Author ORCID Identifier

https://orcid.org/0000-0002-0795-5163

Date of Award

8-13-2019

Degree Type

Closed Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

W. David Wilson

Second Advisor

Gregory M. K. Poon

Third Advisor

Ivaylo N. Ivanov

Abstract

Nucleic acids carry the genetic information that can be passed down through processes that involving the interactions of them with proteins. One of the critical checkpoints of these processes is transcription, where DNA is transcribed to messenger RNA. Transcription factors (TFs) are proteins that regulate the transcription process of genes to messenger RNA. TFs are essential for gene regulation and expression, and too often, these proteins are associated with many diseases, including cancers. Therefore, it is crucial to dissect the fundamental interactions of TF with nucleic acids.

The ETS family of proteins, one of the significant components in gene regulation, are associated with many diseases, including cancers. Members of this family proteins share a unique feature: a conserved DNA binding domain called ETS domain. The ETS domain recognizes DNA sequences specifically at 5’-GGAA/T-3’ and flanking sequences are recognized differently among ETS proteins. Also, the co-structures of ETS proteins-DNA reveal nearly superimposable conformation. Although sharing a conserved binding domain, the role of these proteins is not redundant. The biophysical properties, including how these proteins searching for their target gene sites in the presence of nonspecific competitors in the surrounding environment, remains unclear. This project will focus on better understanding the facilitation mechanisms of ETS TF to support pharmacological control.

In another project, we focus on investigating the selectivity of small molecules toward different structures and sequences of nucleic acids of therapeutic interest. Interactions of these small molecules with different DNA, RNA, and quadruplexes are observed by various biophysical methods, including biosensor surface plasmon resonance, fluorescence spectroscopy, and thermal melting. Altogether, this project aims to understand the structure-function relationship of these selective molecules towards drug development and discovery.

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