Description
- Abstract:
- Prions are unique proteins that can exist in multiple states. In the prion form these proteins self-replicate, directing other like molecules to adopt the prion form. Prions are associated with mammalian spongiform encephalopathies, but they also exist in lower eukaryotes where they confer beneficial phenotypic plasticity on their host. The Saccharomyces cerevisiae prion protein Sup35 is a translation termination factor. In its non-prion form ([psi-]), Sup35 is active, but in its prion form ([PSI+]), Sup35 misfolds into one of multiple [PSI+] variants, compromising its function and leading to translation termination read-through. The [PSI+]strong variant is dominant in cell crosses with [PSI+]weak, but the molecular basis of this dominance is unclear. Here I show that [PSI+]weak co-exists with strong after a cell cross, but during this co-existence there is a gradual loss of weak with each cell generation. [PSI+]weak constitutes a major fraction of total protein in some cells, so these population fluctuations cannot be explained by competition for substrate conversion. Modulating prion complex size by changes in chaperone activity, Sup35 synthesis, and cell division timing lead to a greater retention of [PSI+]weak in the population. These observations point to different transmission efficiencies of [PSI+] variants as a major force impacting the interplay between distinct prion conformers in vivo. Much evidence suggests that maintenance of [PSI+] and [psi-] states is regulated by post-translational quality control pathways, but the effects of co-translational chaperones on prion propagation have only recently been addressed. In eukaryotes, two chaperone families aid in the folding of nascent polypeptides: Ssb1 and Ssb2 (Hsp70) and Prefoldin (Pfd). Genetic studies have linked Ssb1 and Ssb2 to the [PSI+] cycle. I report that loss of Pfd function is mutagenic, which has allowed me to isolate novel dominant [PSI+] modulators that arise from single genetic lesions falling into five complementation groups. Sup35 and Hsp104 are two previously identified genes with dominant effects on [PSI+] propagation. All of the characterized mutants segregate independently of Hsp104, two are linked to Sup35, but none are associated with mutations in Sup35's prion domain.
- Notes:
- Thesis (Ph.D.) -- Brown University (2009)
Access Conditions
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Citation
Strbuncelj, Martina,
"The Impact of Genetic and Epigenetic Interactions on Propagation of the [PSI+] Prion"
(2008).
Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations, Biology and Medicine Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z04B2ZM5
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