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The p53 tumor suppressor protein reduces point mutation frequency of a shuttle vector modified by the chemical mutagens (±)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, aflatoxin B1 and meta-chloroperoxybenzoic acid

Oncogene volume 18, pages 4672–4680 (1999)Cite this article

Abstract

p53 has been postulated to be the guardian of the genome. However, results supporting the prediction that point mutation frequencies are elevated in p53-deficient cells either have not been forthcoming or have been equivocal. To analyse the effect of p53 on point mutation frequency, we used the supF gene of the pYZ289 shuttle vector as a mutagenic target. pYZ289 was treated in vitro by ultraviolet irradiation, aflatoxin B1, (±)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and meta-chloroperoxybenzoic acid and then transfected into p53-deficient cells with or without a p53 expression vector. p53 reduced the mutant frequency up to fivefold when pYZ289 was treated with aflatoxin B1, (±)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene or meta-chloroperoxybenzoic acid but not when it was ultraviolet-irradiated. The p53-dependent mutation frequency reduction was higher at a higher level of premutational lesions for aflatoxin B1 and (±)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and at a lower level of lesions for meta-chloroperoxybenzoic acid. This suggests that the chemical mutagens produce, in a dose-dependent fashion, two kinds of DNA damage, one subject to p53-dependent mutation frequency reduction and the other not. These results indicate that p53 can reduce the point mutation frequency in a shuttle vector treated by chemical mutagens and suggest that p53 can act as guardian of the genome for at least some kinds of point mutations.

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Acknowledgements

We thank T Yagi for the pYZ289 shuttle vector, S Benchimol for the pECM53 p53 expression vector, AJ Levine for the 10(3) cells, and MM Seidman for E. coli MBM7070 as well as for advice and encouragement concerning the use of shuttle vector mutagenesis systems. We also thank M Desrochers for providing the microsomes, A Loranger and N Marceau for advice on immunofluorescence techniques, as well as P Françon and E Pellerin for technical assistance. C Courtemanche held a graduate fellowship from the FCAR of Québec. This work was supported by the Medical Research Council.

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  1. Centre de recherche en cancérologie de l'Université Laval, Pavillon L'Hôtel-Dieu de Québec, Centre hospitalier universitaire de Québec, Québec, G1R 2J6, Canada

    Chantal Courtemanche & Alan Anderson

  2. Département de biologie, Université Laval, Québec, G1K 7P4, Canada

    Chantal Courtemanche & Alan Anderson

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Courtemanche, C., Anderson, A. The p53 tumor suppressor protein reduces point mutation frequency of a shuttle vector modified by the chemical mutagens (±)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, aflatoxin B1 and meta-chloroperoxybenzoic acid. Oncogene 18, 4672–4680 (1999). https://doi.org/10.1038/sj.onc.1202805

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