title: Cancerous hyper-mutagenesis in p53 genes is possibly associated with transcriptional bypass of DNA lesions.
abstract: The database of tumor-associated p53 base substitutions includes about 5% of tumors with two or more base substitutions. These multiplet base substitutions in one tumor are evidence for hyper-mutagenesis. Our retrospective analysis of this database indicates that most multiplets arise from a single transient hyper-mutagenic event in one cell that subsequently proliferated into a clonal tumor. The hyper-mutagenesis, 1.8 x 10(-4) substitutions per base pair, is detected as multiple mutations in p53 genes of tumors. It requires one strongly tumorigenic p53 substitution, usually missense, called the driver mutation. The occurrence frequencies of ancillary base substitutions, those that hitch-hike along with the driver mutation, are independent of their amino acid coding properties. In this respect, they act like neutral mutations. In support of this neutrality, we find that the frequency distribution of hitch-hiking CpG transitions along the p53 exons, their mutational spectrum, approximates the spontaneous pre-selection mutational spectrum of most human tissues and is correlated with the mutational spectrum of p53 pseudogenes in mammalian germ cells. The driver substitutions of multiplets predominantly originate along the transcribed strand while the ancillary substitutions tend to originate along the non-transcribed strand. This data is consistent with a model of time-dependent mutagenesis in non-dividing stem cells for generating multiple strand-asymmetric p53 mutations in tumors. By transcriptional bypass of DNA lesions with concomitant misincorporation, transcriptional mutagenesis generates a transient mutant p53 mRNA. The associated mutant p53 protein could allow the host cell a growth advantage, release from G1-arrest. Then, during subsequent DNA replication and misreading of the same lesion, the damaged base along the transcribed DNA strand would serve as the origin of the p53 base substitution that drives the hyper-mutagenic event leading to tumors with multiple p53 mutations.
authors.affiliation: Biology Department, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA. srodin@coh.org
authors.forename: S N
authors.initials: SN
authors.lastname: Rodin
authors.forename: A S
authors.initials: AS
authors.lastname: Rodin
authors.forename: A
authors.initials: A
authors.lastname: Juhasz
authors.forename: G P
authors.initials: GP
authors.lastname: Holmquist
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D030561:Databases, Nucleic Acid; D016158:Genes, p53; D006801:Humans; D008957:Models, Genetic; D016296:Mutagenesis; D009369:Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004273:DNA, Neoplasm