Photoproduct frequency is not the major determinant of UV base substitution hot spots or cold spots in human cells
The role of UV radiation-induced photoproducts in initiating base substitution mutations in human cells was examined by measuring photoproduct frequency distributions and mutations in a supF tRNA gene on a shuttle vector plasmid transfected into DNA repair-deficient cells (xeroderma pigmentosum, complementation group A) and into normal cells. Frequencies of cyclobutane dimers and pyrimidine-pyrimidone (6-4) photoproducts varied by as much as 80-fold at different dipyrimidine sites within the gene. All transition mutations occurred at dipyrimidine sites, predominantly at cytosine, with a 17-fold variation in mutation frequency between different sites. Removal of greater than 99% of the cyclobutane dimers by in vitro photoreactivation before transfection reduced the mutation frequency while preserving the mutation distribution, indicating that (i) cytosine-containing cyclobutane dimers were the major mutagenic lesions at these sites and (ii) cytosine-containing non-cyclobutane dimer photoproducts were also mutagenic lesions. However, at individual dipyrimidine sites neither the frequency of cyclobutane dimers nor the frequency of pyrimidine-pyrimidone (6-4) photoproducts correlated with the mutation frequency, even in the absence of excision repair. Mutation hot spots occurred at sites with low or high frequency of photoproduct formation and mutation cold spots occurred at sites with many photoproducts. These results suggest that although photoproducts are required for UV mutagenesis, the prominence of most mutation hot spots and cold spots is primarily determined by DNA structural features rather than by the frequency of DNA photoproducts.
- Research Organization:
- National Cancer Institute, Bethesda, MD
- OSTI ID:
- 6467532
- Journal Information:
- Proc. Natl. Acad. Sci. U.S.A.; (United States), Vol. 11
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
MUTATIONS
RADIOINDUCTION
XERODERMA PIGMENTOSUM
GENETIC RADIATION EFFECTS
GENES
MAN
MUTATION FREQUENCY
PLASMIDS
PYRIMIDINE DIMERS
TRANSFER RNA
ULTRAVIOLET RADIATION
ANIMALS
BIOLOGICAL EFFECTS
BIOLOGICAL RADIATION EFFECTS
CELL CONSTITUENTS
DISEASES
ELECTROMAGNETIC RADIATION
GENETIC EFFECTS
MAMMALS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
PRIMATES
RADIATION EFFECTS
RADIATIONS
RNA
SKIN DISEASES
VERTEBRATES
560120* - Radiation Effects on Biochemicals
Cells
& Tissue Culture