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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056800-18
Application #
8415919
Study Section
Special Emphasis Panel (ZRG1-CB-Z (02))
Program Officer
Hamlet, Michelle R
Project Start
1997-09-30
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
18
Fiscal Year
2013
Total Cost
$254,653
Indirect Cost
$85,778
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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Oromendia, Ana B; Amon, Angelika (2014) Aneuploidy: implications for protein homeostasis and disease. Dis Model Mech 7:15-20
Tang, Yun-Chi; Amon, Angelika (2013) Gene copy-number alterations: a cost-benefit analysis. Cell 152:394-405
Knouse, Kristin A; Amon, Angelika (2013) The many sides of CIN. Nat Rev Mol Cell Biol 14:611
Sheltzer, Jason M (2013) A transcriptional and metabolic signature of primary aneuploidy is present in chromosomally unstable cancer cells and informs clinical prognosis. Cancer Res 73:6401-12
Sheltzer, Jason M; Amon, Angelika (2011) The aneuploidy paradox: costs and benefits of an incorrect karyotype. Trends Genet 27:446-53
Chan, Leon Y; Amon, Angelika (2010) Spindle position is coordinated with cell-cycle progression through establishment of mitotic exit-activating and -inhibitory zones. Mol Cell 39:444-54
Tomson, Brett N; Rahal, Rami; Reiser, Vladimir et al. (2009) Regulation of Spo12 phosphorylation and its essential role in the FEAR network. Curr Biol 19:449-60
Monje-Casas, Fernando; Amon, Angelika (2009) Cell polarity determinants establish asymmetry in MEN signaling. Dev Cell 16:132-45
Rahal, Rami; Amon, Angelika (2008) The Polo-like kinase Cdc5 interacts with FEAR network components and Cdc14. Cell Cycle 7:3262-72

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