The tumor suppressor p53 modifies mutational processes in a human lymphoblastoid cell line.
Abnormalities in the p53 gene play an important role in genomic instability and tumorigenesis. Our previous work showed that p53 status is correlated with differential mutability in two closely related human lymphoblastoid cell lines, TK6 and WTK1. WTK1 cells, which contain a mutation in p53 (p53Ile237) show a remarkably increased mutability, larger genetic alterations at the thymidine kinase locus (tk), an increased ability to catalyze recombination, and a delay in the onset of apoptosis after X-irradiation, compared to TK6 (p53 +/+). In the present study, we demonstrate that after transfection and subsequent overexpression of the known dominant negative mutant p53 Ala143 allele (mp53Ala143) in TK6, there were significantly enhanced spontaneous and X-ray-induced mutant frequencies at the tk locus, and delayed onset of X-ray-induced apoptosis, to a similar extent as in WTK1. In addition, high protein expression of mp53Ala143 in transfectants was correlated with both increased mutation frequency and altered apoptosis kinetics. Similar results were obtained with p53 Ile237 transfection into TK6. Our observations indicate that the product of the p53 gene affects mutational processes. We hypothesize that p53 dysfunction can lead to increased mutagenicity at the endogenous tk gene in human lymphoblastoid cell lines either through delayed apoptosis in response to DNA damage or by mediating increased recombination.
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Department of Cancer Biology, Harvard University School of Public Health, Boston, MA 02115, USA.
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D000483:Alleles; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000528:radiation effects*; D006801:Humans; D008214:Lymphocytes; D016296:Mutagenesis / Q000528:radiation effects*; D010957:Plasmids; D011995:Recombination, Genetic; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection
D013937:Thymidine Kinase