First Advisor

Justin Courcelle

Term of Graduation

Summer 2023

Date of Publication

9-13-2023

Document Type

Thesis

Degree Name

Master of Science (M.S.) in Biology

Department

Biology

Language

English

Subjects

DNA interstrand crosslink, DNA repair, psoralen-UVA, resistance

DOI

10.15760/etd.3664

Physical Description

1 online resource (vii, 107 pages)

Abstract

DNA interstrand crosslinks are particularly lethal lesions that form in DNA when certain molecules intercalate between complementary strands of DNA and form covalent bonds with both strands. Once formed, these lesions present an absolute block to replication and transcription, ultimately resulting in cell death. Because of this lethality, chemicals that form DNA interstrand crosslinks are found in nature as defensive chemicals produced by plants and microbes. Moreover, crosslinking agents have proven effective the treatment of dysplastic conditions and are often first line chemotherapeutics.

However, cancer cells can become resistant to DNA interstrand crosslinks. Unlike other DNA lesions, the double-stranded nature of interstrand crosslinks prevents utilization of one strand as a template for the other strand’s repair. Several complex models have been proposed for how a cell may repair interstrand crosslinks, typically involving the sequential contribution of multiple repair pathways. However, these models remain speculative, and the capacity for repair is limited, potentially as low as a single lesion in Escherichia coli, making the question of how cells acquire crosslink resistance a clinically and intellectually important one to address.

In this thesis, I investigate how crosslink resistance develops. In Chapter I, I review historical studies on crosslinking agents and possible mechanisms by which resistance to these agents could arise. In Chapter II, I identify causal mutations in rpoA and acrR leading to psoralen-UVA resistance E. coli and begin to characterize their mechanism of action. In Chapter III, I characterize the regulation of AcrAB-TolC, one of the primary drivers of resistance, and describe how global regulatory elements impact its expression and influence resistance to psoralen-UVA. Finally, in Chapter IV, I conclude with the implications of these findings and suggest future avenues of research.

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Persistent Identifier

https://archives.pdx.edu/ds/psu/40891

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