Reactome: A Curated Pathway Database

Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)

Species Homo sapiens


The Tat protein is a viral transactivator protein that regulates HIV-1 gene expression by controlling RNA Pol II-mediated elongation (reviewed in Karn 1999; Taube et al. 1999; Liou et al. 2004; Barboric and Peterlin 2005). Tat appears to be required in order to overcome the arrest of RNA Pol II by the negative transcriptional elongation factors DSIF and NELF (Wada et al. 1998; Yamaguchi et al. 1999; Yamaguchi et al 2002; Fujinaga et al. 2004). While Pol II can associate with the proviral LTR and initiate transcription in the absence of Tat, these polymerase complexes are non-processive and dissociate from the template prematurely producing very short transcripts (Kao et al. 1987). Tat associates with the RNA element, TAR, which forms a stem loop structure in the leader RNA sequence (Dingwall et al. 1989). Tat also associates with the cellular kinase complex P-TEFb(Cyclin T1:Cdk9) and recruits it to the TAR stem loop structure (Herrmann, 1995) (Wei et al. 1998). This association between Tat, TAR and P-TEFb(Cyclin T1:Cdk9) is believed to bring the catalytic subunit of this kinase complex (Cdk9) in close proximity to Pol II where it hyperphosphorylates the CTD of RNA Pol II (Zhou et al. 2000). The RD subunits of NELF and the SPT5 subunit of DSIF, which associate through RD with the bottom stem of TAR, are also phosphorylated by P-TEFb(Cyclin T1:Cdk9) (Yamaguchi et al. 2002; Fujinaga et al. 2004; Ivanov et al. 2000). Phosphorylation of RD results in its dissociation from TAR. Thus, Tat appears to facilitate transcriptional elongation of the HIV-1 transcript by hyperphosphorylating the RNA Poll II CTD and by removing the negative transcription elongation factors from TAR. In addition, there is evidence that the association of Tat with P-TEFb(Cyclin T1:Cdk9) alters the substrate specificity of P-TEFb enhancing phosphorylation of ser5 residues in the CTD of RNA Pol II (Zhou et al. 2000).

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Additional Information
Compartment nucleoplasm
GO Biological Process positive regulation of viral transcription (0050434)
Name Identifier Synonyms
Human immunodeficiency virus infectious disease 526 [HIV infection]
Literature References
pubMedId Title Journal Year
15719065 A new paradigm in eukaryotic biology: HIV Tat and the control of transcriptional elongation PLoS Biol 2005
9491887 A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA Cell 1998
2825027 Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product Nature 1987
9450929 DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev 1998
10757782 Domains in the SPT5 protein that modulate its transcriptional regulatory properties Mol Cell Biol 2000
14701750 Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element Mol Cell Biol 2004
11940650 Evidence that negative elongation factor represses transcription elongation through binding to a DRB sensitivity-inducing factor/RNA polymerase II complex and RNA. Mol Cell Biol 2002
15183343 HIV-1 infection and regulation of Tat function in macrophages Int J Biochem Cell Biol 2004
2476805 Human immunodeficiency virus 1 tat protein binds trans-activation-responsive region (TAR) RNA in vitro Proc Natl Acad Sci U S A 1989
7853496 Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor J Virol 1995
10199401 NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation Cell 1999
10550206 Tackling Tat J Mol Biol 1999
10866664 Tat modifies the activity of CDK9 to phosphorylate serine 5 of the RNA polymerase II carboxyl-terminal domain during human immunodeficiency virus type 1 transcription Mol Cell Biol 2000
10562489 Tat transactivation: a model for the regulation of eukaryotic transcriptional elongation Virology 1999