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Professor of Biochemistry and Molecular Biology
We are studying the mechanisms and factors that control transcriptional elongation and how this control affects HIV replication, tumorigenesis, and the cellular decision between growth and differentiation.
Recent global analyses indicate that the elongation phase of RNA polymerase (Pol) II transcription plays a much more important role in controlling metazoan gene expression than previously thought. Composed of Cdk9 and Cyclin T, the positive transcription elongation factor b (P-TEFb) plays a key role during transcriptional elongation. It stimulates the processivity of Pol II through phosphorylating the C-terminal domain of the largest subunit of Pol II and a pair of negative elongation factors. This leads to the synthesis of full-length RNA transcripts and the coupling of transcription with pre-mRNA processing. In human cells, not only is P-TEFb critical for the expression of a vast array of cellular genes, it is also an indispensable host cofactor for efficient transcription of the HIV genome. HIV devotes a key regulatory protein Tat and a specialized RNA structure called TAR, which is located at the 5’ end of all viral transcripts, to recruit P-TEFb to the integrated HIV proviral genome to activate transcription.
Recent data from us and others demonstrate that most of cellular P-TEFb exist in two mutually exclusive complexes that are characterized by their different subunit compositions and Cdk9 kinase activity. A catalytically inactive complex termed 7SK snRNP sequesters a major fraction of cellular P-TEFb and also contains the 7SK snRNA and three nuclear proteins, HEXIM1, LARP7 (also termed PIP7S), and BCDIN3. Within this complex, 7SK, an evolutionarily conserved small non-coding RNA, functions as a molecular scaffold to coordinate the interactions among key protein components and maintain the integrity of 7SK snRNP. While HEXIM1 inhibits the Cdk9 kinase activity in a 7SK-dependent manner, LARP7, a La-related protein associated with the 3’ UUUU-OH sequence of 7SK, and BCDIN3, a 7SK-specific capping enzyme, ensure the stability of 7SK.
In contrast to the P-TEFb sequestered in inactive 7SK snRNP, another major fraction of nuclear P-TEFb exist in the transcriptionally active state through association with the bromodomain protein Brd4, which recruits P-TEFb to chromatin templates through interacting with acetylated histones and/or the mediator complex. The recruitment occurs at late mitosis and is essential for promoting early G1 gene expression and cell cycle progression. Thus, through alternatively interacting with its positive and negative regulators, P-TEFb is kept in a functional equilibrium (see figure above). Accumulating evidence indicates that this equilibrium can be dynamically controlled by extracellular signals to modulate the overall levels of active P-TEFb in the cell for optimal gene expression, growth and development. Notably, disrupting 7SK snRNP and shifting the P-TEFb functional equilibrium toward the Brd4-bound, active state can lead to cardiac hypertrophy or mammary epithelial transformation.
We are currently performing structural and functional analyses of the two P-TEFb-containing complexes to study the mechanisms by which P-TEFb activity can be positively or negatively modulated. We are also investigating the signaling pathways that control the formation and disruption of the P-TEFb complexes and the involvement of these pathways in cell growth control, HIV replication/latency reactivation, and oncogenic transformation. Finally, we are identifying and characterizing novel factors that cooperate with P-TEFb to stimulate transcriptional elongation of both HIV and cellular genes.
A capping-independent function of BCDIN3 in stabilizing 7SK snRNA and facilitating the assembly of 7SK snRNP. [Y. Xue, Z. Yang, R. Chen, and Q. Zhou. Submitted]
A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis. [N. He, N.S. Jahchan, E. Hong, M. A. Bayfield, R. J. Maraia, K. Luo, and Q. Zhou (2008). Mol. Cell 29, 588-599]
PP2B and PP1α cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca2+ signaling. [C. Chen, M. Liu, H. Li, Y. Xue, W.N. Ramey, N. He, N. Ai, H. Luo, Y. Zhu, N. Zhou, and Q. Zhou (2008) Genes & Dev. 22, 1356-1368]
Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. [Z. Yang, N. He, and Q. Zhou (2008) Mol. Cell. Biol. 28, 967-976]
Tat competes with HEXIM1 to increase the active pool of P-TEFb for HIV-1 transcription. [M. Barboric, J. H. N. Yik, N. Czudnochowski, Z. Yang, R. Chen, X. Contreras, M. Geyer, B. M. Peterlin, and Q. Zhou (2007) Nuc. Acids Res. 35, 2003-2012]
Modulation of a P-TEFb functional equilibrium for the global control of cell growth and differentiation. [N. He, A. C. Pezda and Q. Zhou (2006) Mol. Cell. Biol. 26, 7068-7076]
The Yin and Yang of P-TEFb regulation: Implications for HIV gene expression and the global control of cell growth and differentiation. [J. H. N. Yik and Q. Zhou (2006) Microbiol. Mol Biol. Rev. 70, 646-659]
Recruitment of P-TEFb for stimulation of transcriptional elongation by bromodomain protein Brd4. [Z. Yang, J. H. N. Yik, R. Chen, M. K. Jang, K. Ozato and Q. Zhou (2005) Mol. Cell 19, 535-545]
A human immunodeficiency virus type 1 Tat-like arginine-rich RNA-binding domain is essential for HEXIM1 to inhibit RNA polymerase II transcription through 7SK snRNA-mediated inactivation of P-TEFb. [J. H. N. Yik, R. Chen, A. C. Pezda, C. S. Samford and Q. Zhou (2004) Mol. Cell. Biol. 24, 5094-5105]
Phosphorylated P-TEFb is tagged for inhibition through association with 7SK snRNA. [R. Chen, Z. Yang and Q. Zhou (2004) J. Biol. Chem. 279, 4153-4160]
Inhibition of P-TEFb (CDK9/cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. [J. H. N. Yik, R. Chen, R. Nishimura, J. L. Jennings, A. J. Link and Q. Zhou (2003) Mol. Cell 12, 971-982]
The 7SK small nuclear RNA inhibits the Cdk9/cyclin T1 kinase to control transcription. [Z. Yang, Q. Zhu, K. Luo, and Q. Zhou (2001) Nature 414, 317-322]
Stimulatory effect of splicing factors on transcriptional elongation. [Y. Fong and Q. Zhou (2001) Nature 414, 929-933]
Last Updated 2009-07-21