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Control of RNA polymerase I transcription initiation and elongation

RNA 聚合酶 I 转录起始和延伸的控制

基本信息

批准号：
8758157
负责人：
David Alan Schneider
金额：
$ 30.87万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8758157
关键词：
Accounting Affect Anabolism Biogenesis Biological Assay Cell Proliferation Cells Cellular biology Chemotherapy-Oncologic Procedure Complex Coupled DNA DNA Polymerase I DNA Polymerase II DNA Sequence Data Data Set Elements Enzymes Equilibrium Eukaryota Eukaryotic Cell Event Fibrinogen Foundations Funding Future Gene Mutation Genetic Transcription Goals In Vitro Indium Individual Kinetics Learning Link Malignant Neoplasms Measurement Measures Modeling Mutation Nuclear Nucleotides Play Point Mutation Polymerase Pre-Clinical Model Process Property Publishing RNA Processing RNA Sequences Reaction Regulation Research Ribosomal DNA Ribosomal RNA Ribosomes Role Site Study models System Testing Therapeutic Intervention Time Trans-Activators Transcript Transcription Elongation Transcription Initiation Variant cancer cell cancer therapy cell growth in vitro Assay in vivo insight mutant neoplastic cell prevent public health relevance reconstitution research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Ribosome synthesis is directly linked to the rates of cell growth and proliferation. Transcription of the ribosomal DNA (rDNA) by RNA polymerase I (Pol I) is the first, rate-limiting step in ribosome assembly. In rapidly growing cells, transcription by Pol I accounts for more than 60% of all cellular transcription. The overall hypothesis of this project is that Pol I has evolved sevral unique features that support efficient, robust activity and these features are logical targets for selective inhibition of ribosome synthesis. To test this hypothesis and expand the understanding of ribosome synthesis in eukaryotic cells, this project will focus on three key aspects of rDNA transcription: 1) enzymatic features of Pol I 2) trans-acting factors that control Pol I and 3) sequences in the rDNA that affect transcription elongation and rRNA processing. Pol I has evolved enzymatic properties that suit its cellular role. For example, recent data suggest that the rate-limiting steps in Pol I versus Pol II transcription elongation may differ. These differences could serve as targets for selective inhibition of ribosome biosynthesis. This project will employ rapid mixing kinetic measurements and modeling of resulting data sets to quantitatively describe Pol I transcription elongation. Additional studies will define the elemental steps in transcription elongation that are influenced by specific subunits or domains of the RNA polymerase. Pol I transcription requires trans-acting factors to support the rate of transcription observed in vivo. To test this hypothesis, contributions of three factors to Pol I activity will be characterized in ivo and in vitro. These three factors associate with the rDNA in vivo and have been implicated previously in transcription by Pol II. This study will identify new roles for evolutionary conserve transcription factors in ribosome biogenesis. Transcription elongation by Pol I is functionally coupled to rRNA processing. Sequence elements in the rDNA may directly influence transcription elongation efficiency and nascent rRNA processing. To test this hypothesis, these elements will be identified using single-turnover elongation rate assays in vitro and sequencing of native- elongating transcripts isolated from growing cells. Mutation of identified pause sites and characterization of ribosome assembly will determine the role of these sequences in rRNA processing. This aim will identify the contribution of DNA elements to the observed orchestration of transcription and rRNA processing. In eukaryotes, several RNA processing events are thought to occur during transcription and this system may serve as a model for the study of these complicated co-transcriptional processes. Transcription by Pol I is a validated target for inhibition of cancer cell proliferation. In order to control cell proliferation via inhibition of Pl I, a detailed understanding of the unique features of rDNA transcription must be established. This study will lay the foundation for ongoing and future projects aimed at selective inhibition of Pol for cancer chemotherapy.

描述（由申请人提供）：