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Journal of Virology, May 2009, p. 4326-4337, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02395-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Role of Kaposi's Sarcoma-Associated Herpesvirus C-Terminal LANA Chromosome Binding in Episome Persistence{triangledown}

Brenna Kelley-Clarke,{dagger} Erika De Leon-Vazquez, Katherine Slain, Andrew J. Barbera,{ddagger} and Kenneth M. Kaye*

Channing Laboratory, Departments of Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, Massachusetts 02115

Received 18 November 2008/ Accepted 9 February 2009

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 1068LKK1070 and 1125SHP1127 severely impaired chromosome binding but did not reduce the other C-terminal LANA functions of self-association or DNA binding. The 1068LKK1070 and 1125SHP1127 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 1068LKK1070 and 1125SHP1127 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 1068LKK1070 and 1125SHP1127 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.

* Corresponding author. Mailing address: Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-4256. Fax: (617) 525-4251. Email: E-mail: kkaye{at}rics.bwh.harvard.edu

{triangledown} Published ahead of print on 18 February 2009.

{dagger} Present address: Department of Global Health, University of Washington, 1616 Eastlake Ave., Seattle, WA 98102.

{ddagger} Present address: Department of Medicine and BCMP, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115.

Journal of Virology, May 2009, p. 4326-4337, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02395-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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