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Journal of Virology, September 2006, p. 8909-8919, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00502-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Interacts with Bromodomain Protein Brd4 on Host Mitotic Chromosomes

Jianxin You,1,{dagger} Viswanathan Srinivasan,2,{dagger} Gerald V. Denis,3 William J. Harrington Jr.,4 Mary E. Ballestas,2,¶ Kenneth M. Kaye,2* and Peter M. Howley1*

Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,1 Channing Laboratory and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115,2 Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118,3 Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 331364

Received 10 March 2006/ Accepted 23 June 2006

The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is required for viral episome maintenance in host cells during latent infection. Two regions of the protein have been implicated in tethering LANA/viral episomes to the host mitotic chromosomes, and LANA chromosome-binding sites are subjects of high interest. Because previous studies had identified bromodomain protein Brd4 as the mitotic chromosome anchor for the bovine papillomavirus E2 protein, which tethers the viral episomes to host mitotic chromosomes (J. You, J. L. Croyle, A. Nishimura, K. Ozato, and P. M. Howley, Cell 117:349-360, 2004, and J. You, M. R. Schweiger, and P. M. Howley, J. Virol. 79:14956-14961, 2005), we examined whether KSHV LANA interacts with Brd4. We found that LANA binds Brd4 in vivo and in vitro and that the binding is mediated by a direct protein-protein interaction between the ET (extraterminal) domain of Brd4 and a carboxyl-terminal region of LANA previously implicated in chromosome binding. Brd4 associates with mitotic chromosomes throughout mitosis and demonstrates a strong colocalization with LANA and the KSHV episomes on host mitotic chromosomes. Although another bromodomain protein, RING3/Brd2, binds to LANA in a similar fashion in vitro, it is largely excluded from the mitotic chromosomes in KSHV-uninfected cells and is partially recruited to the chromosomes in KSHV-infected cells. These data identify Brd4 as an interacting protein for the carboxyl terminus of LANA on mitotic chromosomes and suggest distinct functional roles for the two bromodomain proteins RING3/Brd2 and Brd4 in LANA binding. Additionally, because Brd4 has recently been shown to have a role in transcription, we examined whether Brd4 can regulate the CDK2 promoter, which can be transactivated by LANA.

* Corresponding author. Mailing address for Peter M. Howley: Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: (617) 432-2882. Fax: (617) 432-2884. E-mail: peter_howley{at}hms.harvard.edu. Mailing address for Kenneth M. Kaye: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-4256. Fax: (617) 525-4251. E-mail: kkaye{at}rics.bwh.harvard.edu.

{dagger} J.Y. and V.S. contributed equally to this work.

Present address: University of Alabama School of Medicine, Department of Pediatrics, Birmingham, AL 35233.

Journal of Virology, September 2006, p. 8909-8919, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00502-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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