Somatic mutation theory, DNA repair rates, and the molecular epidemiology of p53 mutations.
The theory of somatic mutagenesis predicts that the frequency pattern of induced selectable mutations along a gene is the product of the probability patterns of the several sequential steps of mutagenesis, e.g., damage, repair, polymerase misreading, and selection. Together, the variance of these component steps is propagated to generate a mutagen's induced mutational spectrum along a gene. The step with the greatest component of variance will drive most of the variability of the mutation frequency along a gene. This most variable step, for UV-induced mutations, is the cyclobutyl pyrimidine dimer repair rate. The repair rate of cyclopyrimidine dimers is quite variable from nucleotide position to nucleotide position and we show that this variation along the p53 gene drives the C-->T transition frequency of non-melanocytic skin tumors. On showing that the kinetics of cyclopyrimidine dimer repair at any one nucleotide position are first order, we use this kinetic and the somatic mutation theory to derive Leq, the adduct frequency along a gene as presented to a DNA polymerase after a cell population reaches damage-repair equilibrium from a chronic dose of mutagen. Leq is the product of the first two sequential steps of mutagenesis, damage and repair, and the frequency of this product is experimentally mapped using ligation-mediated PCR. The concept of Leq is applied to mutagenesis theory, chronic dose genetic toxicology, genome evolution, and the practical problems of molecular epidemiology.
Holmquist
G P
GP
Beckman Research Institute of the City of Hope, Department of Biology, Duarte CA 91010, USA. gholm@smtplink.coh.org
Gao
S
S
D000818:Animals; D004260:DNA Repair; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D017720:Molecular Epidemiology; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D011740:Pyrimidine Dimers / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics
D011740:Pyrimidine Dimers