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.

项目总结/摘要 RNA聚合酶II（Pol II）延伸控制在调节转录中起主要作用 在多细胞生物体的发育和分化过程中。该过程 其特征是负延伸因子（包括NELF和DSIF）的默认作用， 在启动子附近终止启动的聚合酶的转录。这些启动子近端暂停 聚合酶或者通过TTF 2或其它终止因子从模板释放，或者 允许通过正伸长的选择性作用进入生产伸长 因子P-TEFb。P-TEFb的细胞周期蛋白依赖性激酶活性由可逆的 与HEXIM蛋白介导的7SK snRNP的结合。该提案的主要目标是 为了进一步限定用于控制Pol II伸长的机制， 通过核小体转录。我们将使用新开发的生物化学方法， 全球技术，以阐明机制，使转录通过染色质，作用 暂停Pol II在维持启动子可及性中的作用，以及细胞周期蛋白依赖性激酶和 PAF 1复合物在延长控制中的作用。我们还将确定如何控制键的延伸率 因子P-TEFb受7SK snRNP调节，并检查mRNA帽甲基化的作用 伸长控制。主要研究者是爱荷华州大学的教授， 项目将在他的实验室提供的良好环境和设施中进行。 爱荷华州大学卡弗医学院。这里提出的研究应该大大 增加我们对控制基因表达的机制的理解，这将有助于 解释了发生在癌症中的转录失调和延长的劫持 艾滋病病毒控制机器。