LI-FRAUMENI SYNDROME FIBROBLASTS HOMOZYGOUS FOR P53 MUTATIONS ARE DEFICIENT IN GLOBAL DNA-REPAIR BUT EXHIBIT NORMAL TRANSCRIPTION-COUPLED REPAIR AND ENHANCED UV RESISTANCE
LI-FRAUMENI SYNDROME FIBROBLASTS HOMOZYGOUS FOR P53 MUTATIONS ARE DEFICIENT IN GLOBAL DNA-REPAIR BUT EXHIBIT NORMAL TRANSCRIPTION-COUPLED REPAIR AND ENHANCED UV RESISTANCE
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DOI：
10.1073/pnas.92.19.8876
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发表时间：
1995-09-12
影响因子：
11.1
通讯作者：
HANAWALT, PC
中科院分区：
文献类型：
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作者：
FORD, JM;HANAWALT, PC
我们研究了p53肿瘤抑制基因突变是否改变了Li-Fraumeni综合征患者的原代人皮肤成纤维细胞的紫外线敏感性和/或紫外线诱导的DNA损伤修复，Li-Fraumeni综合征患者为p53基因一个等位基因突变的杂合子（p53 wt/mut）和仅表达突变型p53（p53 mut）的亚系，p53 mut细胞比p53 wt/mut细胞对UV细胞毒性的抗性更强，并且表现出更少的UV诱导的凋亡。DNA修复分析显示，与p53 wt/mut或正常细胞相比，p53 mut细胞体内总基因组DNA中环丁烷嘧啶二聚体的去除减少。然而，p53突变细胞保留了优先修复表达基因转录链损伤的能力（转录偶联修复）。这些结果表明，p53功能的丧失可能会导致更大的基因组不稳定性，通过降低DNA修复的效率，但细胞对DNA损伤剂的抗性可能会通过消除细胞凋亡而增强。
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.