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Molecular and Cellular Biology, November 2003, p. 8282-8294, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8282-8294.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Poly(ADP-Ribose) Polymerase 1 and Ste20-Like Kinase hKFC Act as Transcriptional Repressors for Gamma-2 Herpesvirus Lytic Replication

Yousang Gwack,1 Hiroyuki Nakamura,1 Sun Hwa Lee,1 John Souvlis,1 Jason T. Yustein,2 Steve Gygi,3 Hsing-Jien Kung,2 and Jae U. Jung1*

Department of Microbiology and Molecular Genetics, Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772-9102,1 Department of Biological Chemistry, School of Medicine, University of California—Davis Cancer Center, University of California, Davis, California 95817,2 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 021153

Received 9 May 2003/ Returned for modification 30 June 2003/ Accepted 4 August 2003

The replication and transcription activator (RTA) of gamma-2 herpesvirus is sufficient to drive the entire virus lytic cycle. Hence, the control of RTA activity should play an important role in the maintenance of viral latency. Here, we demonstrate that cellular poly(ADP-ribose) polymerase 1 (PARP-1) and Ste20-like kinase hKFC interact with the serine/threonine-rich region of gamma-2 herpesvirus RTA and that these interactions efficiently transfer poly(ADP-ribose) and phosphate units to RTA. Consequently, these modifications strongly repressed RTA-mediated transcriptional activation by inhibiting its recruitment onto the promoters of virus lytic genes. Conversely, the genetic ablation of PARP-1 and hKFC interaction or the knockout of the PARP-1 gene and activity considerably enhanced gamma-2 herpesvirus lytic replication. Thus, this is the first demonstration that cellular PARP-1 and hKFC act as molecular sensors to regulate RTA activity and thereby, herpesvirus latency.

* Corresponding author. Mailing address: Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Dr., Southborough, MA 01772. Phone: (508) 624-8083. Fax: (508) 786-1416. E-mail: jae_jung{at}hms.harvard.edu.

Molecular and Cellular Biology, November 2003, p. 8282-8294, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8282-8294.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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