHV associated malignancies.