Nucleic Acids Research Advance Access published online on March 6, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm063
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Molecular Biology |
Tat competes with HEXIM1 to increase the active pool of P-TEFb for HIV-1 transcription
1Departments of Medicine, Microbiology, and Immunology, Rosalind Russell Medical Research Center, University of California at San Francisco, San Francisco, CA 94143 0703, USA, 2Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA, 3Max-Planck-Institut für molekulare Physiologie, Abteilung Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany and 4School of Life Sciences, Xiamen University, Xiamen 361005, P.R. China
*To whom correspondence should be addressed. Tel: +1 510 643 1697; Fax: +1 510 643 6334; Email: qzhou{at}uclink4.berkeley.edu Correspondence may also be addressed to B. Matija Peterlin. Tel: +1 415 502 1902; Fax: +1 415 502 1901; Email: matija.peterlin{at}ucsf.edu
Received December 11, 2006. Revised January 19, 2007. Accepted January 20, 2007.
Human immunodeficiency virus type 1 (HIV-1) transcriptional transactivator (Tat) recruits the positive transcription elongation factor b (P-TEFb) to the viral promoter. Consisting of cyclin dependent kinase 9 (Cdk9) and cyclin T1, P-TEFb phosphorylates RNA polymerase II and the negative transcription elongation factor to stimulate the elongation of HIV-1 genes. A major fraction of nuclear P-TEFb is sequestered into a transcriptionally inactive 7SK small nuclear ribonucleoprotein (snRNP) by the coordinated actions of the 7SK small nuclear RNA (snRNA) and hexamethylene bisacetamide (HMBA) induced protein 1 (HEXIM1). In this study, we demonstrate that Tat prevents the formation of and also releases P-TEFb from the 7SK snRNP in vitro and in vivo. This ability of Tat depends on the integrity of its N-terminal activation domain and stems from the high affinity interaction between Tat and cyclin T1, which allows Tat to directly displace HEXIM1 from cyclin T1. Furthermore, we find that in contrast to the Tat-independent activation of the HIV-1 promoter, Tat-dependent HIV-1 transcription is largely insensitive to the inhibition by HEXIM1. Finally, primary blood lymphocytes display a reduced amount of the endogenous 7SK snRNP upon HIV-1 infection. All these data are consistent with the model that Tat not only recruits but also increases the active pool of P-TEFb for efficient HIV-1 transcription.
These authors contributed equally to this work.
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