SPECIFIC UV-INDUCED MUTATION SPECTRUM IN THE P53 GENE OF SKIN TUMORS FROM DNA-REPAIR-DEFICIENT XERODERMA-PIGMENTOSUM PATIENTS
SPECIFIC UV-INDUCED MUTATION SPECTRUM IN THE P53 GENE OF SKIN TUMORS FROM DNA-REPAIR-DEFICIENT XERODERMA-PIGMENTOSUM PATIENTS
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DOI：
10.1073/pnas.90.22.10529
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发表时间：
1993-11-15
影响因子：
11.1
通讯作者：
DAYAGROSJEAN, L
中科院分区：
文献类型：
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作者：
DUMAZ, N;DROUGARD, C;DAYAGROSJEAN, L
阳光中的紫外线成分是皮肤癌病因学中的主要致癌物质。我们已经研究了罕见的遗传性综合征着色性干皮病（XP），其特点是在早期暴露的皮肤上发生皮肤肿瘤的发病率非常高，这可能是由于缺乏切除修复紫外线诱导的病变。确定XP皮肤肿瘤中的UV突变谱是有趣的，以便将特定DNA损伤的修复的缺乏与皮肤肿瘤的起始相关联。p53基因在人类癌症中经常突变，并且代表了用于研究突变谱的良好靶标，因为存在>100个表型突变的潜在位点。使用逆转录-PCR和单链构象多态性分析>40个XP皮肤肿瘤（主要是基底细胞癌和鳞状细胞癌），我们发现40%（43个中的17个）包含至少一个p53基因点突变。所有的突变都位于二嘧啶位点，主要是CC序列，这是紫外线诱导的DNA损伤的热点。这些突变中的61%是串联CC -> TT突变，被认为是UV诱导的病变所特有的;这些突变在人体内部肿瘤中未观察到。除了两个突变之外，所有突变都必须是由于非转录链上留下的未修复的二嘧啶损伤的跨损伤合成造成的。这些结果表明，在人体组织中，转录链上存在UV损伤[嘧啶二聚体或嘧啶-嘧啶酮（6-4）光产物]的优先修复。
The UV component of sunlight is the major carcinogen involved in the etiology of skin cancers. We have studied the rare, hereditary syndrome xeroderma pigmentosum (XP), which is characterized by a very high incidence of cutaneous tumors on exposed skin at an early age, probably due to a deficiency in excision repair of UV-induced lesions. It is interesting to determine the UV mutation spectrum in XP skin tumors in order to correlate the absence of repair of specific DNA lesions and the initiation of skin tumors. The p53 gene is frequently mutated in human cancers and represents a good target for studying mutation spectra since there are >100 potential sites for phenotypic mutations. Using reverse transcription-PCR and single-strand conformation polymorphism to analyze >40 XP skin tumors (mainly basal and squamous cell carcinomas), we have found that 40% (17 out of 43) contained at least one point mutation on the p53 gene. All the mutations were located at dipyrimidine sites, essentially at CC sequences, which are hot spots for UV-induced DNA lesions. Sixty-one percent of these mutations were tandem CC --> TT mutations considered to be unique to UV-induced lesions; these mutations are not observed in internal human tumors. All the mutations, except two, must be due to translesion synthesis of unrepaired dipyrimidine lesions left on the nontranscribed strand. These results show the existence of preferential repair of UV lesions [either pyrimidine dimers or pyrimidine-pyrimidone (6-4) photoproducts] on the transcribed strand in human tissues.