Date of Award

Spring 2023

Document Type

Thesis

Terms of Use

© 2023 Paul C. Seth. All rights reserved. This work is freely available courtesy of the author. It may only be used for non-commercial, educational, and research purposes. For all other uses, including reproduction and distribution, please contact the copyright holder.

Degree Name

Bachelor of Arts

Department

Chemistry & Biochemistry Department

First Advisor

Liliya A. Yatsunyk

Abstract

G-quadruplex (GQ) and i-motif (iM) non-canonical DNA structures can be formed by G- and C-rich sequences within the genome, respectively. GQ and iM DNA play important roles in different biological processes and are promising therapeutic targets. Recently, the first left-handed GQ (LHGQ) was discovered and much remains to be learned about the structure and function of LHGQ DNA.

In this thesis, we investigate the biophysical and structural behavior of two LHGQ-forming sequences from the human genome, from the Human Solute Carrier 1 (SLC) and nuclear receptor binding SET domain (NSD) genes. We found that flanking bases play an important role in determining if a sequence forms LHGQ or right-handed GQ (RHGQ). We also investigated the effect of GQ ligand N-methyl mesoporphyrin IX (NMM) on LHGQ DNA. NMM can partially convert LHGQ structures to RHGQ. We report the structure of the SLC GQ in complex with NMM, which forms a GQ with both left and right-handed subunits. Finally, we present preliminary efforts towards crystallizing an iM from the human platelet derived growth factor gene.

The work in this thesis helps further our understanding of the rules that govern the formation of LHGQ DNA. The SLC+NMM structure represents the second reported right-left hybrid GQ and the first in complex with a ligand. These results are an important step towards the understanding of LHGQ DNA and potential development of drugs to harness the biological power of non-canonical DNA.

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