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.
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.
Courtemanche
C
C
Centre de recherche en cancérologie de l'Université Laval, Pavillon L'Hôtel-Dieu de Québec, Centre hospitalier universitaire de Québec, Québec G1R 2J6 Canada.
Anderson
A
A
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D016604:Aflatoxin B1 / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002723:Chlorobenzoates / Q000494:pharmacology; D016153:Genes, Suppressor; D005822:Genetic Vectors / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000187:drug effects*; D009153:Mutagens / Q000494:pharmacology*; D017354:Point Mutation; D012343:RNA, Transfer / Q000235:genetics*; D016159:Tumor Suppressor Protein p53; D014466:Ultraviolet Rays / Q000009:adverse effects
D002723:Chlorobenzoates; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; C096275:supF tRNA; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D012343:RNA, Transfer; D016604:Aflatoxin B1; C000433:3-chloroperbenzoic acid