Trichothiodystrophy fibroblasts are deficient in the repair of ultraviolet-induced cyclobutane pyrimidine dimers and (6-4) photoproducts

毛发硫营养不良成纤维细胞缺乏紫外线诱导的环丁烷嘧啶二聚体和 (6-4) 光产物的修复

• 批准号: 14570819
• 负责人: MIYAGAWA Sachiko
• 金额: $ 1.92万
• 依托单位: Nara Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570819/
• 关键词: Trichothiodystrophy; Ultraviolet light; DNA damage; DNA repair; TFIIH; XPD; Nucleotide excision repair; Photocarcinogenesis; ヌクレチオド除去修後; 光線過敏症

A photosensitive form of trichothiodystrophy (TTD) results from mutations in the same XPD gene as the DNA repair-deficient genetic disorder xeroderma pigmentosum group D (XP-D). Nevertheless, unlike XP, no increase in skin cancers appears in patients with TTD. Although the ability to repair ultraviolet (UV)-induced DNA damage has been examined to explain their cancer-free phenotype, the information accumulated to date is contradictory. In this study, we determined the repair kinetics of cyclobutane pyrimidine dimers (CPD) and (6-4)photoproducts (6-4PP) in three TTD cell strains using an enzyme-linked immunosorbent assay. We found that all three TTD cell strains are deficient in the repair of CPD and of 6-4PP. UV sensitivity correlated well with the severity of repair defects. Moreover, accumulation of repair proteins (XPB and proliferating cell nuclear antigen) at localized DNA damage sites, detected using micropore UV irradiation combined with fluorescent antibody labeling, reflected their DNA repair activity. Importantly, mutations of the XPD gene affected both the recruitment of the TFIIH complex to DNA damage sites and the TFIIH expression. Our results suggest that there is no major difference in the repair defect between TTD and XPD and that the cancer-free phenotype in TTD is unrelated to a DNA repair defect.

光敏型的皮肤硫营养不良（TTD）是由与DNA修复缺陷型遗传性疾病着色性干皮病D组（XP-D）相同的XPD基因突变引起的。然而，与XP不同，TTD患者的皮肤癌发病率没有增加。虽然修复紫外线（UV）诱导的DNA损伤的能力已被检查，以解释他们的无癌表型，迄今为止积累的信息是矛盾的。在这项研究中，我们确定了环丁烷嘧啶二聚体（CPD）和（6-4）光产物（6- 4 PP）在三个TTD细胞株的修复动力学使用酶联免疫吸附测定。我们发现，所有三种TTD细胞株都缺乏CPD和6-4PP的修复。紫外线敏感性与修复缺陷的严重程度相关。此外，积累的修复蛋白（XPB和增殖细胞核抗原）在本地化的DNA损伤位点，检测使用紫外线照射结合荧光抗体标记，反映了它们的DNA修复活性。重要的是，XPD基因的突变影响TFIIH复合物向DNA损伤位点的募集和TFIIH表达。我们的研究结果表明，TTD和XPD之间的修复缺陷没有重大差异，TTD中的无癌表型与DNA修复缺陷无关。

项目成果

Imoto K. et al.: "The Total Amount of DNA Damage Determines Ultraviolet-radiation-induced Cytotoxicity After Uniform or Localized Irradiation of Human Cells"J Invest. Dermatol.. 119. 1177-1182 (2002)

Imoto K. 等人：“DNA 损伤总量决定了人体细胞均匀或局部照射后紫外线辐射诱导的细胞毒性”J Invest。

Nishiwaki Y: "Trichothiodystrophy fibroblasts are deficient in the repair of UV-induced cyclobutane pyrimidine dimers and (6-4) photoproducts"J Invest Dermatol. 112 (Feb 2^<nd> on line). (2004)

Nishiwaki Y：“毛发硫营养不良成纤维细胞在修复紫外线诱导的环丁烷嘧啶二聚体和 (6-4) 光产物方面存在缺陷”J Invest Dermatol。

Yoko Nishiwaki: "Trichothiodystropy fibroblasts are deficient in the repair of UV-induced cyclobutane pyrimidine dimers and (6-4) photo products"J Invest Darmatol. 122(On line). (2004)

Yoko Nishiwaki：“毛发硫营养不良成纤维细胞在修复紫外线诱导的环丁烷嘧啶二聚体和 (6-4) 光产物方面存在缺陷”J Invest Darmatol。

Imoto K: "The total amount of DNA damage determines ultraviolet-radiation-induced cytotoxicity after uniform or localized irradiation of human cells"J Invest Dermatol. 119. 1177-1182 (2002)

Imoto K：“DNA 损伤的总量决定了人体细胞均匀或局部照射后紫外线辐射诱导的细胞毒性”J Invest Dermatol。

Kyoko Imoto: "The total amount of DNA damage determines ultraviolet-radiation-induced cytotoxicity after uniformor localized irradiation of human cells"J Invest Darmatol. 119. 1177-1182 (2002)

Kyoko Imoto：“DNA 损伤的总量决定了人体细胞均匀或局部照射后紫外线辐射诱导的细胞毒性”J Invest Darmatol。