Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry, Organic

Date of Defense

10-15-2022

Graduate Advisor

James K. Bashkin

Committee

James S. Chickos

Alexei V. Demchenko

Eike B. Bauer

Abstract

Pyrrole-imidazole polyamides (PIPs) are nanomolecular compounds designed to fit in the tight space of DNA minor grooves. As analogs of Netropsin and Distamycin A, PIPs are specifically designed to recognize the base pairs of DNA sequences. PIPs have many biological applications, such as regulating gene expression, biochemistry pathway regulations, and suppressing the development of cancer cells. SETMAR gene is the chimeric fusion of the SET domain with the mariner transposase. Its protein (Metnase) has functions involving DNA repairs in the NHEJ pathway, regulating gene expression, DNA decatenation, etc. Despite not having an active transposable element, SETMAR still has an unknown function in cancer development. Some reports show that SETMAR mRNA increases by 70 times in glioblastoma cancer cells, as well as in other types of cancer cells. Understanding the mechanism of SETMAR in the cancer cell is essential, and suppressing the overexpression of SETMAR is a goal for anti-cancer development.

Our goal in this project was to design new sequences of polyamides based on the previously discovered conserved SETMAR gene binding locations at the TIR (Terminal Inverted Repeat) sequence. We have tested the binding affinity of our polyamides with our collaborators' assistance through surface plasmon resonance, fluorescence anisotropy, and competitive DNA binding. We modified the polyamide sequence by substituting pyrrole with β-alanine to reduce the rigidity of the continuous chain of heterocycles and introduced an additional charge to the N-terminus of our polyamide sequences.

Download

Share

COinS