Mechanism of Action LANA Encoded by KSHV

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DESCRIPTION (Provided by the applicant): Kaposi's sarcoma herpesvirus (KSHV) is a gammaherpesvirus associated with human malignancies including Kaposi's sarcoma and body cavity based lymphomas (BCBLs) or pleural effusion lymphomas (PELs). One of the latency-associated nuclear antigen (LANA) is constitutively expressed in all latently infected KSHV cells and is involved in the maintenance of the KSHV genome and transcriptional regulation. LANA tethers the KSHV genome to host chromosomes through association with cis-acting DNA element(s) at the left of the viral genome. LANA also associates with chromosomal proteins including histone H 1 potentially tethering the viral genome to host chromosome. There is an increasing body of evidence demonstrating that LANA is critical for KSHV persistence in human malignancies. The specific aims of this proposal are: (1) To investigate the role of LANA in regulating viral and cellular gene expression in KSHV infected growth-transformed cells. (2) To identify and characterize LANA associated proteins and to determine the functional consequences resulting for these specific. (3) To identify additional binding sites for LANA on the KSHV genome and (4) to determine functional domains of LANA which is involved in DNA binding, transcriptional regulation and maintenance of KSHV genome in infected cells. These aims will provide critical information for elucidating the mechanisms by which LANA functions in contributing to KSHV pathogenesis and associated human malignancies.