Date

May 2012

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Physiology & Pharmacology

Institution

Oregon Health & Science University

Abstract

Genomic DNAs are continuously exposed to a wide variety of DNA-damaging agents generated from both endogenous and exogenous sources. As a consequence, various DNA lesions can be formed. Cells have evolved multiple mechanisms to either repair or tolerate DNA lesions. One of the DNA damage tolerance mechanisms is translesion DNA synthesis (TLS), a process carried out by specialized DNA polymerases (TLS polymerases). TLS polymerases can prevent cancer formation by catalyzing accurate replication bypass of specific DNA lesions and performing DNA repair synthesis, but on different DNA substrates, they may also promote carcinogenesis and chemotherapeutic resistance by introducing mutations in crucial genes during error-prone replication bypass of DNA lesions or performing TLS past DNA lesions induced by chemotherapeutic agents. Research leading to the understanding of the cellular functions of individual TLS polymerase and the development of small molecule inhibitors targeting TLS polymerases that are implicated in carcinogenesis and chemotherapeutic resistance is thus critically important to gain insight into how cancer and chemotherapeutic resistance arise and to discover novel adjunct cancer therapeutics (the functions of each TLS polymerase and its implications for cancer risk and opportunities as therapeutic targets are extensively reviewed in Chapter 1). In this regard, the aim of the first part of the dissertation (Chapter 2) was to discover biochemical functions of the newly discovered DNA polymerase ν in order to elucidate the biological functions of this enzyme. The size, stereochemistry, and location of DNA lesions significantly dictate the identity of DNA polymerases involved in the bypass. Therefore, in order to understand the functions of DNA polymerases, it is essential to investigate the identity of DNA polymerases that cells utilize to process different types of lesions. Given the significance of this research, the aim of the second part of the dissertation (Chapter 3 and Chapter 4) was to identify DNA polymerases involved in the replication bypass of DNA−peptide cross-links. As DNA−peptide cross-links can be formed by linkage through N[superscript 6] position of deoxyadenosine or N[superscript 2] position of deoxyguanosine, resulting in major groove or minor groove lesions, respectively, studies were conducted to investigate DNA polymerases involved in the processing of these two different types of peptide cross-links. One of the TLS polymerases, polymerase κ, is implicated in carcinogenesis and chemotherapy resistance, since it is overexpressed in gliomas and can catalyze TLS past DNA−DNA interstrand cross-links induced by the chemotherapeutic agent, mitomycin C. Thus, this enzyme can serve as an important target for cancer therapy. With this regard, the aim of the third part of the dissertation (Chapter 5) was to identify small molecule inhibitors of pol κ. Collectively, the results presented in this dissertation will significantly move research toward the understanding of the contributions of TLS polymerases to carcinogenesis and chemotherapeutic resistance, as well as the development of novel combination cancer therapeutics to combat cancers.

Identifier

doi:10.6083/M47P8WD2

School

School of Medicine

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