Age is the greatest carcinogen, yet the mechanism by which the incidence of cancer dramatically increases as humans age is unclear. In an effort to better understand this phenomenon, we have sought to develop a system in the yeast, Saccharomyces cerevisiae that shows one of the hallmarks of cancer - genomic instability - as a function of cellular age. Specifically, we examined the relationship between aging and genomic instability by monitoring loss of heterozygosity (LOH) on two different chromosomes during replicative aging in yeast. We discovered that aging yeast mother cells underwent a switch to a nearly 100-fold increase in LOH in their progeny. After the switch, the increased rate of LOH remained constant throughout the remainder of the lifespan. Extending lifespan did not alter the onset nor frequency of age-induced LOH, suggesting that the aging """"""""clock"""""""" that sets off hyper-LOH is distinct from that which regulated replicative lifespan. Furthermore, age-induced LOH is qualitatively distinct; in young cells LOH proceeds primarily by reciprocal recombination, whereas in old cells it is non-reciprocal and proceeds by break-induced ? replication with a striking daughter cell bias. We now propose to use the powerful collection of resources and tools available in S. cerevisiae to develop our understanding about age-induced LOH. We anticipate that genes and processes identified in this analysis will lead us to a molecular understanding of how genomic instability increases in aging yeast cells. These may then serve as means to identify genes and processes in human cells that become defective with age and ultimately lead to aging-dependent diseases such as cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023779-05
Application #
7440257
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Mccormick, Anna M
Project Start
2004-06-01
Project End
2010-09-29
Budget Start
2008-06-01
Budget End
2010-09-29
Support Year
5
Fiscal Year
2008
Total Cost
$309,400
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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