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J. Virol. doi:10.1128/JVI.01681-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Inhibition of the cyclin-dependent kinases at the beginning of the human cytomegalovirus infection specifically alters the levels and localization of the RNA polymerase II carboxyl-terminal domain kinases cdk9 and cdk7 at the viral transcriptosome

Department of Cellular and Molecular Medicine, School of Pharmacy and Pharmaceutical Sciences, and Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093-0712

^* To whom correspondence should be addressed. Email: dspector{at}ucsd.edu.

	Abstract

We previously reported that defined components of the host transcription machinery are recruited to human cytomegalovirus immediate early (IE) transcription sites, including cdk9 and cdk7 (S. Tamrakar, A. J. Kapasi, D. H. Spector, J. Virol. 79: 15477-15493, 2005). In this report, we further document the complexity of this site, referred to as the transcriptosome, through identification of additional resident proteins, including viral UL69 and cellular cyclin T1, Brd4, HDAC1 and HDAC2. To examine the role of cyclin dependent kinases (cdks) in the establishment of this site, we used Roscovitine, a specific inhibitor of cdk1, cdk2, cdk7 and cdk9, that alters processing of viral IE transcripts and inhibits expression of viral early genes. In the presence of Roscovitine, IE2, cyclin T1, Brd4, HDAC1, and HDAC2 accumulate at the transcriptosome. However, accumulation of cdk9 and cdk7 was specifically inhibited. Roscovitine treatment also resulted in decreased levels of cdk9 and cdk7 RNA. There was a corresponding reduction in cdk9 protein, but only a modest decrease in cdk7 protein. However, overexpression of cdk9 does not compensate for the effects of Roscovitine on cdk9 localization or viral gene expression. Delaying the addition of Roscovitine until 8 hours post infection prevented all of the observed effects of the cdk inhibitor. These data suggest that IE2 and multiple cellular factors needed for viral RNA synthesis accumulate within the first 8 hours at the viral transcriptosome and that functional cdk activity is required for the specific recruitment of cdk7 and cdk9 during this time interval.

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