Publication Date

2020

Document Type

Thesis

Committee Members

Yong-jie Xu, M.D., Ph.D. (Advisor); Michael Kemp, Ph.D. (Committee Member); Jeffrey B. Travers, M.D., Ph.D. (Committee Member)

Degree Name

Master of Science (MS)

Abstract

Cancer is a life-threatening illness and innovative research is therefore required to fuel the development of new anti-cancer therapies. As an anti-proliferative drug, hydroxyurea (HU) has been used in the treatment of various neoplastic and non-neoplastic diseases such as sickle cell anemia, psoriasis, and viral infections. HU is a well-known inhibitor of ribonucleotide reductase (RNR), an enzyme that generates dNTPs for DNA replication and repair. In our genetic screen in fission yeast looking for mutants with defects in checkpoint response, we also found a set of mutants that are highly sensitive to HU but with a functional checkpoint response. It is likely that in addition to the RNR suppression, HU induces cell lethality by a previously less understood mechanism involving perturbations of various metabolic pathways. This study is to identify new metabolic genes whose mutations sensitize the cells to HU in order to better understand the cell-killing mechanisms of HU. We have identified new mutation in erg12 gene, which encodes the mevalonate kinase enzyme in the ergosterol biosynthesis pathways. While characterizing the erg12 mutant, we have unexpectedly found five multi-copy suppressors including mns1, uge1, chs1, mug109 and hba1. Results from this study may help to better understand the cell-killing mechanisms of HU, the side effects, and drug resistance associated with the HU-based chemotherapies. They may also promote therapeutic innovations for the benefits of patients with cancer or fungal infections.

Page Count

72

Year Degree Awarded

2020


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