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Transcription factor positioning and function during promoter opening

启动子开放过程中转录因子的定位和功能

基本信息

批准号：
8051908
负责人：
MICHAEL S BARTLETT
金额：
$ 13.09万
依托单位：
PORTLAND STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2011-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8051908
关键词：
Active Sites Address Affect Amino Acids Archaea Aromatic Amino Acids Bacterial Typing Cells Complex Congenital Abnormality DNA DNA Maintenance DNA Sequence DNA mapping DNA-Directed RNA Polymerase Defect Development Disease Environment Evolution Fingers Gene Expression Gene Expression Process Genes Genetic Transcription Genome Health Hereditary Disease Homologous Gene Human Hybrids Life Maintenance Malignant Neoplasms Modeling Movement Mutagenesis Mutation Organism Outcome Phenylalanine Play Positioning Attribute Process Proteins RNA Polymerase II Regulation Relative (related person)Research Proposals Rest Role Single-Stranded DNA Structure Surface System Testing Transcription Factor TFIIB Transcription Initiation Travel Tryptophan Tyrosine Work developmental disease insight novel polypeptide promoter public health relevance research study role model transcription factor transcription factor TFIIE

项目摘要

DESCRIPTION (provided by applicant): Differences on the constraints guiding the evolution of regulation in these domains of life. This research proposal seeks an understanding of the roles for transcription factors in assisting initiation of gene expression by RNA polymerases (RNAPs). It specifically addresses the position and function of two transcription factors, TFB and TFE, structurally and functionally conserved from archaea to humans. The significance of understanding the position and function of archaeal transcription factors to human health rests in the likelihood that human homologs of these transcription factors have the same or very similar functions that are required for proper gene expression, and that perturbations that alter their function or the function of interacting partners can cause diseases of gene dysregulation, including cancer and congenital developmental defects. This work aims to identify the structural interactions that underlie the process of transcription initiation. We expect to gain novel insight into the fine-scale positioning and function of TFB and TFE. In particular, we will have enough information about the positioning of the B-finger to create models for its function in the dynamic process of initiation, and we will also be able to test the effects of specific mutations in the B-finger using these models. We will also gain unprecedented insight into the orientation of the TFE polypeptide in transcription complexes, and will be able to identify putative interacting surfaces that can also be mutagenized and tested to elucidate function in more detail. Results from the experiments proposed here will help to drive a deeper understanding not just of the archaeal mechanism, but also of the roles for TFIIB and TFIIE (or, more specifically, the N-terminus of its alpha subunit) in transcription initiation by eukaryotic RNAP II. We also anticipate our work will help facilitate a comparison between eukaryotic-type and bacterial promoter opening mechanisms. While very different transcription factors (TFB and TFE versus sigma) assist their respective RNAPs in the process, in the end, the outcome, an elongating RNA polymerase, is geometrically the same from the point of view of the transcription bubble, the RNA-DNA hybrid, and the active site itself. When the functional similarities and differences between the two systems are understood better, we will be poised to better understand the effects of these. PUBLIC HEALTH RELEVANCE In human developmental disorders and cancers, changes in specific parts of the genome cause alterations in gene expression; as a consequence of this, cells may lose the ability to cooperate with their neighbors, and birth defects, genetic disease, or cancer can result. A detailed understanding of how these changes affect the gene expression process is incomplete, in part because the process of gene expression is not completely understood. To address this problem, I am studying the detailed mechanism of gene expression in a group of organisms called the archaea. Archaea have a transcription system that is very similar to the transcription system in human cells, though much less complicated. Therefore, they provide a relatively simple model for understanding the basic mechanisms of human gene expression.

描述(由申请人提供)：在指导这些生活领域的监管演变的约束方面的差异。这项研究计划试图了解转录因子在协助RNA聚合酶(RNAP)启动基因表达中的作用。它专门讨论了两个转录因子TFB和TFE的位置和功能，从古生物到人类，它们在结构和功能上都是保守的。了解古细菌转录因子的位置和功能对人类健康的意义在于，这些转录因子的人类同源物可能具有正常基因表达所需的相同或非常相似的功能，并且改变它们的功能或相互作用伙伴的功能的扰动可以导致基因失调的疾病，包括癌症和先天性发育缺陷。这项工作旨在确定转录启动过程中的结构相互作用。我们期望对TFB和TFE的精细定位和功能有新的见解。特别是，我们将有足够的信息关于B手指的位置，以建立其在启动的动态过程中的功能模型，我们还将能够使用这些模型来测试B手指特定突变的影响。我们还将前所未有地深入了解TFE多肽在转录复合体中的定位，并将能够识别假定的相互作用表面，这些表面也可以被突变和测试，以更详细地阐明功能。这些实验的结果不仅有助于加深对古生物机制的理解，也有助于加深对TFIIB和TFIIE(或更具体地说，其阿尔法亚基的N端)在真核细胞RNAP II转录启动中的作用的理解。我们还预计我们的工作将有助于比较真核类型和细菌启动子的开放机制。虽然非常不同的转录因子(TFB和TFE与sigma)在这一过程中帮助它们各自的RNAP，但最终，从转录泡、RNA-DNA杂交和活性部位本身的角度来看，结果是延长的RNA聚合酶在几何上是相同的。当我们更好地了解这两个系统之间的功能异同时，我们就可以更好地了解这些影响。与公共健康相关在人类发育障碍和癌症中，基因组特定部分的变化会导致基因表达的变化；结果是，细胞可能失去与邻居合作的能力，从而可能导致出生缺陷、遗传病或癌症。对这些变化如何影响基因表达过程的详细了解是不完整的，部分原因是对基因表达过程还没有完全了解。为了解决这个问题，我正在研究一组被称为古生菌的生物体中基因表达的详细机制。古生菌的转录系统与人类细胞的转录系统非常相似，尽管复杂得多。因此，它们为理解人类基因表达的基本机制提供了一个相对简单的模型。