Switching the Fate of mRNAs for Mitochondrial Biogenesis

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dc.contributor.advisorLiu, Yien
dc.contributor.committeeMemberTu, Benjaminen
dc.contributor.committeeMemberMcKnight, Steven L.en
dc.contributor.committeeMemberConrad, Nicholasen
dc.creatorLee, Chien-Deren
dc.creator.orcid0000-0002-6093-9613
dc.date.accessioned2019-08-02T19:23:36Z
dc.date.available2019-08-02T19:23:36Z
dc.date.created2017-05
dc.date.issued2017-03-02
dc.date.submittedMay 2017
dc.date.updated2019-08-02T19:23:36Z
dc.descriptionThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.en
dc.description.abstractmRNAs encoding mitochondrial biogenesis proteins are co-regulated in a manner closely linked to metabolism. In yeast growing in glucose, mitochondrial biogenesis is repressed, but must be induced upon glucose depletion to enable energy production using alternative carbon sources such as ethanol or acetate through mitochondrial respiration. Yeast cells growing in glucose constitutively transcribe nuclear-encoded mitochondrial ribosomal mRNAs at a basal level. However, instead of sharing a common upstream activating sequence for transcription, those mRNAs all harbor a common sequence motif within their 3'UTRs. Puf3p, an RNA-binding protein, can directly bind to this class of mRNA transcripts to promote degradation in glucose medium. However, the function of Puf3p upon glucose depletion is not clear. In the first part of this study, I show how Puf3p responds to glucose availability to switch the fate of its bound transcripts that encode proteins required for mitochondrial biogenesis. This regulation allows cell to quickly respond to glucose depletion by switching the degradation fate of those mRNAs to translation. Thus, yeast can activate pre-existing mRNA without relying on de novo transcription for mitochondrial biogenesis. I then show Puf3p is subjected to phosphorylation downstream of a glucose sensing pathway. Puf3p is hypophosphorylated in glucose medium; however, upon glucose depletion, Puf3p becomes heavily phosphorylated within its N-terminal region of low complexity, associates with polysomes, and promotes translation of its target mRNAs. In the second part of this study, I show that phosphorylation of Puf3p is required for translational activation of its bound mRNAs. Strikingly, a Puf3p mutant that prevents its phosphorylation no longer promotes mRNA translation but also becomes trapped in intracellular foci in an mRNA-dependent manner. These findings suggest how the inability to properly resolve Puf3p-containing RNA-protein granules via a phosphorylation-based mechanism might be toxic to a cell. The toxicity might be due to sequestration of translational factors in the Puf3p RNA protein granule in a manner reminiscent of neurodegenerative disease-related protein aggregation.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1111291939
dc.identifier.urihttps://hdl.handle.net/2152.5/7085
dc.language.isoenen
dc.subjectGlucoseen
dc.subjectRNA, Messengeren
dc.subjectRNA-Binding Proteinsen
dc.subjectSaccharomyces cerevisiaeen
dc.subjectSaccharomyces cerevisiae Proteinsen
dc.titleSwitching the Fate of mRNAs for Mitochondrial Biogenesisen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineIntegrative Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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UT Southwestern Graduate School of Biomedical Sciences