MECHANISMS OF CHEMICAL MUTAGENESIS IN MAMMALIAN CELLS

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The objective of this research program is to elucidate the relationship between DNA precursor levels and mutagenesis in mammalian cells. Our previous results suggested that perturbation of deoxynucleotide pool levels by the mutagen 5-bromodeoxyuridine (BrdU) plays a key role in the induction of mutation and sister chromatid exchange (SCE). We plan to take several approaches to study the role that DNA precursor levels play mutagenesis by BrdU and other mutagens. These approaches will include: 1) isolate Chinese hamster cell mutants with alterations in deoxynucleotide metabolism and determine the effect that the mutational alterations have on frequencies of mutation and SCE; 2) determine whether cells with intrinsic differences in nucleotide metabolism (human B and T lymphoblasts) have differences in spontaneous mutation frequencies and mutagen sensitivities; 3) determine whether deoxynucleotide pool alterations are involved in the expression of several human chromosomal breakage syndromes; 4) study the effect of deoxynucleotide pool imbalance on rates of DNA synthesis and the role of channeling of DNA precursors in mutagenesis; 5) identify the actual DNA base changes when deoxynucleotide pool imbalances influence mutagenesis; and 6) examine the role of DNA methylation and mismatch repair in mammalian cell mutagenesis. These studies should enable us to determine the relationship between DNA precursor levels and mutagenesis. This information may lead to predictions concerning the susceptibility of a particular cell type to mutagenesis and possibly malignant transformation, based on that cell's deoxynucleotide metabolism.