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Determination of KSHV lytic DNA replication origin using SMARD and its control mechanism
AuthorMcDowell, Maria E.
AdvisorVerma, Subhash C.
Biochemistry and Molecular Biology
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While it is clear that Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS) lesions and non-Hodgkins lymphomas such as primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD), the molecular mechanism of lytic replication is still unclear. It is during lytic phase of viral life cycle virions are produced and tumorigenesis is induced in the host, thereby demonstrating the importance of discerning the mechanism of lytic replication in order to advance anti-viral treatments. KSHV lytic replication is initiated by ORF50/RTA, an immediate early lytic protein, which acts as a transcription factor activating downstream lytic factors. Previous research has indicated that RTA, along with other lytic proteins, binds to KSHV origin of lytic replication (oriLyt) in order to initiate viral DNA synthesis essential for virion production. One of these proteins is the KSHV processivity factor, ORF59, which has been shown to be crucial for the synthesis of viral transcripts by viral polymerase, ORF9. As part of this study, we have determined that although an ex-vivo assay suggests that KSHV possess two fully functional origins of lytic replication (oriLyt-L and oriLyt-R), the virus primarily uses oriLyt-L for initiating replication. Here, we also demonstrate that ORF59 is phosphorylated by a viral kinase, ORF36, which modulates its processivity function required for virion production. We also analyzed the interaction of cellular factors with ORF59 in initiating lytic replication and as a result determined that PRMT1 and PRMT5, protein argenine methyltransferase 1 and 5, to be involved in modifying chromatin confirmation at oriLyt and thereby playing an important role in initiating lytic replication.