Different removal of ultraviolet photoproducts in genetically related xeroderma pigmentosum and trichothiodystrophy diseases.
Different removal of ultraviolet photoproducts in genetically related xeroderma pigmentosum and trichothiodystrophy diseases.
复制标题
遗传相关的着色性干皮病和毛发硫营养不良疾病中紫外线光产物的不同去除。
作者：
E. Eveno;F. Bourre;X. Quilliet;O. Chevallier;L. Roza;A. Eker;W. Kleijer;O. Nikaido;M. Stefanini;J. Hoeijmakers
为了了解不同核苷酸切除修复缺陷型人类综合征中皮肤癌遗传易感性的异质性，我们研究了环丁烷嘧啶二聚体（CPD）和嘧啶（6-4）嘧啶酮（6-4PP）光产物在来自甲状腺营养不良（TTD）患者的细胞中的修复。TTD与皮肤癌发病率的增加无关，尽管50%的患者是光敏的，并且在核苷酸切除修复途径中携带缺陷，类似于着色性干皮病患者。然而，与TTD形成鲜明对比的是，着色性干皮病非常容易患癌症。为了解决这个明显的矛盾，进行了两种类型的研究：（a）在转染SV 40转化的成纤维细胞之前，用或不用光裂合酶处理，再活化含有活性转录的报告基因的UV照射质粒;和（B）通过免疫印迹分析，使用SV 40 - 100中的损伤特异性mAb，测定UV诱导的CPD和6- 4 PP在基因组DNA中的去除动力学。转化和未转化的成纤维细胞代表所有遗传TTD互补组。结果显示，来自光敏性TTD患者的所有细胞系在携带非CPD病变（包括6-4PP）的转染质粒中有效表达Cat或荧光素酶基因，并且在免疫印迹分析后在整个基因组中显示野生型或近野生型（在3个细胞系中为50-70%）6-4PP修复。然而，CPD损伤（其修复在整个基因组中是有缺陷的）也阻断转染质粒中报告基因的表达。来自非光敏TTD患者的两个细胞系在整个基因组中表现出两种光产物的野生型修复水平。提出了一个关于TTD中分子缺陷背景下病变特异性修复的模型。缺陷的CPD修复和有效的6-4PP修复子途径在TTD患者的癌症预防的意义进行了讨论。
To understand the heterogeneity in genetic predisposition to skin cancer in different nucleotide excision repair-deficient human syndromes, we studied repair of cyclobutane pyrimidine dimers (CPDs) and of pyrimidine(6-4)pyrimidone (6-4PP) photoproducts in cells from trichothiodystrophy (TTD) patients. TTD is not associated with increased incidence of skin cancer, although 50% of the patients are photosensitive and carry a defect in the nucleotide excision repair pathway, similar to Xeroderma pigmentosum patients. However, in striking contrast to TTD, Xeroderma pigmentosum is highly prone to cancer. To address this apparent paradox, two types of studies were conducted: (a) reactivation of UV-irradiated plasmids harboring actively transcribed reporter genes, with or without photolyase treatment before transfection of SV40-transformed fibroblasts; and (b) the kinetics of removal of UV-induced CPDs and 6-4PPs in genomic DNA by immunoblot analysis using lesion-specific mAbs in SV40-transformed and untransformed fibroblasts representative of all genetic TTD complementation groups. Results showed that all cell lines from photosensitive TTD patients efficiently express Cat or luciferase genes in transfected plasmids carrying non-CPD lesions, including 6-4PP, and display wild-type or near-wild-type (50-70% in 3 cell lines) 6-4PP repair in the overall genome after immunoblot analysis. However, CPD lesions (the repair of which is defective in the overall genome) also block the expression of the reporter gene in transfected plasmids. Two cell lines from nonphotosensitive TTD patients showed wild-type levels of repair for both photoproducts in overall genome. A model on the lesion-specific repair in the context of the molecular defect in TTD is proposed. The implication of the defective CPD repair and efficient 6-4PP repair subpathways in cancer prevention in TTD patients is discussed.
开发用于检测哺乳动物细胞 DNA 中光产物的放射免疫测定法。
DOI：
10.1016/0005-2787(81)90066-6
发表时间：
1981
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Mitchell,DL;Clarkson,JM
通讯作者：
Clarkson,JM