Defense Date

4-3-2007

Availability

Worldwide Access

Submission Type

thesis

Degree Name

MS

Department

Medicinal Chemistry

School

Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences

Committee Chair

Steven Firestine

Committee Member

Aleem Gangjee

Committee Member

David A. Johnson

Committee Member

Marc W. Harrold

Keywords

DNA bending, TFO, transcription regulation

Abstract

The conformation of DNA has been shown to play an important role in the regulation of gene expression. A consequence of this finding is that agents that alter the conformation of DNA should also affect the regulation of gene expression. To explore this, we used tethered-triple helix oligonucleotides (TFO) to bend DNA. We show that the expression of a luciferase gene is regulated by the presence of an induced DNA bend. Bends occurring in the same orientation as RNA polymerase binding result in a 93% increase in expression. In contrast, bends induced in that opposite direction resulted in a 51% decrease in expression. These results prompted us to investigate the synthesis of three small molecules with the potential to induce a sequence selective bend in DNA. These studies revealed that the compounds were able to induce a DNA bend counter to an intrinsic bend present in a target DNA fragment.

Format

PDF

Language

English

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