It has become apparent that RNA polymerase II (RNAPII) elongation control plays a major role in regulating transcription throughout development and differentiation of multi-cellular organisms. The process is characterized by the default action of negative elongation factors, including NELF and DSIF that halt transcription of initiated polymerases near promoters. These poised polymerases are either released from the template by TTF2 or other termination factors or are allowed to enter productive elongation through the selective action of the positive elongation factor, P-TEFb. The cyclin dependent kinase activity of P-TEFb is regulated by reversible association with the 7SK snRNP mediated by HEXIM proteins. The main goal of this proposal is to further define the mechanisms utilized to control RNAPII elongation. The approach will employ biochemical and molecular methods in human and mouse cells and in the model organism, Drosophila. In the first aim, the function of P-TEFb and the potential role of premature termination in regulating transcription will be studied. Part of the plan includes in vitro biochemical approaches;however global analyses are planned in which transcription of all genes will be examined using chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq).
The second aim focuses on cellular mechanisms utilized to control P- TEFb and how these may involved in conferring selectivity to the genes activated by P-TEFb. Here again genome wide mapping of P-TEFb regulatory factors will be carried out. In the final aim the roles of the termination factor TTF2 will be addressed. In addition to its role in mitotic repression of transcription elongation, studies will examine its role in transcription coupled DNA repair, premature termination at the 52 end of genes, and in termination following normal 32 end formation. The principle investigator is a professor at the University of Iowa and this project will be carried out in the excellent environment offered by his lab and the facilities in the University of Iowa, College of Medicine.

Public Health Relevance

Project Narrative The proposed research in this application will make a major contribution toward understanding the basic cellular mechanisms that control transcription. It is critical to understand how transcription is regulated because abnormalities in this process are responsible developmental defects, cancer and other pathologies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Sledjeski, Darren D
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University of Iowa
Schools of Medicine
Iowa City
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Liu, Pingyang; Xiang, Yanhui; Fujinaga, Koh et al. (2014) Release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein (snRNP) activates hexamethylene bisacetamide-inducible protein (HEXIM1) transcription. J Biol Chem 289:9918-25
Gu, Jianyou; Babayeva, Nigar D; Suwa, Yoshiaki et al. (2014) Crystal structure of HIV-1 Tat complexed with human P-TEFb and AFF4. Cell Cycle 13:1788-97
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Cheng, Bo; Li, Tiandao; Rahl, Peter B et al. (2012) Functional association of Gdown1 with RNA polymerase II poised on human genes. Mol Cell 45:38-50
Peterlin, B Matija; Brogie, John E; Price, David H (2012) 7SK snRNA: a noncoding RNA that plays a major role in regulating eukaryotic transcription. Wiley Interdiscip Rev RNA 3:92-103
Nguyen, Duy; Krueger, Brian J; Sedore, Stanley C et al. (2012) The Drosophila 7SK snRNP and the essential role of dHEXIM in development. Nucleic Acids Res 40:5283-97
Cojocaru, Marilena; Bouchard, Annie; Cloutier, Philippe et al. (2011) Transcription factor IIS cooperates with the E3 ligase UBR5 to ubiquitinate the CDK9 subunit of the positive transcription elongation factor B. J Biol Chem 286:5012-22

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