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Department of Biochemistry

Research Interests

Understanding how mRNA levels are controlled in eukaryotes requires dissection of the intricate pathway responsible for the synthesis and processing of mRNA. Previously, we obtained evidence for a general eukaryotic transcription regulatory process that controls the number of polymerase molecules that are able to produce full-length mRNAs. We discovered P-TEFb, a cyclin dependent kinase that plays a key role in this elongation control process. The kinase activity of P-TEFb is generally required for expression of eukaryotic genes and recent results indicate that cells carefully regulate P-TEFb through an unusual association with a small RNA called 7SK. We are currently engaged in projects to uncover the mechanism of P-TEFb function and how it is regulated. The AIDS virus, HIV, encodes a protein, Tat, that enables the virus to take over the control of P-TEFb. We are studying Tat-transactivation and are examining the mechanism of action of drugs that target this critical step in the HIV life cycle. We have shown that one such drug, flavopiridol, targets the kinase activity of P-TEFb and this can block the growth of cancer cells and at lower concentrations block HIV replication.

Our basic research on factors that influence elongation by RNA polymerase II also uncovered the first RNA polymerase II termination factor, TTF2. Current results indicate that this factor plays a role in mitotic repression of transcription elongation and, perhaps, DNA repair. We have developed new in vitro assays to study the mechanistic details of the interaction of RNA processing machinery with the transcription complex. Overall, we use biochemical, molecular and cellular techniques to advance our understanding of the control of RNA polymerase II elongation and how that process influences RNA processing, HIV replication and cancer growth.

Recently, we began global studies of P-TEFb function. Using ChIP-chip and ChIP-seq we are mapping the positions of RNA polymerase II and elongation factors across the human genome.

Recent Publications

Cheng, B and Price, D.H. (2008) Analysis of Factor Interactions with RNA Polymerase II Elongation Complexes Using a New Electrophoretic Mobility Shift Assay. Nucl. Acids Res. doi: 10.1093/nar/gkn630.

Krueger, B.K., Jeronimo, C., Roy, B.B., Bouchard, A., Barrandon,C., Byers, S.A., Searcey, C.E., Cooper, J.J., Bensaude, O., Cohen, E.A., Coulombe, B, and Price, D.H. (2008) LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated Nucl. Acids Res. 36:2219-29.

Price, D.H. (2008) Poised polymerases: on your mark…get set…go!, Mol. Cell 30:7-10.

Jeronimo, C., Forget, D., Bouchard, A., Li, Q., Chua, G., Poitras, C., Thérien, C., Bergeron, D., Bourassa, S., Greenblatt, J., Chabot, B., Poirier, G.G., Hughes, T.R., Blanchette, M., Price, D.H. and Coulombe, B. (2007) Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Mol. Cell 27: 262-74

Sedore, S.C., Byers, S.A., Biglione, S., Maury, W.J., and Price, D.H. (2007) Manipulation of P-TEFb control machinery by HIV: Recruitment of P-TEFb from the large form by Tat and binding of HEXIM1 to TAR. Nuc. Acids. Res. 35:4347-58.

Cheng, B. and Price, D.H. (2007) Properties of RNA polymerase II elongation complexes before and after the P-TEFb-mediated transition into productive elongation. J. Biol. Chem. 282:21901-12.

Li, Q., Cooper, J.J., Altwerger, G.H., Feldkamp, M.D., Shea, M.A., and Price, D.H. (2007) HEXIM1 is a promiscuous double-stranded RNA binding protein and interacts with RNAs in addition to 7SK in cultured cells. Nuc. Acids. Res. 25:2503-2512.

Peterlin, B.M, Price, D.H (2006) Controlling the elongation phase of transcription with P-TEFb Mol. Cell 23:297-305.

Barboric, M., Kohoutek, J., Price, J.P., Blazek, D., Price, D.H., Peterlin, B.M. (2005) Interplay between 7SK snRNA and oppositely charged regions in HEXIM1 direct the inhibition of P-TEFb. EMBO J. 24:4291-303.

Palangat M, Renner D.B., Price D.H., Landick R. (2005) A negative elongation factor for human RNA polymerase II inhibits the anti-arrest transcript-cleavage factor TFIIS. Proc. Natl. Acad. Sci. U S A. 102:15036-41.

Adamson, T.E., Shutt, D.C., and Price, D.H. (2005) Functional coupling of cleavage and polyadenylation with transcription of mRNA. J. Biol. Chem. 280:32262-71.

Affiliations

Biochemistry Department
Molecular and Cellular Biology Program

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