Errors made during DNA synthesis contribute significantly to the burden of spontaneous mutagenesis in most organisms. Cells have evolved complex mechanisms for correcting such errors, presumably to reduce the mutational load to tolerable levels. One such pathway, mismatch correction, operates specifically upon mispairs formed by misinsertion of an incorrect nucleotide during DNA synthesis. Generalized mismatch repair in E. coli is initiated by the product of the mutS gene, a protein that recognizes and binds to mispairs in DNA. Cells that carry mutations in the mutS gene show elevated rates of spontaneous mutagenesis. Other laboratories have recently identified a possible mammalian analog of mutS on the basis of sequence similarity between the mutS gene and cDNAs derived from human and rodent cells. Mammalian cell lines in which the genomic DNA corresponding to the cDNA has been deleted might be expected to show an elevated rate of spontaneous mutagenesis. Spontaneous mutant frequencies were measured at the ouabain resistance locus in a chinese hamster cell line (DG22) carrying such a deletion and found to be indistinguishable (<1.7 x 10-7) from wild type BH4 cells (<1.1 x 10-7). The mutant frequency in BH4 cells was induced at least 100-fold to 1.0 x 10-5 when a transient nucleotide pool imbalance was created by treatment with 5 mM thymidine; surprisingly, the mutant frequency in DG22 cells was unchanged (<2.3 x 10-7) by such treatment. Studies are currently in progress to determine the basis for this lack of mutagenic response to a presumed nucleotide pool imbalance.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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