DNA damage-induced cell cycle checkpoints have been postulated to be important in maintaining genetic stability by arresting or delaying the cell cycle to allow time for repair of recombinogenic DNA damage. Loss-of-function mutations that abolish checkpoints and increase genetic instability have been observed in cancer cells and may contribute to rapid proliferation and/or resistance to chemotherapeutic drugs and radiation therapy. Cell cycle checkpoint genes may function in a signal transduction pathway in which the presence of DNA damage is relayed to both the cell cycle machinery and the transcription apparatus to upregulate DNA repair genes. The purpose of this proposal is to elucidate the genetic pathway by which the Saccharomyces cerevisiae RAD9 checkpoint reduces genetic instability that results from homologous recombination between repeated sequences (ectopic recombination). We have previously described a chromosomal translocation assay that can measure genetic instability in yeast rad9 mutants.
The first aim i s to identify specific genes or combinations of genes in the RAD9- mediated signal transduction pathway which reduce the radiation- associated stimulation of translocations.
The second aim i s to examine the contribution of other cell cycle checkpoints in maintaining genetic stability.
The third aim i s to understand whether checkpoints also reduce the radiation-associated recombination between yeast Ty elements. The results obtained in this study may also elucidate current ideas concerning genomic stability in eukaryotic organisms: 1) that elevated levels of recombinases may be important in DNA repair of double-strand breaks (DSBs) generated by DNA replication, 2) that signal transduction pathways that trigger the G2-M checkpoint and control genetic stability are redundant, 3) that the non-random accumulation of genetic changes observed in checkpoint mutants may partially result from recombination between retrotransposons.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070105-09
Application #
6522366
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
1995-08-01
Project End
2003-03-14
Budget Start
2002-08-01
Budget End
2003-03-14
Support Year
9
Fiscal Year
2002
Total Cost
$209,250
Indirect Cost
Name
Albany Medical College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208