The HIV transactivator TAT binds to the CDK-activating kinase and activates the phosphorylation of the carboxy-terminal domain of RNA polymerase II

Howard Hughes Medical Institute, Department of Medicine, University of California at San Francisco, San Franscisco, California USA.
Genes & Development (Impact Factor: 10.8). 11/1997; 11(20):2645-57. DOI: 10.1101/gad.11.20.2645
Source: PubMed


The human immunodeficiency virus encodes the transcriptional transactivator Tat, which binds to the transactivation response (TAR) RNA stem-loop in the viral long terminal repeat (LTR) and increases rates of elongation rather than initiation of transcription by RNA polymerase II (Pol II). In this study, we demonstrate that Tat binds directly to the cyclin-dependent kinase 7 (CDK7), which leads to productive interactions between Tat and the CDK-activating kinase (CAK) complex and between Tat and TFIIH. Tat activates the phosphorylation of the carboxy-terminal domain (CTD) of Pol II by CAK in vitro. The ability of CAK to phosphorylate the CTD can be inhibited specifically by a CDK7 pseudosubstrate peptide that also inhibits transcriptional activation by Tat in vitro and in vivo. We conclude that the phosphorylation of the CTD by CAK is essential for Tat transactivation. Our data identify a cellular protein that interacts with the activation domain of Tat, demonstrate that this interaction is critical for the function of Tat, and provide a mechanism by which Tat increases the processivity of Pol II.


Available from: Koh Fujinaga, Apr 04, 2014
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    • "It is necessary for the assembly of various transcription co-activators such as positive transcription elongation factor b (PTEFb), which contains CDK9/CyclinT1 and histone acetyl transferases [22]. Tat has also been shown to regulate the activation of C-terminal domain kinase in phosphorylation of C-terminal domain of RNA pol II [23]. Most importantly, arginine rich motif of Tat protein interacts with the stem loop structure of transactivation region (TAR) of mRNA and regulates the rate of transcription elongation. "
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    PLoS ONE 10/2013; 8(10):e77595. DOI:10.1371/journal.pone.0077595 · 3.23 Impact Factor
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    • "Studies suggest the interaction between Tat and its cellular counterpart is critical for the function of Tat and the increased processivity of Pol II. Oligonucleotides have been investigated for inhibition of Tat binding to this recognition site in biochemical assays, but they failed to disrupt HIV-1 replication in acute infection of primary lymphocytes [58]. Natural 4-phenylcoumarins isolated from Marila pluricostata were identified as Tat antagonists and were able to inhibit HIV-1 replication in cell-based assays [24]. "
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    • "Therefore, lack of specificity may result in off-target effects causing increased side effects, however absolute specificity may result in a lack of efficacy due to redundancy in signaling. Towards increasing kinase inhibitor specificity, we previously reported that a pseudo-substrate peptide for cyclin-dependent kinase 7 inhibits transcriptional activation by the Tat protein of the human immunodeficiency virus [54,55]. A similar approach may be useful in the inhibition of kinases important for RA therapy. "
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