The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription

The human positive transcription elongation factor P-TEFb, consisting of a CDK9/cyclin T1 heterodimer, functions as both a general and an HIV-1 Tat-sp ecific transcription factor(1,2). P-TEFb activates transcription by phospho rylating RNA polymerase (Pol) II, leading to the formation of processive el ongation complexes. As a Tat cofactor, P-TEFb stimulates HIV-1 transcriptio n by interacting with Tat and the transactivating responsive (TAR) RNA stru cture located at the 5' end of the nascent viral transcript(3). Here we ide ntified 7SK, an abundant and evolutionarily conserved small nuclear RNA (sn RNA) of unknown function(4,5), as a specific P-TEFb-associated factor. 7SK inhibits general and HIV-1 Tat-specific transcriptional activities of P-TEF b in vivo and in vitro by inhibiting the kinase activity of CDK9 and preven ting recruitment of P-TEFb to the HIV-1 promoter. 7SK is efficiently dissoc iated from P-TEFb by treatment of cells with ultraviolet irradiation and ac tinomycin D. As these two agents have been shown to significantly enhance H IV-1 transcription and phosphorylation of Pol II (refs 6-8), our data provi de a mechanistic explanation for their stimulatory effects. The 7SK/P-TEFb interaction may serve as a principal control point for the induction of cel lular and HIV-1 viral gene expression during stress-related responses. Our studies demonstrate the involvement of an snRNA in controlling the activity of a Cdk-cyclin kinase.