Acute and chronic hypoxia exists within the microenvironment of solid tumours and drives therapy resistance, genetic instability and metastasis. Despite its importance in solid tumour progression, very little is known regarding the functional consequences of hypoxia-mediated changes in the expression of DNA repair proteins. I studied the relationship between hypoxia and DNA repair using a prolonged chronic hypoxic gas treatment model in a variety of human tumour cell lines to mimic the dynamic state of proliferation and DNA repair in cells distant from the tumour blood vasculature. I observed decreased expression of homologous recombination (HR) and base excision repair (BER) proteins due to a novel mechanism involving decreased protein synthesis. Error-free HR was suppressed 3-fold under 0.2% O2 as measured by the DR-GFP reporter system and functional BER was impaired as assessed with a functional glycosylase assay. This decrease in protein expression and function resulted in increased sensitivity to the DNA damaging agents MMC, cisplatin, H2O2 and MMS. Additionally, chronically hypoxic cells were relatively radiosensitive (OER = 1.37) when compared to acutely hypoxic or anoxic cells (OER = 1.96 - 2.61). As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, I evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. I observed increased clonogenic killing in HR-deficient hypoxic cells following inhibition or depletion of PARP1. PARP-inhibited hypoxic cells accumulated γH2AX foci consistent with an accumulation of collapsed replication forks. Additionally, tumour xenografts exposed to PARP1 inhibition showed increased γH2AX and cleaved caspase-3 expression in hypoxic subregions with suppressed RAD51 protein expression and decreased ex vivo clonogenic survival. I conclude that persistent down-regulation of DNA repair components by the microenvironment could result in faulty DNA repair with significant implications for therapeutic response and genetic instability in human cancers. Specifically, hypoxic cells may be sensitized to PARP inhibitors and other agents targeting repair pathways down-regulated by hypoxia as a consequence of microenvironment-mediated “contextual synthetic lethality”.

Thesis (Ph.D.)--University of Delaware, 2008. / Principal faculty advisor: Eric B. Kmiec, Dept. of Biological Sciences. Includes bibliographical references.

Thesis (M.S.)--University of Massachusetts Amherst, 2008. / Includes bibliographical references (p. 61-62).

Thesis (Ph.D.)--University of Delaware, 2008. / Principal faculty advisor: Eric B. Kmiec, Dept. of Biological Sciences. Includes bibliographical references.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1991. / Vita. Abstract. Includes bibliographical references (leaves 70-75). Also available via the Internet.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xix, 295 p.; also includes graphics (some col.) Includes bibliographical references (p. 277-295). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--Michigan State University. Pathology, 2008. / Title from PDF t.p. (Proquest, viewed on Aug. 25, 2009) Includes bibliographical references (p. 109-126). Also issued in print.

Thesis--University of Florida. / Description based on print version record. Typescript. Vita. Includes bibliographical references (leaves 72-79).

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Human Genetics. Title from resource description page. Includes bibliographical references.

Thesis (Ph. D.)--Illinois State University, 1990. / Title from title page screen, viewed November 30, 2005. Dissertation Committee: Arlan Richardson (chair), Herman E. Brockman, Alan Katz, Lynne A. Lucher, David Weber. Includes bibliographical references (leaves 120-131) and abstract. Also available in print.