Aneuploidy is defined as an alteration in chromosome number that is not a multiple of the haploid complement. Such karyotypic changes are frequently associated with human disease. Aneuploidy is the leading cause of miscarriages and mental retardation in humans. It is also prominently associated with cancer: more than 90% of all solid human tumors are aneuploid. Understanding the relationship between aneuploidy and tumorigenesis is thus vital if we want to make progress in our battle against this disease. The studies proposed here will contribute towards this goal. We have previously examined the effects of aneuploidy on cell physiology by analyzing the effects of additional chromosomes on yeast cells. We observe that the presence of extra chromosomes impairs cell proliferation, causes phenotypes that are indicative of proteotoxic stress and results in genome instability. All these phenotypes are due to the proteins produced from the additional chromosomes. We will now determine the molecular bases of these phenotypes in established aneuploid yeast strains and determine the kinetics with which these phenotypes arise using inducible aneuploidy systems.
In Specific Aim 1 we will characterize protein aggregates in aneuploid yeast strains. We will furthermore test the hypothesis that chromosome imbalances in aneuploids lead to protein stoichiometry imbalances, which cause proteotoxic stress and an increased burden on the cell's protein quality control systems.
In Specific Aim 2 we will further investigate how aneuploidy brings about genome instability. Specifically, we will determine how aneuploidy causes an increase in recombinatorial repair.
In Specific Aim 3 we will develop an inducible chromosome mis-segregation system that allows us to create more complex aneuploidies and to study the immediate consequences of aneuploidy on the cell. Together, we believe that these studies will shed light on how aneuploidy affects cell physiology and how the condition contributes to tumorigenesis.
Aneuploidy is the leading cause of miscarriages and mental retardation in humans. It is also prominently associated with cancer: more than 90% of all solid human tumors are aneuploid. Understanding the impact of aneuploidy on cellular physiology is thus vital if we want make progress towards understanding tumorigenesis. The long-term goal of our studies is to define this impact. We use the budding yeast S. cerevisiae to address this question. Given that the processes governing cellular homeostasis are highly conserved from yeast to man, it is likely that our studies will provide the foundation for determining the effects of aneuploidy on normal human cells and cancer cells.
| Santaguida, Stefano; Richardson, Amelia; Iyer, Divya Ramalingam et al. (2017) Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System. Dev Cell 41:638-651.e5 |
| Beach, Rebecca R; Ricci-Tam, Chiara; Brennan, Christopher M et al. (2017) Aneuploidy Causes Non-genetic Individuality. Cell 169:229-242.e21 |
| Knouse, Kristin A; Wu, Jie; Hendricks, Austin (2017) Detection of Copy Number Alterations Using Single Cell Sequencing. J Vis Exp : |
| Sinha, Raunak; Hoon, Mrinalini; Baudin, Jacob et al. (2017) Cellular and Circuit Mechanisms Shaping the Perceptual Properties of the Primate Fovea. Cell 168:413-426.e12 |
| Sheltzer, Jason M; Ko, Julie H; Replogle, John M et al. (2017) Single-chromosome Gains Commonly Function as Tumor Suppressors. Cancer Cell 31:240-255 |
| Torres, Eduardo M; Springer, Michael; Amon, Angelika (2016) No current evidence for widespread dosage compensation in S. cerevisiae. Elife 5:e10996 |
| Dodgson, Stacie E; Kim, Sharon; Costanzo, Michael et al. (2016) Chromosome-Specific and Global Effects of Aneuploidy in Saccharomyces cerevisiae. Genetics 202:1395-409 |
| Knouse, Kristin A; Wu, Jie; Amon, Angelika (2016) Assessment of megabase-scale somatic copy number variation using single-cell sequencing. Genome Res 26:376-84 |
| Santaguida, Stefano; Vasile, Eliza; White, Eileen et al. (2015) Aneuploidy-induced cellular stresses limit autophagic degradation. Genes Dev 29:2010-21 |
| Blank, Heidi M; Sheltzer, Jason M; Meehl, Colleen M et al. (2015) Mitotic entry in the presence of DNA damage is a widespread property of aneuploidy in yeast. Mol Biol Cell 26:1440-51 |
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