Aneuploidy is a hallmark of cancer and the leading cause of miscarriages in humans. Determining the causes and consequences of aneuploidy is thus vital for understanding the principles underlying tumor formation and infertility. The long-term goal of our studies is to define the mechanisms that prevent chromosome mis-segregation and thus aneuploidy and the consequences of aneuploidy on cell proliferation at the molecular level. The three Specific Aims of this proposal are aimed at addressing these two questions.
In Specific Aim 1, we use molecular and biochemical approaches to determine how the Mitotic Exit Network, a regulatory network essential for promoting exit from mitosis, is regulated. In particular, we will determine, how the GTPase of this pathway is controlled and, using this information, develop in vivo read outs for the activity of the GTPase.
In Specific Aim 2 we will investigate how a surveillance mechanism known as the spindle position checkpoint affects MEN activity. Specifically, we will determine how the spindle position checkpoint component Kin4 regulates the MEN and test the hypothesis that division of the yeast cell in a MEN inhibitory zone (the mother cell) and a MEN activating zone (the bud) is the mechanism whereby spindle position is sensed in yeast.
In Specific Aim 3 will characterize the consequences of aneuploidy. We have discovered that many yeast strains with one or two extra chromosomes are delayed in G1. We will determine the cause(s) of this G1 delay. Furthermore we will identify genes that mediate this G1 delay by identifying loss of function alleles and high copy plasmids that shorten the G1 delay in aneuploids. Their analysis will shed light on how aneuploidy delays cell cycle progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056800-16
Application #
8019093
Study Section
Nuclear Dynamics and Transport (NDT)
Program Officer
Hamlet, Michelle R
Project Start
1997-09-30
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
16
Fiscal Year
2011
Total Cost
$274,983
Indirect Cost
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
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
Dodgson, Stacie E; Kim, Sharon; Costanzo, Michael et al. (2016) Chromosome-Specific and Global Effects of Aneuploidy in Saccharomyces cerevisiae. Genetics 202:1395-409
Torres, Eduardo M; Springer, Michael; Amon, Angelika (2016) No current evidence for widespread dosage compensation in S. cerevisiae. Elife 5:e10996
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
Pfau, Sarah J; Amon, Angelika (2015) A System to Study Aneuploidy In Vivo. Cold Spring Harb Symp Quant Biol 80:93-101
Santaguida, Stefano; Vasile, Eliza; White, Eileen et al. (2015) Aneuploidy-induced cellular stresses limit autophagic degradation. Genes Dev 29:2010-21
Santaguida, Stefano; Amon, Angelika (2015) Short- and long-term effects of chromosome mis-segregation and aneuploidy. Nat Rev Mol Cell Biol 16:473-85
Bonney, Megan E; Moriya, Hisao; Amon, Angelika (2015) Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes. Genes Dev 29:898-903
Santaguida, Stefano; Amon, Angelika (2015) Aneuploidy triggers a TFEB-mediated lysosomal stress response. Autophagy 11:2383-4
Oromendia, Ana B; Amon, Angelika (2014) Aneuploidy: implications for protein homeostasis and disease. Dis Model Mech 7:15-20

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