Yong-jie Xu (Advisor), Michael G. Kemp (Committee Member), Ravi P. Sahu (Committee Member)
Master of Science (MS)
Cancer is one of the leading causes of death and a worldwide health issue. Intensive studies have been conducted in the past to unearth new anti-cancer agents. One such anti-proliferative drug is hydroxyurea (HU). HU has been used in clinics for ≥ 100 years to treat various neoplastic and non-neoplastic diseases. Although newer agents have been developed, as a WHO-enlisted essential medicine, it remains the staple drug for the management of chronic myeloproliferative disorders and sickle cell anemia. A better understanding of the HU-induced cell death may improve or expand the therapeutic spectrum of this clinically important drug. HU arrests DNA replication and causes DNA damage in proliferating cells by inhibiting ribonucleotide reductase (RNR), which is thought to be responsible for its cytotoxic and hence the therapeutic effects. While studying the DNA replication checkpoint activated by HU, we unexpectedly discovered a new set of "non-chk" mutants in fission yeast that are highly sensitive to HU. Our preliminary and published data have shown that these non-chk mutants are not killed by arrested DNA replication but by a previously unknown mechanism involving perturbations of various metabolic pathways. This study is to take the unbiased genetic approach to characterize an extensive collection of the "non-chk" mutants that are highly sensitive to HU. In addition to the previously identified erg11-1 and hem13-1 mutations, we have identified in this study new mutations in the two genes erg7 and erg25 encoding the enzymes lanosterol synthase and C-4 methylsterol oxidase in the ergosterol biosynthesis pathway that dramatically sensitizes the cells to HU. Since fission yeast is an established model for studying the cellular mechanisms that are conserved in humans, this study may help to understand the novel cell-killing mechanism of HU and hence promote therapeutic innovations.
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
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