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Kajal Davi Thesis F.pdf (1.92 MB)

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The role of suc22-S239F mutation in sensitizing fission yeast to the replication stress induced by hydroxyurea

Davi, Kajal
http://orcid.org/0009-0008-8694-2387
http://rave.ohiolink.edu/etdc/view?acc_num=wright1715533526454806

Abstract Details

2024, Master of Science (MS), Wright State University, Pharmacology and Toxicology.
Genetic mutations can significantly impact the cell’s susceptibility to environmental stress. The fission yeast Schizosaccharomyces pombe is an established eukaryotic model for studying the cellular responses to various environmental stresses. This work investigated a missense mutation (S239F) identified in Suc22, the small subunit of the ribonucleotide reductase (RNR). RNR is an essential enzyme for the biosynthesis of dNTPs required for DNA replication and repair. We found that the suc22-S239F mutation increases the susceptibility to the replication stress induced by hydroxyurea (HU), not the DNA-damaging agents such as UV, methyl methanesulfate, and CPT. HU is a drug commonly used in laboratories to instigate DNA replication stress as it is an inhibitor of RNR. The intricate mechanisms governing the cellular responses to HU have been extensively studied in the past decades, and the involvement of suc22-S239F mutation presents a new dimension to our understanding of cellular responses to replication stress. The Suc22 is indispensable for DNA synthesis and cell survival. The suc22-S239F mutation involves substituting serine at position 239 with phenylalanine within the small subunit of RNR. Here we show that fission yeast bearing the suc22-S239F mutation exhibits significantly increased sensitivity to chronic replication stress, not acute replication stress induced by HU as compared to wild-type cells. Previous studies have demonstrated that the increased sensitivity to chronic treatment with HU can be caused by several interconnected pathways such as replication stress, oxidative stress, and cytokines arrest. Our results showed that while the replication checkpoint remains functional, the HU sensitivity of the suc22-S239F mutant is likely due to replication stress, not oxidative stress. Therefore, the suc22-S239F mutation acts as an intriguing entry point to studying the intricate mechanisms through which genetic variations amplify the cell susceptibility to replication stress. These findings not only enhance our understanding of stress-induced cytotoxicity but also hold potential implications for the development of innovative therapeutics for the treatment of cancer or other diseases.
Yong-jie Xu, M.D., Ph.D (Advisor)
Ravi P. Sahu, Ph.D. (Committee Member)
Michael Kemp, Ph.D. (Committee Member)
82 p.
Pharmacology; Toxicology
DNA replication checkpoint; Hydroxyurea; Ribonucleotide Reductase; Schizosaccharomyces pombe

Recommended Citations

Citations

  • Davi, K. (2024). The role of suc22-S239F mutation in sensitizing fission yeast to the replication stress induced by hydroxyurea [Master's thesis, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1715533526454806

    APA Style (7th edition)

  • Davi, Kajal. The role of suc22-S239F mutation in sensitizing fission yeast to the replication stress induced by hydroxyurea. 2024. Wright State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright1715533526454806.

    MLA Style (8th edition)

  • Davi, Kajal. "The role of suc22-S239F mutation in sensitizing fission yeast to the replication stress induced by hydroxyurea." Master's thesis, Wright State University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=wright1715533526454806

    Chicago Manual of Style (17th edition)

wright1715533526454806
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© 2024, all rights reserved.
This open access ETD is published by Wright State University and OhioLINK.
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