Theses and Dissertations

Issuing Body

Mississippi State University

Advisor

Wise, Dwayne

Committee Member

Reichert, Nancy

Committee Member

Donaldson, R. Janet

Committee Member

Coats, S. Karen

Committee Member

Ryan, L. Peter

Date of Degree

5-1-2011

Document Type

Dissertation - Open Access

Degree Name

Doctor of Philosophy

College

College of Arts and Sciences

Department

Department of Biological Sciences

Abstract

Oxidative stress (OS) occurs when DNA repair mechanisms are overcome by the amount of single and double strand DNA breaks caused by an accumulation of reactive oxygen species (ROS). Genomic instability (GI) by microsatellite instability (MSI) accumulation is characterized by changes in DNA single tandem repeats (STR) as a direct result of ROS. Deregulation of DNA repair and tumor suppressor pathways have been described as causes of tumor progression and metastasis. Studies in mammals have focused on GI and the implications of increased mutation frequency due to accumulation of MSI leading to development of diseases, including infertility and cancer. Ovarian cancer is a deadly disease displaying the highest mortality rate among gynecological cancers. Hereditary ovarian cancer displays GI that can be established early in primordial germinal cells (PCGs) development and migration across the genital ridge, where PGCs are exposed to ROS damage. The hypothesis of this study was ROS-induced GI is marked by the accumulation of MSI on repetitive sequences of DNA that override DNA repair, tumor suppressor and redox homeostasis pathways. In this study, we induced ROS in human ovarian cell lines by hydrogen peroxide (H2O2) exposure, as well as evaluated mouse PGCs to determine whether MSI occurs in specific regions of human and mouse genomes. Our results show that MSI was present in specific markers after ROS-induced damage in human ovarian cells and in mouse Sod1 knockout PGCs during cell migration, both of which accumulate specific mutations caused by free radical damage. Ovarian tumor cells and mouse PGCs showed an increase of MSI in 12 human and 5 mouse repetitive markers that are located near important genes related to DNA repair, tumor suppression, cell proliferation, apoptosis and differentiation. This could be a signal that leads to tumor initiation, formation and progression in adult ovarian cells due to improper DNA repair and tumor suppression mechanisms or in disruption of PGC migration that determines germinal cell pool selection during early embryonic development due to absence of cell antioxidant mechanisms. Therefore, these specific unstable STRs are novel biomarkers that could be useful in early diagnostics, prognosis, and successful therapy of ovarian tumorigenesis.

URI

https://hdl.handle.net/11668/15221

Comments

BRCA1||ROS||MMR||genomic instability||Ovarian cancer||SOD1

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