Mutagenesis Advance Access published online on June 13, 2007
Mutagenesis, doi:10.1093/mutage/gem021
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Wild-type p53 reduces radiation hypermutability in p53-mutated human lymphoblast cells
Department of Environmental and Radiological Health Sciences 1Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO 80523, USA
Many studies have shown that an alteration of p53 affects various cellular responses to DNA damage after treatment with ionizing radiation. The human lymphoblast cell WTK1, which contains a mutant p53 (ile237), is 10-fold hypermutable at the thymidine kinase (tk) locus compared with TK6 cells, which are from the same donor but contain wild-type p53. These results implied that the specific p53 mutation found in WTK1 may actively contribute to mutagenesis in a gain of function manner. To further investigate this, the present experiments involved transfecting WTK1 cells with a wild-type p53 vector; this restored p53 activity in WTK1 cells, as evidenced by radiation-induced expression of p21. We compared radiosensitivity, as measured both by clonogenic survival and the induction of apoptosis, as well as mutant fractions (MFs) at the tk locus. WTK1 cells expressing wild-type p53 were more sensitive to 
-ray-induced toxicity as measured by either clonogenic survival or apoptosis. The mutation assays revealed that both the spontaneous and -ray-induced MFs were significantly decreased in WTK1 cells expressing wild-type p53; the MFs were similar to those observed in p53-null NH32 cells, also derived from the same donor. These results indicate that wild-type p53 can reduce the apparent gain-of-function hypermutable effects of a particular p53 gene mutation and thereby help maintain genomic stability.
* To whom correspondence should be addressed: Qinming Zhang M.D. M.Sc., Department of Environmental and Radiological Health Sciences, Colorado State University, 1618 Campus Delivery, Fort Collins, CO 80523, USA. Tel: +970 491 2688; Fax: +970 491 0623; Email: zhangqm{at}colostate.edu
Received on February 8, 2007; revised on April 12, 2007; accepted on April 20, 2007.
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