Semester

Fall

Date of Graduation

2007

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Weixin Wang.

Abstract

The DNA damage response is a complex network of signals that coordinate to protect cells from accumulating mutations that lead to the development of cancer. Upon the introduction of DNA damage from either environmental or endogenous sources, the DNA damage response coordinates the control of cell cycle with DNA repair mechanisms to ensure genomic integrity within the cell. Mutations in proteins in this pathway lead to genomic instability and early onset of cancer. BRCA1 is a protein that plays a critical role in response to DNA damage caused by ionizing radiation and is responsible for approximately 50% of inherited breast and ovarian cancers. A key element in the response to DNA damage is the exact type of lesion produced. Irofulven represents a novel DNA damaging agent that may provide insight into specific signals involved. It also remains to be determined if tumors that have mutations in BRCA1 may be more or less sensitive to treatment with irofulven. The exact method by which irofulven kills cells also remains to be determined. Many chemotherapeutics are potent inducers of apoptosis and irofulven has been shown to activate elements of the apoptotic pathway. Previous work in our lab has shown the ability of irofulven to activate ATM and CHK2. Based on the fact that BRCA1 lies directly downstream in this pathway, we hypothesized that it plays a key role in the irofulven induced DNA damage response.;In our current study, we determined that BRCA1 plays a role in regulation of S and G2/M cell cycle checkpoints after irofulven exposure. We also demonstrated that DNA repair via homologous recombination plays a role in response to DNA damage induced by irofulven and that cells deficient in such repair are more sensitive to irofulven. Lastly, we demonstrated that the activation of apoptosis by irofulven is regulated by caspases 2 and 9, while caspase 8 seems to render cells resistant. Taken together, this study expanded our knowledge of signaling pathways activated by irofulven and provides a basis for targeted treatment in BRCA1 deficient breast and ovarian cancers.

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