Mutator phenotypes in mammalian cell mutants with distinct biochemical defects and abnormal deoxyribonucleoside triphosphate pools.

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Abstract
Recent studies of in vitro DNA synthesis have shown that fidelity of replication is influenced by the relative concentrations of deoxyribonucleoside triphosphates (dNTP). Reconstituted prokaryotic replication systems were used to copy defined natural templates. Specific incorporation errors apparently can be induced by an appropriate bias of the precursor pools. The recent demonstration of mutator phenotypes among mutant Chinese hamster ovary cell lines with altered intracellular dNTP pools has allowed extension of the in vitro observations to eukaryotic replication and repair mechanisms. Three mutant murine 5-49 T-lymphosarcoma cell lines are described with altered dNTP pools and increased rates of spontaneous mutation to dexamethasone resistance and 6-thioguanine resistance. These lines have demonstrable defects in known structural gene products. Two of the cell lines are heterozygous for mutations affecting the M1 subunit of ribonucleoside diphosphate reductase; the other mutant is deficient in deoxycytidylate deaminase. In each line these mutations result in deranged endogenous dNTP pools and increased rates of spontaneous mutation, which are characteristic of the cell line and independent of the 2 genetic markers examined. Normalization of the dNTP pools of the deaminase-deficient cells suppresses its mutator phenotype. Abnormal dNTP pools seem to cause enhanced mutagenesis in mammalian cells.