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J Virol. 2009 May;83(9):4326-37. doi: 10.1128/JVI.02395-08. Epub 2009 Feb 18.

Role of Kaposi's sarcoma-associated herpesvirus C-terminal LANA chromosome binding in episome persistence.

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  • 1Departments of Medicine, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) LANA is an 1,162-amino-acid protein that tethers terminal repeat (TR) DNA to mitotic chromosomes to mediate episome persistence in dividing cells. C-terminal LANA self-associates to bind TR DNA. LANA contains independent N- and C-terminal chromosome binding regions. N-terminal LANA binds histones H2A/H2B to attach to chromosomes, and this binding is essential for episome persistence. We now investigate the role of C-terminal chromosome binding in LANA function. Alanine substitutions for LANA residues (1068)LKK(1070) and (1125)SHP(1127) severely impaired chromosome binding but did not reduce the other C-terminal LANA functions of self-association or DNA binding. The (1068)LKK(1070) and (1125)SHP(1127) substitutions did not reduce LANA's inhibition of RB1-induced growth arrest, transactivation of the CDK2 promoter, or C-terminal LANA's inhibition of p53 activation of the BAX promoter. When N-terminal LANA was wild type, the (1068)LKK(1070) and (1125)SHP(1127) substitutions also did not reduce LANA chromosome association or episome persistence. However, when N-terminal LANA binding to chromosomes was modestly diminished, the substitutions in (1068)LKK(1070) and (1125)SHP(1127) dramatically reduced both LANA chromosome association and episome persistence. These data suggest a model in which N- and C-terminal LANA cooperatively associates with chromosomes to mediate full-length LANA chromosome binding and viral persistence.

PMID:
19225000
PMCID:
PMC2668501
DOI:
10.1128/JVI.02395-08
[PubMed - indexed for MEDLINE]
Free PMC Article
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