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Journal of Virology, November 2006, p. 10772-10786, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00804-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus LANA-1 Interacts with the Short Variant of BRD4 and Releases Cells from a BRD4- and BRD2/RING3-Induced G₁ Cell Cycle Arrest

Matthias Ottinger,^1,2 Thomas Christalla,¹ Kavita Nathan,¹ Melanie M. Brinkmann,^1, Abel Viejo-Borbolla,^1, and Thomas F. Schulz^1*

Institut für Virologie, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, D-30625 Hannover, Germany Department of Pathology, Harvard Medical School, Boston, Massachusetts

Received 19 April 2006/ Accepted 13 August 2006

The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen 1 (LANA-1) is required for the replication of episomal viral genomes. Regions in its N-terminal and C-terminal domains mediate the interaction with host cell chromatin. Several cellular nuclear proteins, e.g., BRD2/RING3, histones H2A and H2B, MeCP2, DEK, and HP1, have been suggested to mediate this interaction. In this work, we identify the double-bromodomain proteins BRD4 and BRD3/ORFX as additional LANA-1 interaction partners. The carboxy-terminal region of the short variant of BRD4 (BRD4^S) containing the highly conserved extraterminal domain directly interacts with an element in the LANA-1 carboxy-terminal domain. We show that ectopically expressed BRD4^S and BRD2/RING3 delay progression into the S phase of the cell cycle in epithelial and B-cell lines and increase cyclin E promoter activity. LANA-1 partly releases epithelial and B cells from a BRD4^S- and BRD2/RING3-induced G₁ cell cycle arrest and also promotes S-phase entry in the presence of BRD4^S and BRD2/RING3. This is accompanied by a reduction in BRD4^S-mediated cyclin E promoter activity. Our data are in keeping with the notion that the direct interaction of KSHV LANA-1 with BRD4 and other BRD proteins could play a role in the G₁/S phase-promoting functions of KSHV LANA-1. Further, our data support a model in which the LANA-1 C terminus contributes to a functional attachment to acetylated histones H3 and H4 via BRD4 and BRD2, in addition to the recently demonstrated direct interaction (A. J. Barbera, J. V. Chodaparambil, B. Kelley-Clarke, V. Joukov, J. C. Walter, K. Luger, and K. M. Kaye, Science 311:856-861, 2006) of the LANA-1 N terminus with histones H2A and H2B.

Published ahead of print on 23 August 2006.

Present address: Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA.

Present address: Department of Cell and Molecular Biology, Centro Nacional de Biotecnologia, CSIC, Madrid, Spain.

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