Molecular Basis of DNA Specific and Non-Specific Site Recognition by ETS Transcription Factors

ETS 转录因子 DNA 特异性和非特异性位点识别的分子基础

• 批准号: 1411502
• 负责人: Gregory Poon
• 金额: $ 51.04万
• 依托单位: Washington State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1411502&HistoricalAwards=false
• 关键词: Molecular; Basis; DNA; Specific; Non

Genetic information inside the cell is managed by proteins known as transcription factors, which are essential to life. 'ETS' (short for E-26) is a family of related transcription factors found in all multi-celled animals and they participate in a wide range of biological functions in the cell. To perform their functions, ETS proteins must interact with DNA at specific sites identified by the sequence of four chemical constituents in DNA (A, C, G, and T). This research will investigate how ETS proteins recognize their target DNA sites, and in turn inform the broader process by which cells develop and adapt to their biological environment. Knowledge from this project will serve as the basis for training several graduate and undergraduate students, as well as for developing curricular material at Washington State University and Georgia State University. The particular demographics of these institutions stand to benefit significantly from NSF support in STEM disciplines in general and biophysical science in particular.The ETS family of transcription factors is ubiquitous in animals (the Metazoa) and regulates the transcription of large networks of genes. Their biological functions depend on site-specific DNA recognition as determined by a structurally conserved DNA-binding domain (known as the ETS domain). Although ETS domains share strong structural conservation, their amino acid sequences are also highly divergent. Preliminary data on PU.1 and Ets-1, two ETS members that represent the extremes of primary sequence divergence, indicate that this diversity encodes distinctive differences in DNA recognition by ETS members. This project is aimed at delineating the mechanisms of sequence recognition utilized by ETS proteins through the kinetics and coupling of the thermodynamics of site recognition to the solution environment. A major focus of this proposal is to systematically define the diversity among ETS members, using PU.1 and Ets-1 as model systems, under solution conditions that mimic the cellular environment, in which binding sites are embedded within nonspecific DNA and the solution environment is semi-dilute.

细胞内部的遗传信息由称为转录因子的蛋白质管理，这对生命至关重要。 “ ETS”（E-26的缩写）是在所有多细胞动物中发现的一个相关转录因子的家族，它们参与细胞中的广泛生物学功能。为了执行其功能，ETS蛋白必须在由DNA中四个化学成分的序列鉴定出的特定位点与DNA相互作用（A，C，G和T）。这项研究将研究ETS蛋白如何识别其靶DNA位点，进而为细胞发展和适应其生物学环境的更广泛的过程提供信息。该项目的知识将成为培训几名研究生和本科生的基础，以及在华盛顿州立大学和佐治亚州立大学开发课程材料的基础。这些机构的特殊人口统计学将从NSF的一般学科中，尤其是生物物理科学中的NSF支持显着受益。转录因子的ETS家族在动物（后生动物）中无处不在，并调节大型基因网络的转录。它们的生物学功能取决于由结构保守的DNA结合结构域（称为ETS域）确定的位点特异性DNA识别。尽管ETS结构域具有强大的结构保护，但它们的氨基酸序列也有高度分歧。关于PU.1和ETS-1的初步数据，代表主要序列差异极端的两个ETS成员表明，这种多样性编码ETS成员DNA识别的独特差异。该项目旨在描述ETS蛋白通过动力学和位点识别热力学与溶液环境的热力学耦合所使用的序列识别机制。该提案的主要重点是系统地定义ETS成员之间的多样性，使用PU.1和ETS-1作为模型系统，在模仿细胞环境的解决方案条件下，其中结合位点嵌入非特异性DNA中，溶液环境是半径的。