P-TEFb

Figure 1. RNA polymerase II elongation control. Pol II comes under the control of negative elongation factors (DSIF and NELF) shortly after initiation. P-TEFb mediates a transition into productive elongation by phosphorylating the two negative factors and the polymerase and is regulated by association with the 7SK snRNP.

The positive transcription elongation factor, P-TEFb, is a multiprotein complex that plays an essential role in the regulation of transcription by RNA polymerase II (Pol II) in eukaryotes.[1] Immediately following initiation Pol II becomes trapped in promoter proximal paused positions on the majority of human genes (Figure 1).[2][3] P-TEFb is a cyclin dependent kinase that can phosphorylate the DRB sensitivity inducing factor (DSIF)[4] and negative elongation factor (NELF),[5] as well as the carboxyl terminal domain of the large subunit of Pol II[6] 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.[7] Treatment of cells with the P-TEFb inhibitors DRB or flavopidirol leads to loss of mRNA production and ultimately cell death.[6][8]

  1. ^ Zhou Q, Li T, Price DH. RNA Polymerase II Elongation Control. Annu Rev Biochem 2012.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ a b 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.
  7. ^ 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.
  8. ^ Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 2001; 276:31793-9.