Summary
A number of metals have been demonstrated to be mutagens in procaryotic and eucaryotic organisms as well as carcinogens in experimental animals. Epidemiologic studies have indicated that Ni, Cr, and As are involved in human carcinogenesis. We have hypothesized that the active molecular species is the cation and that metal induced mutations result from incorrect base-substitutions during DNA replication. This is supported by the observations that metal ions diminish the fidelity of DNA synthesis in vitro using a variety of DNA polymerases. There is a significant correlation between the metals that decrease fidelity and those that have been reported to be mutagenic and carcinogenic. Thus, metal carcinogens are no exception to the general postulate that carcinogens can be identified by their effects on DNA.
Similar content being viewed by others
References
Agarwal SS, Dube DK, Loeb LA (1979) On the fidelity of DNA replication. VII. Accuracy of E. coli DNA polymerase I. J Biol Chem 254:101–106
Battula N, Loeb LA (1975) On the fidelity of DNA replication. II. Characterization of polynucleotides with errors in base-pairing synthesized by avian myeloblastosis deoxyribonucleic acid polymerase. J Biol Chem 250:4405–4409
Dube DK, Loeb LA (1975) Manganese as a mutagenic agent during in vitro DNA synthesis. Biochem Biophys Res Commun 67:1041–1046
Eichhorn GL, Shin YA (1968) Interaction of metal ions with polynucleotides and related compounds. XII. The relative effect of various metal ions on DNA helicity. J Am Chem Soc 90:7323–7328
Hall ZW, Lehman IR (1968) An in vitro transversion by a mutationally altered T4-induced DNA polymerase. J Mol Biol 36:321–333
Hoffman DJ, Niyogi SK (1977) Metal mutagens and carcinogens RNA synthesis rates in a distinct manner. Science 198:513–514
Kunkel TA, Loeb LA (1979) On the fidelity of DNA replication: Effect of divalent metal ion activators and deoxyribonucleoside triphosphate pools on in vitro mutagenesis. J Biol Chem 254:5718–5725
Linn S, Kairis M, Holliday R (1976) Decreased fidelity of DNA polymerase activity isolated from aging human fibroblasts. Proc Natl Acad Sci USA 73:2818–2822
Loeb LA, Weymouth LA, Kunkel TA, Gopinathan KP, Beckman RA, Dube DK (1979) On the fidelity of DNA replication. In: Cold Spring Harbor Symp. Quant. Biol. XLIII. Cold Spring Harbor Laboratory, New York pp 921–927
Luke MZ, Hamilton L, Hollocher TC (1975) Beryllium-induced mis-incorporation by a DNA polymerase. Biochem Biophys Res Commun 62:497–501
Miyaki M, Murata I, Osabe M, OnoT (1977) Effect of metal cations on misincorporation by E. coli DNA polymerases. Biochem Biophys Res Commun 77:854–860
Murray MJ, Flessel CP (1976) Metal-polynucleotide interactions. A comparison of carcinogenic and non-carcinogenic metals in vitro. Biochim Biophys Acta 425:256–261
Radman M, Vallani G, Boiteux S, Defais M, Caillet-Fauquet P (1977) On the mechanism and genetic control of mutagenesis due to carcinogenic mutagens. In: Watson JD, Hiatt H (eds) Origins of human cancer, Book B: Mechanisms of carcinogenesis, Vol 4. Cold Spring Harbor Laboratory. Cold Spring Harbor, New York, pp 903–922
Seal G, Shearman CW, Loeb LA (1979) On the fidelity of DNA replication: Studies with human placenta DNA polymerases. J Biol Chem 254:5229–5237
Sirover MA, Dube DK, Loeb LA (1979) On the fidelity of DNA synthesis VIII. Metal activation of E. coli DNA polymerase I. J Biol Chem 254:107–111
Sirover MA, Loeb LA (1976) Infidelity of DNA synthesis in vitro screening for potential metal mutagens or carcinogens. Science 194:1434–1436
Sirover MA, Loeb LA (1976) Metal-induced infidelity during DNA synthesis. Proc Natl Acad Sci USA 73:2331–2335
Sirover MA, Loeb LA (1977) On the fidelity of DNA replication. Effect of metals on synthesis with avian myeloblastosis DNA polymerase. J Biol Chem 252:3605–3610
Slater JP, Tamir I, Loeb LA, Mildvan AS (1972) The mechanism of E. coli deoxyribonucleic acid polymerase I: Magnetic resonance and kinetic studies of the role of metals. J Biol Chem 247:6784–6794
Sloan DL, Loeb LA, Mildvan AS, Feldman RJ (1975) Conformation of deoxynucleoside triphosphate substrates on DNA polymerase I from E. coli as determined by nuclear magnetic relaxation. J Biol Chem 250:8913–8920
Sunderman Jr, FW (1978) Carcinogenic effects of metals. Fed Proc 37:40–46
Tkeshelashvili LK, Shearman CW, Koplitz RM, Zakour RA, Loeb LA (1979) Effects of As Se, and Cr. Proc Am Assoc Cancer Res 20:263
Tkeshelashvili LK, Shearman CW, Zakour RA, Koplitz RM, Loeb LA (1980) Effects of arsenic, selenium and chromium on the fidelity of DNA synthesis. Cancer Res 40:2455–2460
Wang TSF, Sedwick WD, Korn D (1974) Nuclear deoxyribonucleic acid polymerase. Purification and properties of the homogeneous enzyme from human KB cells. J Biol Chem 249:841–850
Weymouth LA, Loeb LA (1978) Mutagenesis during in vitro DNA synthesis. Proc Natl Acad Sci USA 75:1924–1928
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zakour, R.A., Tkeshelashvili, L.K., Shearman, C.W. et al. Metal-induced infidelity of DNA synthesis. J Cancer Res Clin Oncol 99, 187–196 (1981). https://doi.org/10.1007/BF00412453
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00412453