Somatic mutation theory, DNA repair rates, and the molecular epidemiology of p53 mutations

被引:59
作者
Holmquist, GP
Gao, SW
机构
[1] Beckman Res. Inst. City of Hope, Department of Biology, Medical Center, Duarte
[2] University of Texas, Houston Health Science Center, Department of Internal Medicine, Houston, TX 77030
关键词
repair rate; cyclopyrimidine dimer; skin cancer; p53; chronic dosis; molecular epidemiology; spontaneous mutation; genetic toxicology; sequence evolution;
D O I
10.1016/S1383-5742(96)00045-2
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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 L-eq, 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. L-eq 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 L-eq is applied to mutagenesis theory, chronic dose genetic toxicology, genome evolution, and the practical problems of molecular epidemiology.
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页码:69 / 101
页数:33
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