Radioresistant MTp53-expressing rat embryo cell transformants exhibit increased DNA-dsb rejoining during exposure to ionizing radiation

被引:41
作者
Bristow, RG
Hu, QY
Jang, A
Chung, S
Peacock, J
Benchimol, S
Hill, R
机构
[1] Princess Margaret Hosp, Ontario Canc Inst, Dept Res, Div Expt Therapeut, Toronto, ON M5G 2M9, Canada
[2] Princess Margaret Hosp, Ontario Canc Inst, Dept Res, Div Cellular & Mol Biol, Toronto, ON M5G 2M9, Canada
[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada
[4] Univ Toronto, Dept Radiat Oncol, Toronto, ON M5G 2M9, Canada
基金
英国医学研究理事会;
关键词
p53; H-ras; radioresistance; apoptosis; cell cycle arrests; DNA repair;
D O I
10.1038/sj.onc.1201935
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Recent data suggest that aberrant function of the wild type p53 protein (WTp53) may alter cellular survival following DNA damage through cellular pathways involving apoptosis and cell-cycle checkpoints, but little is known concerning it's possible role in DNA repair. In the present study, the ionizing radiation sensitivity was determined for a series of rat embryo fibroblast (REF) cell lines transfected with an activated form of the H-ras oncogene alone, or in combination with a variety of missense-mutant p53 (MTp53) alleles. Transformed REF clones which expressed exogenous MTp53 and p21(ras) proteins (CLASS II clones) were generally radioresistant in culture as determined by higher values surviving fraction after 2 Gy (SF2 value) radiation dose required to reduce survival to a fraction of 0.1 (D10 value), compared either to transformed REF clones expressing p21(ras) protein alone (CLASS I clones), or to non-transfected REF control cell lines expressing baseline endogenous levels of p21(ras) and WTp53 protein. The increased radioresistance observed in the CLASS II clones (following both HDR-and LDR-irradiation), was significantly correlated with increased expression of MTp53 protein, and a decreased radiation-induced G1 arrest response, The variability observed in clonogenic radiosensitivity among REF clones was not explained by differential radiation-induced apoptosis. Using the Comet assay performed after continuous low dose-rate (LDR)irradiation, MTp53-expressing REF clones were also found to be more proficient at the rejoining of DNA double-strand breaks (DNA-dsb), compared to WTp53-expressing REF clones. These results suggest that an enhanced DNA and cellular repair capacity may, in part, explain the increased radiation survival observed in some MTp53-expressing transformed fibroblasts and tumours.
引用
收藏
页码:1789 / 1802
页数:14
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