Price, David - University of Iowa - Department of Biochemistry

个人简介

Education BS, Dept of Chemistry, North Carolina State University PhD, Dept of Chemistry, Florida State University Post Doctoral Fellow, Dept of Biology, Caltech Post Doctoral Fellow, Dept of Chemistry, Caltech

研究领域

Understanding how mRNA levels are controlled in eukaryotes requires dissection of the intricate pathways responsible for the synthesis and processing of mRNA. Previously, we uncovered evidence for a regulatory process in higher eukaryotes that controls the fraction of initiated RNA polymerase II (Pol II) molecules able to produce full-length mRNAs. We then 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 eukaryotic gene expression and thus P-TEFb function is highly regulated. We are currently engaged in projects to more fully understand the mechanisms utilized in Pol II elongation control. In this regard we continue to employ viruses that infect human cells because they reveal unexpected ways to exploit elongation control. For example, the AIDS retrovirus, HIV, encodes a protein, Tat, that enables the virus to take over the control of P-TEFb. We have begun to work with Jeff Meier (Internal Medicine) to examine the transcriptional life cycle of the human cytomegalovirus (HCMV). Transcription and RNA processing are temporally and mechanistically intertwined and we persist in investigating how the two processes affect each other. We are also collaborating with Donal Luse (Cleveland Clinic) concerning the interplay of the elongation control machinery and chromatin. We employ in vitro assays in which the function of specific factors can be evaluated and have recently taken advantage of isolated nuclei to accurately report on transcription and RNA processing in cells. Using CRISPR genome editing technology and small molecules that inhibit or degrade specific proteins we can manipulate cells and follow up with nucleotide-resolution bioinformatics analysis of the pattern of transcription in the isolated nuclei. These and other innovative techniques provide us with unique opportunities to advance our understanding of the molecular mechanisms that control gene expression. The studies are useful in the development of therapies for viral infections and cancer.

近期论文

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Tan, J. L., Fogley, R. D., Flynn, R. A., Ablain, J., Yang, S., Saint-André, V., Fan, Z. P., Do, B. T., Laga, A. C., Fujinaga, K., Santoriello, C., Greer, C. B., Kim, Y. J., Clohessy, J. G., Bothmer, A., Pandell, N., Avagyan, S., Brogie, J. E., van Rooijen, E., Hagedorn, E. J., Shyh-Chang, N., White, R. M., Price, D. H., Pandolfi, P. P., Peterlin, B. M., Zhou, Y., Kim, T. H., Asara, J. M., Chang, H. Y., Young, R. A. & Zon, L. I. (2016). Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma.. Molecular cell, 62(1), 34-46. DOI: 10.1016/j.molcel.2016.03.013. Nilson, K. A., Guo, J., Turek, M. E., Brogie, J. E., Delaney, E., Luse, D. S. & Price, D. H. (2015). THZ1 Reveals Roles for Cdk7 in Co-transcriptional Capping and Pausing.. Molecular cell, 59(4), 576-87. DOI: 10.1016/j.molcel.2015.06.032. Guo, J., Li, T., Schipper, J., Nilson, K., Fordjour, F., Cooper, J., Gordân, R. & Price, D. (2014). Sequence specificity incompletely defines the genome-wide occupancy of Myc. Genome Biol, 15(10), 482. Gu, J., Babayeva, N. D., Suwa, Y., Baranovsky, A. G., Price, D. H. & Tahirov, T. H. (2014). Crystal structure of HIV-1 Tat complexed with human P-TEFb and AFF4. Cell Cycle. Fowler, T., Ghatak, P., Price, D. H., Conaway, R., Conaway, J., Chiang, C. M., Bradner, J. E., Shilatifard, A. & Roy, A. L. (2014). Regulation of MYC Expression and Differential JQ1 Sensitivity in Cancer Cells. PLoS One, 9, e87003. DOI: 10.1371/journal.pone.0087003. Guo, J., Turek, M. E. & Price, D. H. (2014). Regulation of RNA polymerase II termination by phosphorylation of Gdown1. J Biol Chem, [Epub ahead of print]. Davis, M. A., Guo, J., Price, D. H. & Luse, D. S. (2014). Functional interactions of the RNA polymerase II-interacting proteins Gdown1 and TFIIF. J Biol Chem, [Epub ahead of print]. Liu, P., Xiang, Y., Fujinaga, K., Bartholomeeusen, K., Nilson, K., Price, D. H. & Peterlin, B. M. (2014). Release of P-TEFb from 7SK snRNP activates HEXIM1 transcription. J Biol Chem, [Epub ahead of print]. Van Duyne, R., Guendel, I., Jaworski, E., Sampey, G., Klase, Z., Chen, H., Zeng, C., Kovalskyy, D., El Kouni, M. H., Lepene, B., Patanarut, A., Nekhai, S., Price, D. H. & Kashanchi, F. (2013). Effect of mimetic CDK9 inhibitors on HIV-1-activated transcription. Journal of molecular biology, 425(4), 812-29. Guo, J., Price, D. H. (2013). RNA polymerase II transcription elongation control. Chem Rev, 113(11), 8583-603.