Ionizing radiation or hydroxyurea (HU) induce cell cycle delays mediated by checkpoint controls. Caffeine treatment can override checkpoint controls and permit cell cycle progression into mitosis, resulting in sensitivity to radiation and HU. Radiosensitivity is especially enhanced in p53-defective cells. The mechanism by which caffeine can override checkpoint controls will be examined in the fission yeast Schizosaccharomyces pombe. Mutants have been isolated which cannot be sensitized to radiation or HU by caffeine. Two are altered in rhp6 and retain checkpoint functions in the presence of caffeine. Based on comparisons with the budding yeast system, it i suggested that rhp6 requires fission yeast homologues of Ubr1 and Rad18. To test this model, fission yeast homologues of these genes will be isolated, and corresponding mutants will be constructed and subsequently tested for mutant phenotypes predicted by the model. The additional five previously identified fission yeast mutations that can override caffeine sensitization will be characterized. Roles in repair and cell cycle progression will be tested to support or modify the model.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077421-02
Application #
2896421
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
1998-04-15
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Utah
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112