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Shaw Thesis Final Updated (5-30).pdf (4.2 MB)

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Discovery and characterization of pathways involved in FUS and TDP43-induced toxicity in yeast

Shaw, Weston Joseph
http://rave.ohiolink.edu/etdc/view?acc_num=wright1590866939400956

Abstract Details

2020, Master of Science (MS), Wright State University, Anatomy.
High-throughput genome-scale studies are becoming increasingly common as a means to discover genetic interactions. This methodology is particularly efficient when performed in the budding yeast Saccharomyces cerevisiae. Here, we (1) overexpress a large human gene library in yeast to assess how many of them are toxic, and (2) use the list of genes generated above to refine and analyze human genes previously identified to enhance toxicity of two ALS-associated proteins, FUS and TDP-43. By introducing each of 13,500 human genes into yeast, we demonstrated that the majority of these genes (about 97%) are not toxic to yeast when overexpressed. These results indicated that toxicity of human genes, such as FUS and TDP-43, are very likely due to their interactions with specific cellular pathways, rather than simply a non-specific effect of their overexpression in yeast. This is supported by our analysis showing that the toxic human genes are enriched in RNA metabolic processes and DNA transcription, both of which are conserved between yeast and human. Our lab previously identified a preliminary list of 685 human genes that enhance toxicity of FUS and TDP-43 in yeast. However, none of these genes were tested for their own toxicity, so they were possibly false positives, and never were removed from the list. Using the toxic genes identified above, we refined the enhancers list from 685 to 358 genes, out of which 138 genes enhanced TDP-43 toxicity, 335 genes enhanced FUS toxicity, and 115 genes enhanced both. Interestingly, functional classification of the genes that enhance toxicity from both FUS and TDP-43 revealed a group of cell cycle regulators that have been linked to the DNA damage response (DDR) and repair. Given that FUS and TDP-43 are RNA-binding proteins that have been implicated in DDR, these results suggest a possible mechanism of FUS and TDP-43 toxicity involving their abnormal activation of the cell cycle.
Shulin Ju, Ph.D. (Advisor)
Thomas Brown, Ph.D. (Committee Member)
Christopher Wyatt, Ph.D. (Committee Member)
72 p.
Cellular Biology; Molecular Biology
ALS; FUS; TDP-43; genetic screen; human gene enhancers; yeast

Recommended Citations

Citations

  • Shaw, W. J. (2020). Discovery and characterization of pathways involved in FUS and TDP43-induced toxicity in yeast [Master's thesis, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1590866939400956

    APA Style (7th edition)

  • Shaw, Weston. Discovery and characterization of pathways involved in FUS and TDP43-induced toxicity in yeast. 2020. Wright State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright1590866939400956.

    MLA Style (8th edition)

  • Shaw, Weston. "Discovery and characterization of pathways involved in FUS and TDP43-induced toxicity in yeast." Master's thesis, Wright State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1590866939400956

    Chicago Manual of Style (17th edition)

wright1590866939400956
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This open access ETD is published by Wright State University and OhioLINK.