Specific mutagens reproducibly activate specific oncogenes in a specific tissue. Resulting tumors often show the oncogene to have a specific mutation at one particular nucleotide position. The reproducible mutation may be due to this nucleotide position being either modified frequently or misrepaired frequently. We developed a novel technique, the Ligation Mediated-Polymerase Chain Reaction, to map alkylated adducts and ultraviolet light induced adducts in vivo at the nucleotide level of resolution on sequencing gels; even repair rates were quantified at nucleotide resolution. With this discovery, we will relate reproducible hot spots for oncogene activation to hot spots for adduct formation or to slow spots for adduct repair. Technology for mapping adduct frequency will be tailored to other alkylating agents, and to benzopyrene, dimethyl-benzanthracene, and aflatoxin, mutagens responsible for oncogene activation. Results from adduct mapping of p53 and several ras and myc oncogenes in murine tissue culture systems will be applied to mouse model systems.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA054773-03
Application #
3199311
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1991-08-01
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Gao, S; Drouin, R; Holmquist, G P (1994) DNA repair rates mapped along the human PGK1 gene at nucleotide resolution. Science 263:1438-40
Holmquist, G P (1994) Chromatin self-organization by mutation bias. J Mol Evol 39:436-8