The long-term goals of this project are to understand how the function of the mitotic spindle is integrated into the cell cycle in the budding yeast Saccharomyces cerevisiae. The spindle checkpoint is an evolutionarily conserved mitotic regulatory system that arrests cells when chromosomes are not properly aligned on the mitotic spindle apparatus. Mutations in spindle checkpoint genes have been implicated in genomic instability and tumor progression in humans. Various ant-tumor chemotherapeutic agents, like taxol, cause human cells to arrest in mitosis by activating the spindle checkpoint. We will use a combination of genetic approaches to determine the role that a single chromosome domain, the kinetochore, plays in the spindle checkpoint. We will also determine if a single chromosome is capable of activating the spindle checkpoint and we will determine the role that tension plays in the activation process. We will use a synthetic lethal screen with to explore the complexity that exists within the spindle checkpoint pathways. Our experiments will identify some of the important regulatory mechanisms that control genomic stability in a variety of cell types. The spindle checkpoint genes may identify molecular targets for chemotherapeutic intervention in some cancers and birth defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM040334-15
Application #
6625703
Study Section
Genetics Study Section (GEN)
Program Officer
Deatherage, James F
Project Start
1988-07-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
15
Fiscal Year
2003
Total Cost
$296,352
Indirect Cost
Name
University of Virginia
Department
Biochemistry
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Keyes, Brice E; Burke, Daniel J (2009) Irc15 Is a microtubule-associated protein that regulates microtubule dynamics in Saccharomyces cerevisiae. Curr Biol 19:472-8
Daniel, Jewel A; Keyes, Brice E; Ng, Yvonne P Y et al. (2006) Diverse functions of spindle assembly checkpoint genes in Saccharomyces cerevisiae. Genetics 172:53-65