Formation and repair of DNA lesions in the p53 gene: relation to cancer mutations?
The number and diversity of mutations in the p53 mutation data base provides indirect evidence that implicates environmental mutagens in human carcinogenesis. The p53 gene has a large mutational target size; more than 280 out of 393 amino acids are found mutated in tumors. We argue that there is possibly a limited involvement of selection for specific mutations in the central domain of the protein, and that the distribution of DNA damage along the p53 gene caused by environmental carcinogens can be correlated with the mutational spectra, i.e., hotspots and types of mutations, of certain cancers. This concept has been validated by experiments with sunlight and the cigarette smoke component benzo[a]pyrene representing the polycyclic aromatic hydrocarbon class of carcinogens. The damage/repair data obtained for these mutagens can predict certain parameters of the mutational spectra including the distribution of hotspots in human nonmelanoma skin cancers and lung cancers from smokers. Future studies with suspected mutagens may help to implicate causative agents involved in other cancers, such as colon and breast cancer, where the exact carcinogen has not yet been identified but an environmental factor is suspected.
Pfeifer
G P
GP
Department of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA. gpfeifer@smtplink.coh.org
Denissenko
M F
MF
D044503:5-Methylcytosine; D000818:Animals; D001564:Benzo(a)pyrene / Q000009:adverse effects; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics; D002274:Carcinogens, Environmental / Q000009:adverse effects / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives / Q000737:chemistry; D018736:DNA Adducts; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair; D003641:Deamination; D016158:Genes, p53 / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics; D051379:Mice; D016296:Mutagenesis; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics; D012641:Selection, Genetic; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics; D012907:Smoking / Q000009:adverse effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology; D014466:Ultraviolet Rays / Q000009:adverse effects
D002274:Carcinogens, Environmental; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D044503:5-Methylcytosine; D003596:Cytosine