Date of Award

1-1-2011

Document Type

Campus Access Thesis

Department

College of Pharmacy

Sub-Department

Pharmaceutical Science

First Advisor

Mike Wyatt

Abstract

The effect of folate on cancer prevention has been examined in a number cellular and epidemiological studies, yet unanswered questions remain. For example, recent studies raised questions regarding the timing of folic acid supplementation. High folate status tends to have a protective effect against cancer and low folate status tends to be pro carcinogenic. However, folic acid supplementation may paradoxically accelerate the growth of pre-existing cancer. Folate is required for faithful DNA synthesis because a folate derivative is utilized to synthesize an important DNA precursor, thymidylate. Deprivation of thymidylate causes the incorporation of uracil into DNA, which is removed by Base Excision Repair (BER). The role of BER in the cellular response to folate deficiency was studied in the breast cancer cell line, MDA-MB-231, using polymerase beta; (Pol beta;) knockdown and add back sublines. The results showed that Pol beta; status affected the amount of DNA damaged caused by folate deficient conditions. Pol beta; status also affected subcellular localization of another BER enzyme, Poly-ADP-ribose polymerase (PARP1). Moreover, the study also found an increase in sensitivity to PARP inhibition under folate deficient conditions. Taken together, the results demonstrate that BER status influences the sensitivity of cancer cells to folic acid deficiency, and suggests that targeting BER enzymes might heighten sensitization of cancer cells to chemotherapy.

Rights

© 2011, Virginia Noxon

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