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

点击翻译按钮获取中文摘要

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.