Control of Transcription in Eukaryotic Cells

真核细胞转录的控制

• 批准号: 7201661
• 负责人: Donal Luse
• 金额: $ 33.75万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201661
• 关键词: Adenoviruses; Affect; Be++ element; Beryllium; Binding; C-terminal; Cells; Complex; DNA; DNA Sequence; DNA-Directed RNA Polymerase; Databases; Distal; Elements; Eukaryotic Cell; Fingers; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Health; Human; In Vitro; Individual; Knowledge; Laboratories; Late Promoters; Location; Modeling; Molecular; Mutation; Nature; Peptide Initiation Factors; Point Mutation; Polymerase; Positioning Attribute; Procedures; Process; Property; Proteins; Public Health; RNA; RNA Polymerase II; RNA Splicing; Rate; Relative (related person); Research; Research Personnel; Role; Site; Staging; Structure; TATA Box; TATA-Box Binding Protein; Testing; Thinking; Transcript; Transcription Factor TFIIB; Transcription Initiation Site; Tube; Work; base; concept; crosslink; human TAF1 protein; insight; mutant; negative elongation factor; novel; positional cloning; promoter; transcription factor; transcription factor TFIIF

DESCRIPTION (provided by applicant): It is increasingly evident that the transition from initiation to transcript elongation by RNA polymerase II is a major regulatory checkpoint in eukaryotic gene expression. During the current support period our laboratory has made significant advances in characterizing this transition. We have devised a working model for promoter clearance, the initial step in this process. Our clearance model includes the novel concept of an important role for transcript initiation factors. We have also demonstrated that a distinct postclearance transition occurs from 25-35 bases downstream of transcription start. Our analysis of the ability of RNA polymerase II to pass through the postclearance stage has suggested new insights into mechanisms through which polymerase can be trapped at this point in transcription. In the current application, we propose four specific aims, through which we will (i) test our initial models for the clearance and postclearance transitions (ii) determine the roles of individual transcription factors in these transitions, and (iii) identify underlying DNA sequences, which have important effects on these transitions. Relevance to Public Health: Many genes whose correct expression is essential for human health are controlled through the extended pausing of the transcriptional machinery at a point just after the transcription of genetic information has initiated. It is not currently known how these "regulated gates" operate. In order to ultimately manipulate these gates for the benefit of human health, it is essential to uncover the molecular mechanisms involved. The research proposed here is aimed at providing this knowledge. The clearance and postclearance transitions which we study are test tube models for the regulatory points observed in the cell.

描述（由申请人提供）：越来越明显的是，通过RNA聚合酶II从起始到转录延长的转变是真核基因表达中的主要调控检查点。在当前的支持期间，我们的实验室在表征这种转变方面取得了重大进展。我们已经设计了启动子清除的工作模型，这是该过程的第一步。我们的清除模型包括转录起始因子的重要作用的新概念。我们还证明了一个明显的后清除转换发生在转录起始点下游25-35个碱基处。我们对RNA聚合酶II通过后清除阶段的能力的分析提出了对聚合酶在转录过程中被困在这一点上的机制的新见解。在当前的应用中，我们提出了四个具体的目标，通过这些目标，我们将（i）测试我们的初始模型的清除和清除后转换（ii）确定在这些转换中的单个转录因子的作用，和（iii）确定潜在的DNA序列，这对这些转换有重要影响。与公共卫生的相关性：许多基因的正确表达对人类健康至关重要，这些基因是通过在遗传信息转录开始后的某个时间点上延长转录机制的暂停来控制的。目前尚不清楚这些“管制闸门”如何运作。为了最终操纵这些门以造福人类健康，揭示所涉及的分子机制至关重要。这里提出的研究旨在提供这方面的知识。我们研究的清除和清除后转换是细胞中观察到的调节点的试管模型。