Degree
Master of Science
Program
Biology
Supervisor
Dr. Jim Karagiannis
Abstract
Tuberous sclerosis complex (TSC) is an inherited genetic disorder caused by loss-of-function mutations in either TSC1 or TSC2. Their respective gene products regulate the mechanistic target of rapamycin (mTOR) signaling pathway, which serves as an activator of cellular proliferation, metabolism, and cell survival. Orthologs of the TSC1 and TSC2 genes exist in a wide range of organisms, including the commonly used and genetically tractable model eukaryote, Schizosaccharomyces pombe. To better understand the functional roles of S. pombe tsc1 and tsc2, I exploited recent advances in genetic interaction biology to identify and characterize genes that modulate the phenotypic effects of tsc1 and tsc2 gene deletions. As part of this work, I found ypa1 (encoding a peptidyl-prolyl cis-trans isomerase) and fft3 (encoding an ATP-dependent DNA helicase) to be negatively interacting with both tsc1 and tsc2. Importantly, while the loss of either ypa1 or fft3 in isolation had negligible effects on colony growth, their loss in tsc1Δ or tsc2Δ backgrounds resulted in significant growth impediments. Thus, the inhibition of either ypa1 or fft3 might represent an “Achilles’ heel” of cells defective in tsc1 or tsc2 function. Lastly, I found that the negative interaction between ypa1 and tsc2 is conserved in mammalian cells. This suggests that the targeted inhibition of the orthologous gene product in humans epitomizes a novel therapeutic strategy to combat the TSC pathology.
Recommended Citation
Rayhan, Ashyad, "Exploiting Fission Yeast Genetic Interaction Data to Identify Disease-Specific Drug Targets for Tuberous Sclerosis Complex" (2017). Electronic Thesis and Dissertation Repository. 5067.
https://ir.lib.uwo.ca/etd/5067