THE TUMOR-SUPPRESSOR P53 MODIFIES MUTATIONAL PROCESSES IN A HUMAN LYMPHOBLASTOID CELL-LINE

Abnormalities in the p53 gene play an important role in genomic instab ility and tumorigenesis. Our previous work showed that p53 status is c orrelated with differential mutability in two closely related human ly mphoblastoid cell lines, TK6 and WTK1. WTK1 cells, which contain a mut ation in p53 (p53Ile(237)) show a remarkably increased mutability, lar ger genetic alterations at the thymidine kinase locus (tk), an increas ed ability to catalyze recombination, and a delay in the onset of apop tosis after X-irradiation, compared to TK6 (p53 +/+). In the present s tudy, we demonstrate that after transfection and subsequent overexpres sion of the known dominant negative mutant p53 Ala(143) allele (mp53Al a(143)) in TK6, then were significantly enhanced spontaneous and X-ray -induced mutant frequencies at the tk locus, and delayed onset of X-ra y-induced apoptosis, to a similar extent as in WTK1. In addition, high protein expression of mp53Ala(143) in transfectants was correlated wi th both increased mutation frequency and altered apoptosis kinetics. S imilar results were obtained with p53 Ile(237) transfection into TK6. Our observations indicate that the product of the p53 gene affects mut ational processes. We hypothesize that p53 dysfunction can lead to inc reased mutagenicity at the endogenous rk gene in human lymphoblastoid cell Lines either through delayed apoptosis in response to DNA damage or by mediating increased recombination.