Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance.
We investigated whether mutations in the p53 tumor suppressor gene alter UV sensitivity and/or repair of UV-induced DNA damage in primary human skin fibroblasts from patients with Li-Fraumeni syndrome, heterozygous for mutations in one allele of the p53 gene (p53 wt/mut) and sublines expressing only mutant p53 (p53 mut). The p53 mut cells were more resistant than the p53 wt/mut cells to UV cytotoxicity and exhibited less UV-induced apoptosis. DNA repair analysis revealed reduced removal of cyclobutane pyrimidine dimers from overall genomic DNA in vivo in p53 mut cells compared with p53 wt/mut or normal cells. However, p53 mut cells retained the ability to preferentially repair damage in the transcribed strands of expressed genes (transcription-coupled repair). These results suggest that loss of p53 function may lead to greater genomic instability by reducing the efficiency of DNA repair but that cellular resistance to DNA-damaging agents may be enhanced through elimination of apoptosis.
Ford
J M
JM
Department of Biological Sciences, Stanford University, CA 94305-5020, USA.
Hanawalt
P C
PC
D017209:Apoptosis; D002470:Cell Survival; D002999:Clone Cells; D004260:DNA Repair / Q000235:genetics*; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts; D006720:Homozygote; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008856:Microscopy, Fluorescence; D009154:Mutation; D009369:Neoplasms / Q000209:etiology; D011740:Pyrimidine Dimers / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*; D013762:Tetrahydrofolate Dehydrogenase; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects
D011740:Pyrimidine Dimers; D016159:Tumor Suppressor Protein p53; D013762:Tetrahydrofolate Dehydrogenase