RNA polymerase II elongation control

RNA 聚合酶 II 延伸控制

• 批准号: 9895832
• 负责人: David H Price
• 金额: $ 58.83万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895832
• 关键词: Biochemical; Chromatin; Complex; Cyclin-Dependent Kinases; DNA Polymerase II; DNA-Directed RNA Polymerase; Defect; Development; Disease; Environment; Gene Expression; Genetic Transcription; Goals; HIV; HIV Infections; Iowa; Malignant Neoplasms; Mediating; Medicine; Methods; Methylation; Nucleosomes; Organism; Play; Polymerase; Positive Transcriptional Elongation Factor B; Process; Properdin; Proteins; Research Personnel; Role; Small Nuclear Ribonucleoproteins; Techniques; Universities; college; factor EF-P; mRNA capping; negative elongation factor; professor; promoter; termination factor

Project Summary/Abstract RNA polymerase II (Pol II) 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 promoter-proximal paused 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 Pol II elongation and to enable efficient transcription through nucleosomes. We will use newly developed biochemical methods and global techniques to elucidate mechanisms enabling transcription through chromatin, the role of paused Pol II in maintaining promoter accessibility, and the role of cyclin dependent kinases and the PAF1 complex in elongation control. We will also determine how the key elongation control factor P-TEFb is regulated by the 7SK snRNP and examine the role of mRNA cap methylation in elongation control. 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, Carver College of Medicine. The studies proposed here should significantly increase our understanding of mechanisms controlling gene expression and this will be useful in explaining the dysregulation of transcription that occurs in cancer and the hijacking of elongation control machinery by the AIDs virus.

项目摘要/摘要 RNA聚合酶II（POL II）伸长控制在调节转录中起主要作用 整个多细胞生物的发育和差异。该过程是 以负伸长因素的默认作用为特征，包括NELF和DSIF 启动子附近的启动聚合酶的停止转录。这些启动子暂停 聚合酶要么由TTF2从模板中释放，要么是其他终止因素，或者是 允许通过阳性伸长的选择性作用进入生产性伸长率 因子，p-Tefb。 P-TEFB的细胞周期蛋白依赖性激酶活性由可逆调节 与Hexim蛋白介导的7SK SNRNP相关。该提议的主要目标是 进一步定义用于控制pol II伸长的机制并启用有效的机制 通过核小体转录。我们将使用新开发的生化方法和 阐明通过染色质转录的机制的全球技术， 暂停了Pol II在维持启动子的可及性方面，以及细胞周期蛋白依赖性激酶的作用和 伸长控制中的PAF1复合物。我们还将确定如何控制关键的伸长率控制 因子P-TEFB受7SK SNRNP调节，并检查mRNA帽甲基化的作用 在伸长控制中。主要调查员是爱荷华大学的教授， 项目将在他的实验室和设施中提供的绝佳环境中进行 爱荷华大学卡弗医学院。这里提出的研究应大量 增加我们对控制基因表达的机制的理解，这将在 解释在癌症中发生转录的失调和伸长的劫持 通过艾滋病病毒控制机械。