Date

6-2015

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular and Medical Genetics

Institution

Oregon Health & Science University

Abstract

Fanconi anemia (FA) and Bloom syndrome (BS) are disorders defined by the genome instability that leads to chromosomal abnormalities known as radials. This instability is thought to be a large factor contributing to increased predisposition to cancer seen in these patients. However, the exquisite sensitivity of these cells to most DNA damaging agents limits the available chemotherapeutics that can be tolerated. Thus it is imperative that new chemotherapeutic agents be identified, and that new drugs are studied thoroughly to determine if they are safe specifically for these patients. The information presented here is a collection of manuscripts pertaining to chromosomal radials in FA and BS, and the possibility of using PARP inhibitor as a chemotherapeutic agent in patients who have these disorders. These data identified BS radials as anomalous chromosome structures, identical to FA radials, thus allowing for the continued study of the disorders in parallel. Secondly, the minimal lesion responsible for radial formation was identified as a double strand break and the fate of radial containing cells shown to be elimination via PARP-dependent mitotic cell death. Lastly, PARP inhibitor was studied in detail as it has been identified as a possible chemotherapeutic option for FA patients. While there were specific effects of PARP inhibitor unique to FA and BS cells, a detailed analysis was performed to better understand the general mechanism of action. Most importantly, PARP inhibitor was able to induce multipolar division and chromosome instability in non-cancerous and HR- proficient cells suggesting that the cytotoxic effects of PARP inhibitor are more universal than initially realized.

Identifier

doi:10.6083/M4S46QP8

School

School of Medicine

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