The Role of Ribosome-Associated Protein Quality Control in a Prion-Based Epigenetic State

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Date

2022

Authors

Whitty, Phaedra

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Publisher

University of Oregon

Abstract

Prions are heritable, alternatively-folded proteins that have been implicated in rare but fatal mammalian neurodegenerative diseases. However, they can also act as a beneficial epigenetic mechanism in budding yeast and other organisms by altering various cellular pathways such as gene expression and metabolism. A recently discovered yeast prion allows cells to adopt a ‘live fast, die young’ strategy, accelerating growth rate at the cost of a shortened lifespan. The [BIG+] prion is a form of Pus4, a highly conserved RNA-modifying enzyme, and exhibits the following phenotypes: accelerated cell proliferation, increased cell size, shortened lifespan, and increased protein synthesis activity. The mechanism by which the [BIG+] prion induces this change remains unknown, but increased translation activity may provide clues to its mechanism. Therefore, this thesis investigates the ribosome-associated protein quality control pathway (RQC), a cellular system involved in maintaining translation efficacy, as a potential contributor to the [BIG+] protein synthesis phenotypes. A genetic approach was taken to knock out each of four genes coding for proteins involved in RQC. Luciferase reporter assays were used to examine the difference in translation phenotypes of these mutant strains in the context of the naïve and prion states. A significant change in the [BIG+] translation phenotype of mutants as compared to non-prion strains suggested the involvement of at least two genes in the RQC pathway, Hbs1 and Rli1. These results are some of the first mechanistic insights into how this prion affects translation, encouraging future investigations of the involvement of the RQC pathway in the [BIG+] state.

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Keywords

Prion, Protein, Yeast, Quality control, Translation

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