The role of the environmental stress response in aneuploid and cell cycle-arrested budding yeast
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terhorst-terhorst-phd-biology-2021-thesis .pdf
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Thesis PDF
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9.42 MB
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Author(s)
Terhorst, Allegra Louise
Advisor(s)
Vander Heiden, Matthew
Date Issued
September 2021
Publisher
Massachusetts Institute of Technology
Abstract
Size matters in eukaryotic cells. Inability to maintain cell size homeostasis, or the coordination between growth and division, has direct consequences on cellular functions and fitness. Eukaryotic cells have developed mechanisms to ensure proper coordination of biomass accumulation and cell cycle progression. Cell growth can regulate cell cycle progression, and cells are required to grow to a “critical size” before entrance into the cell cycle. Much less is known about how cell cycle progression affects biomass accumulation, specifically, what happens to cell growth when cell cycle progression is slowed or halted. Here, I investigate this question using two models of cell cycle delay and arrest in S. cerevisiae: aneuploidy and temperature sensitive cdc (cdc-ts) mutants.
I first show that the environmental stress response (ESR) a gene expression pattern that represses ribosome biogenesis, is activated in both heterogeneous populations of aneuploid cells as well as complex aneuploid strains with one or more additional or lost chromosomes. Although my results here contradict a previous study using heterogeneous aneuploid populations, I show that their heterogeneous aneuploid populations did exhibit the ESR, but their euploid control population was grown into stationary phase, tainting their analysis. I see that in complex aneuploid strains, growth rate correlates to ESR strength and ribosomal fraction of the proteome, but this correlation is lost when strains are grown in a nutrient-limiting chemostat. Furthermore, there is a similar loss of ribosomes in the heterogeneous aneuploid populations. Next, I study size regulation in cdc-ts mutants, which arrest in the cell cycle at the restrictive temperature, and also see ribosome downregulation and ESR activation. Similar ESR activation and ribosome loss occurs in cells when either the TORC1 pathway or Ras/PKA pathway is inhibited. When I hyperactivate the Ras/PKA pathway during cdc-ts arrests, cells no longer exhibit the ESR and have significant loss of viability. I show that these strains no longer downregulate ribosomes and attenuate cell size growth. These studies have profound insights into how the ESR helps coordinate cell growth and cell cycle progression when the two are uncoupled.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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