Role of TP53 in repair of N-(deoxyguanosin-8-yl)-4-aminobiphenyl adducts in human transitional cell carcinoma of the urinary bladder.
The global genomic repair of DNA adducts was examined in human papillary transitional cell carcinoma (TCC) cell lines after exposure to N:-hydroxy-4-acetylaminobiphenyl (N-OH-AABP), the proximate carcinogenic metabolite of the human bladder carcinogen 4-aminobiphenyl (ABP). (32)P-post-labeling analysis of TCC cultures exposed to N-OH-AABP revealed a major adduct, identified as the 3',5'-bisphosphate derivative of N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP). The amount of adduct formation in TCC10 was dependent upon the dose and the duration of exposure and ranged between 1 and 5 adducts/10(7) nucleotides. To test if p53 regulates repair of the dG-C8-ABP adduct in genomic DNA, an isogeneic set of cell lines was obtained by infection of the TCC10 cultures with a retroviral construct expressing a trans-dominant mutant of p53, namely a Val-->Ala mutation at codon 143. The TDM143-TCC10 line expressing the mutant form of p53 was selected. The rate of repair of dG-C8-ABP was compared between TCC10 and TDM143-TCC10 cultures after treatment with 15 microM N-OH-AABP. The rate of disappearance of the adduct was monitored over a period of time after chemical treatment. (32)P-post-labeling analysis of dG-C8-ABP in parental TCC10 showed its rapid removal, the majority of adducts disappearing within 48 h. In contrast to TCC10, TDM143-TCC10 was relatively slower in removal of dG-C8-ABP. After 24 h DNA repair TDM143-TCC10 showed an approximately 3-fold greater amount of dG-C8-ABP compared with TCC10. These results imply that p53 plays a role in the repair of ABP adducts and that in p53 null cells the unrepaired DNA damage could cause accumulation of mutations, which might contribute to increased genomic instability and neoplastic progression.
Torino
J L
JL
Department of Pharmacology, University of Wisconsin, Madison, WI 53706, USA.
Burger
M S
MS
Reznikoff
C A
CA
Swaminathan
S
S
D000611:Aminobiphenyl Compounds / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000378:metabolism; D018736:DNA Adducts / Q000096:biosynthesis / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D016158:Genes, p53 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016296:Mutagenesis / Q000235:genetics; D009154:Mutation; D016133:Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; C001365:N-hydroxy-4-acetylaminobiphenyl; C053420:N-(deoxyguanosin-8-yl)-4-aminobiphenyl; D003849:Deoxyguanosine