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Medientyp:
E-Artikel
Titel:
Mutator Phenotypes in Mammalian Cell Mutants with Distinct Biochemical Defects and Abnormal Deoxyribonucleoside Triphosphate Pools
Beteiligte:
Weinberg, Guy;
Ullman, Buddy;
Martin, David W.
Erschienen:
National Academy of Sciences of the United States of America, 1981
Erschienen in:
Proceedings of the National Academy of Sciences of the United States of America, 78 (1981) 4, Seite 2447-2451
Sprache:
Englisch
ISSN:
0027-8424
Entstehung:
Anmerkungen:
Beschreibung:
Recent studies of in vitro DNA synthesis have shown that fidelity of replication is influenced by the relative concentrations of deoxyribonucleoside triphosphates (dNTPs). Several investigators have used reconstituted prokaryotic replication systems to copy defined natural templates and have shown that specific incorporation errors 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. We describe here three mutant murine T-lymphosarcoma cell lines with altered dNTP pools and increased rates of spontaneous mutation to dexamethasone resistance and 6-thioguanine resistance. Unlike previously described mammalian cells with mutator phenotypes, these three lines have demonstrable defects in known structural gene products. Two of these cell lines are heterozygous for mutations affecting the M1 subunit of ribonucleoside diphosphate reductase; the other mutant is deficient in deoxycytidylate deaminase. In each cell line these mutations result in deranged endogenous dNTP pools and increased rates of spontaneous mutation, which are shown to be characteristic of the cell line and independent of the two genetic markers examined. Furthermore, normalization of the dNTP pools of the deaminase-deficient cells suppresses its mutator phenotype. Thus, abnormal dNTP pools seem to cause enhanced mutagenesis in mammalian cells.