Abstract
Human immunodeficiency virus type 1 (HIV-1) Tat transactivation is an essential step in the viral life cycle. Over the past several years, it has become widely accepted that Tat exerts its transcriptional effect by binding the transactivation-responsive region (TAR) and enhancing transcriptional elongation. Consistent with this hypothesis, it has been shown that Tat promotes the binding of P-TEFb, a transcription elongation factor composed of cyclin T1 and cdk9, and the interaction of Tat with P-TEFb and TAR leads to hyperphosphorylation of the C-terminal domain (CTD) of RNA Pol II and increased processivity of RNA Pol II. A recent report, however, has generated renewed interest that Tat may also play a critical role in transcription complex (TC) assembly at the preinitiation step. Using in vivo chromatin immunoprecipitation assays, the authors reported that the HIV TC contains TBP but not TBP-associated factors. The stimulatory effect involved the direct interaction of Tat and P-TEFb and was evident at the earliest step of TC assembly, the TBP-TATA box interaction. In this article, we will review this data in context of earlier data which also support Tat's involvement in transcriptional complex assembly. Specifically, we will discuss experiments which demonstrated that Tat interacted with TBP and increased transcription initiation complex stability in cell free assays. We will also discuss studies which demonstrated that over expression of TBP alone was sufficient to obtain Tat activated transcription in vitro and in vivo. Finally, studies using self-cleaving ribozymes which suggested that Tat transactivation was not compatible with pausing of the RNA Pol II at the TAR site will be discussed.
Highlights
Transcription of the Human immunodeficiency virus type 1 (HIV-1) provirus is characterized by an early, Tat-independent and a late, Tat-dependent phase
The more recent finding that Tat promotes the binding of P-TEFb, a transcription elongation factor composed of cyclin T1 and cdk9 [10] and, more recently, Brd4 in the active nuclear complex [11] seemed consistent with the elongation model
It has been shown that the interaction of Tat with P-TEFb and transactivation-responsive region (TAR) leads to hyperphosphorylation of the C-terminal domain (CTD) of RNA Pol II and increased processivity of RNA Pol II [12,13,14,15,16,17,18,19,20,21,22]
Summary
While these studies have renewed interest in the role of Tat in promoting transcription initiation, the idea is certainly not new. Based on these results and earlier studies that Tat increased transcription initiation complex stability in cell free assays [48], the authors speculated in this paper that Tat may increase the association or dissociation of TFIID, or recruit a particular species of functionally different TFIID to the HIV template. To determine the synergy between Tat and GAL4-TBP in the absence of any DNA-bound activator, the G1-38HIV reporter was transfected into HeLa cells with the GAL4hTBP and a Tat expression vector. They concluded that abortive transcripts may reflect transcription that occurs as a consequence of replication induced by T antigen in cell lines tested These data were consistent with earlier reports on Tat's effect of TC complex stability when using cell-free assays [48].
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