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 in a DHFR+, HGPRT+ derivative of a chinese hamster cell line (DG22) carrying such a deletion were measured at the HGPRT locus one week after removal from HAT medium and found to be four-fold higher (22 x 10E-6) than in wild-type BH4 cells (5.5 x 10E-6). These data suggest that deletion of the mammalian mutS analog confers a weak mutator phenotype and are consistent with the hypothesis that this gene plays a role in mismatch repair. Confirmation of this hypothesis will require direct biochemical evidence of deficient mismatch repair in vitro and in vivo as well as a demonstration that reintroducing the cloned gene restores the wild-type phenotype.
