The Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 is associated with malignancies such as Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. These tumors primarily occur in immune suppressed individuals, including organ transplant recipients and AIDS patients. In infected cells, KSHV is primarily latent and the viral DNA is maintained as a multiple copy extrachromosomal element or episome. KSHV latency-associated nuclear antigen (LANA) colocalizes with mitotic chromosomes and KSHV DNA. LANA is required for KSHV DNA with a specific cis-acting sequence to persist as an episome in infected cells. This data is consistent with LANA tethering KSHV episomes to chromosomes to mediate efficient segregation of KSHV episomes to progeny cells. Recent work shows that LANA is phosphorylated. The objectives of this proposal are (i) to characterize LANA's phosphorylation status in KSHV infected cells, (ii) to define the residues of LANA that are phosphorylated; (iii) to assess the effect of phosphorylation on LANA's functions. These experiments may identify targets for pharmacological intervention in the treatment of Kaposi's sarcoma and KSHV-associated malignancies.
|Kelley-Clarke, Brenna; Ballestas, Mary E; Srinivasan, Viswanathan et al. (2007) Determination of Kaposi's sarcoma-associated herpesvirus C-terminal latency-associated nuclear antigen residues mediating chromosome association and DNA binding. J Virol 81:4348-56|
|Kelley-Clarke, Brenna; Ballestas, Mary E; Komatsu, Takashi et al. (2007) Kaposi's sarcoma herpesvirus C-terminal LANA concentrates at pericentromeric and peri-telomeric regions of a subset of mitotic chromosomes. Virology 357:149-57|
|Barbera, Andrew J; Ballestas, Mary E; Kaye, Kenneth M (2004) The Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 N terminus is essential for chromosome association, DNA replication, and episome persistence. J Virol 78:294-301|
|Srinivasan, Viswanathan; Komatsu, Takashi; Ballestas, Mary E et al. (2004) Definition of sequence requirements for latency-associated nuclear antigen 1 binding to Kaposi's sarcoma-associated herpesvirus DNA. J Virol 78:14033-8|
|Komatsu, Takashi; Ballestas, Mary E; Barbera, Andrew J et al. (2004) KSHV LANA1 binds DNA as an oligomer and residues N-terminal to the oligomerization domain are essential for DNA binding, replication, and episome persistence. Virology 319:225-36|
|Ballestas, M E; Kaye, K M (2001) Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mediates episome persistence through cis-acting terminal repeat (TR) sequence and specifically binds TR DNA. J Virol 75:3250-8|