The RNA polymerase II core promoter is a structurally and functionally diverse regulatory element that lies at the center of the transcription process. For instance, the presence or absence of a specific core promoter motif, such as the TATA or DPE, can be required for the proper regulation of a gene. Notably, the lack of sufficient knowledge of the core promoter is a critical limiting factor in the understanding of transcriptional regulatory mechanisms. The proposed research is designed to advance the analysis of eukaryotic transcription in important new directions. One key area is the study of the TRF2-based transcription system, particularly in conjunction with the TCT core promoter motif. TRF2 (TBP-related factor 2) is conserved among metazoans, but unlike TBP (TATA box-binding protein), TRF2 does not bind to the TATA box. Transcription of TATA-less TCT-dependent core promoters (nearly all core promoters that contain the TCT motif are TATA-less) requires TRF2 but not TBP. Notably, purified TRF2 functions as a transcription factor on TCT-dependent promoters in vitro. It thus appears that there is a TRF2-based transcription system that is distinct from the well-known TBP/TFIID-based transcription system.
Specific Aim 1 seeks to determine the composition of TRF2 complexes and to analyze the functions of TRF2 and TRF2-associated proteins via cell- based and genetic approaches.
Specific Aim 2 proposes to identify TCT-specific basal transcription factors that are required, in addition to TRF2, for TCT-dependent transcription. The analysis of the factors that constitute the TRF2-based transcription system would be an important contribution to transcription. Moreover, some TRF2-associated proteins and TCT- specific basal factors may serve as a link to the regulation of the ribosomal protein gene network. This proposal also seeks to expand the knowledge of the core promoter itself.
Specific Aim 3 is directed toward the exploration and discovery of new core promoter motifs. The proposed studies in this grant should provide valuable new information on novel transcription systems as well as new core promoter motifs and types. Principal Investigator: Kadonaga, James T. 2R01 GM041249-26 2.

Public Health Relevance

These studies will lead to a better understanding of gene regulation, and will therefore provide new insights into the molecular basis and potential treatment of human diseases, such as many forms of cancer, that involve abnormalities in the control of the expression of genes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Sledjeski, Darren D
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University of California San Diego
Schools of Arts and Sciences
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Duttke, Sascha H C (2014) RNA polymerase III accurately initiates transcription from RNA polymerase II promoters in vitro. J Biol Chem 289:20396-404
Kedmi, Adi; Zehavi, Yonathan; Glick, Yair et al. (2014) Drosophila TRF2 is a preferential core promoter regulator. Genes Dev 28:2163-74
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Wang, Yuan-Liang; Duttke, Sascha H C; Chen, Kai et al. (2014) TRF2, but not TBP, mediates the transcription of ribosomal protein genes. Genes Dev 28:1550-5
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Theisen, Joshua W M; Gucwa, James S; Yusufzai, Timur et al. (2013) Biochemical analysis of histone deacetylase-independent transcriptional repression by MeCP2. J Biol Chem 288:7096-104
Juven-Gershon, Tamar; Kadonaga, James T (2010) Regulation of gene expression via the core promoter and the basal transcriptional machinery. Dev Biol 339:225-9
Parry, Trevor J; Theisen, Joshua W M; Hsu, Jer-Yuan et al. (2010) The TCT motif, a key component of an RNA polymerase II transcription system for the translational machinery. Genes Dev 24:2013-8
Theisen, Joshua W M; Lim, Chin Yan; Kadonaga, James T (2010) Three key subregions contribute to the function of the downstream RNA polymerase II core promoter. Mol Cell Biol 30:3471-9

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