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P-TEFb
The positive transcription elongation factor, P-TEFb, plays an essential role in the regulation of transcription by RNA polymerase II (Pol II) in eukaryotes.〔Zhou Q, Li T, Price DH. RNA Polymerase II Elongation Control. Annu Rev Biochem 2012.〕 Immediately following initiation Pol II becomes trapped in promoter proximal paused positions on the majority of human genes (Figure 1).〔Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, et al. c-Myc regulates transcriptional pause release. Cell 2010; 141:432-45.〕〔Cheng B, Li T, Rahl PB, Adamson TE, Loudas NB, Guo J, et al. Functional association of Gdown1 with RNA polymerase II poised on human genes. Mol Cell 2012; 45:38-50.〕 P-TEFb is a cyclin dependent kinase that can phosphorylate the DRB sensitivity inducing factor (DSIF)〔Wada T, Takagi T, Yamaguchi Y, Ferdous A, Imai T, Hirose S, et al. DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev 1998; 12:343-56.〕 and negative elongation factor (NELF),〔Yamaguchi Y, Takagi T, Wada T, Yano K, Furuya A, Sugimoto S, et al. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 1999; 97:41-51.〕 as well as the carboxyl terminal domain of the large subunit of Pol II〔Marshall NF, Peng J, Xie Z, Price DH. Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J Biol Chem 1996; 271:27176-83.〕 and this causes the transition into productive elongation leading to the synthesis of mRNAs. P-TEFb is regulated in part by a reversible association with the 7SK snRNP.〔Peterlin BM, Brogie JE, Price DH. 7SK snRNA: a noncoding RNA that plays a major role in regulating eukaryotic transcription. Wiley Interdiscip Rev RNA 2012; 3:92-103.〕 Treatment of cells with the P-TEFb inhibitors DRB or flavopidirol leads to loss of mRNA production and ultimately cell death.〔〔Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 2001; 276:31793-9.〕
== Discovery, Composition and Structure ==
P-TEFb was identified and purified as a factor needed for the generation of long run-off transcripts using an in vitro transcription system derived from Drosophila cells.〔Marshall NF, Price DH. Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J Biol Chem 1995; 270:12335-8.〕 It is a cyclin dependent kinase containing the catalytic subunit, Cdk9, and a regulatory subunit, cyclin T in Drosophila.〔Peng J, Marshall NF, Price DH. Identification of a cyclin subunit required for the function of Drosophila P-TEFb. J Biol Chem 1998; 273:13855-60.〕 In humans there are multiple forms of P-TEFb which contain Cdk9 and one of several cyclin subunits, cyclin T1, T2, and K.〔Fu TJ, Peng J, Lee G, Price DH, Flores O. Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription. J Biol Chem 1999; 274:34527-30.〕〔Peng J, Zhu Y, Milton JT, Price DH. Identification of multiple cyclin subunits of human P-TEFb. Genes Dev 1998; 12:755-62.〕 P-TEFb associates with other factors including the bromodomain protein BRD4,〔Yang Z, Yik JH, Chen R, He N, Jang MK, Ozato K, et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell 2005; 19:535-45.〕 and is found associated with a large complex of proteins called the super elongation complex.〔Smith E, Lin C, Shilatifard A. The super elongation complex (SEC) and MLL in development and disease. Genes Dev 2011; 25:661-72.〕〔He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell 2010; 38:428-38.〕 Importantly, for the AIDS virus, HIV, P-TEFb is targeted by the HIV Tat protein〔Kao SY, Calman AF, Luciw PA, Peterlin BM. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 1987; 330:489-93.〕 which bypasses normal cellular P-TEFb control and directly brings P-TEFb to the promoter proximal paused polymerase in the HIV genome.〔Zhu Y, Pe'ery T, Peng J, Ramanathan Y, Marshall N, Marshall T, et al. Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. Genes Dev 1997; 11:2622-32.〕〔Garber ME, Wei P, Jones KA. HIV-1 Tat interacts with cyclin T1 to direct the P-TEFb CTD kinase complex to TAR RNA. Cold Spring Harbor symposia on quantitative biology 1998; 63:371-80.〕
The structures of human P-TEFb containing Cdk9 and cyclin T1 and the HIV Tat•P-TEFb complex have been solved using X-ray crystallography. The first structure solved demonstrated that the two subunits were arranged as has been found in other cyclin dependent kinases.〔Baumli S, Lolli G, Lowe ED, Troiani S, Rusconi L, Bullock AN, et al. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. EMBO J 2008; 27:1907-18.〕 Three amino acid substitutions were inadvertently introduced in the subunits used for the original structure and a subsequent structure determination using the correct sequences demonstrated the same overall structure except for a few significant changes around the active site.〔Tahirov TH, Babayeva ND, Varzavand K, Cooper JJ, Sedore SC, Price DH. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature 2010; 465:747-51.〕 The structure of HIV Tat bound to P-TEFb demonstrated that the viral protein forms extensive contacts with the cyclin T1 subunit (Figure 2).〔
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