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Molecular genetics of human diseases with defect in transcription and DNA repair

转录和 DNA 修复缺陷人类疾病的分子遗传学

基本信息

批准号：
11307056
负责人：
TANAKA Kiyoji
金额：
$ 21.9万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

To counteract the immediate and cytotoxic response of transcription interference by DNA inzuries, transcription-coupled repair (TCR), a specialized pathway that efficiently removes lesions froom the transcribed strand, has evolved. Genetic defects in TCR form the molecular basis of the severe neuro-developmental disorder Cockayne syndrome (CS), underscoring the biological relevance of TCR. Our aim is to analyze the TCR mechanism and the relevance of its defect to CS symptom. We discovered a novel protein designated XAB2 that interacts with CSA, CSB and RNA polymerase II as well as XPA, and is involved in transcription and TCR. We found That CSA protein is rapidly translocated to the nuclear matrix after UV irradiation. The translocation of CSA (CS group A) required the CSB (CS group B) protein. In UV-irradiated cells, CSA protein co-localized with the hyperphosphorylated form of RNA polymerase II, engaged in transcription elongation. The translocation of CSA was also induced by treatment of the cells with cisplatin or hydrogen peroxide, both of which produce damage that.is subjected to TCR, but not induced by the treatment with dimethyl sulfate, which Produces damage that is not subjected to TCR. The hydrogen peroxide-induced translocation of CSA was also CSB-dependent. These findings establish a link between TCR and the nuclear matrix mediated by CSA. In addition, we report that mice lacking both the XPA (Group A-xeroderma pigmentosum) and CSB genes show apparent ataxia from an early postnatal age and display marked structural abnormalities in cerebellum Reduced neurogenesis and increased apoptotic cell death in the cerebellar external granular layer were also observed. These results indicate that the XPA and CSB gene defects cause neurodysfunctions affecting neuronal cell proliferation and survival, and that XPA and CSB have additive roles in the developing mouse nervous system.

为了抵消DNA干扰的即时细胞毒性反应，转录偶联修复(TCR)，一种有效地从转录链上移除损伤的专门途径，已经进化出来。TCR的遗传缺陷构成了严重的神经发育障碍Cockayne综合征(CS)的分子基础，强调了TCR的生物学相关性。我们的目的是分析TCR的机制及其缺陷与CS症状的相关性。我们发现了一种新的蛋白质，命名为XAB2，它与CsA、CSB、RNA聚合酶II以及XPA相互作用，并参与转录和TCR。我们发现，CsA蛋白在紫外线照射后迅速转移到核基质中。CsA(CS组)的转位需要CSB(CS组B组)蛋白。在紫外线照射的细胞中，CsA蛋白与过度磷酸化的RNA聚合酶II共定位，参与转录延伸。顺铂或过氧化氢处理细胞也能诱导CsA的易位，两者的损伤都受到TCR的影响，但不能被硫酸二甲酯诱导，后者产生的损伤不受TCR的影响。过氧化氢诱导的CsA易位也是CSB依赖的。这些发现建立了TCR和CsA介导的核基质之间的联系。此外，我们还报道，缺乏XPA(A组-着色性干皮病)和CSB基因的小鼠从出生后早期就表现出明显的共济失调，小脑结构异常，小脑外颗粒层神经发生减少和细胞凋亡增加。这些结果表明，XPA和CSB基因缺陷导致神经功能障碍，影响神经细胞的增殖和存活，并且XPA和CSB在发育中的小鼠神经系统中具有相加作用。

项目成果

期刊论文数量（46）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fumio Ide, Naoko Iida, Yoko Nakatsuru, Hideaki Oda, Kiyoji Tanaka and Takatoshi Ishikawa: "Mice deficient in the nucleotide excision repair gene XPA have elevated sensitivity to benzo[a]pyrene induction of lung tumors"Carcinogenesis. 21. 1263-1265 (2000)

Fumio Ide、Naoko Iida、Yoko Nakatsuru、Hideaki Oda、Kiyoji Tanaka 和 Takatoshi Ishikawa：“核苷酸切除修复基因 XPA 缺陷的小鼠对苯并[a]芘诱导肺部肿瘤的敏感性升高”致癌作用。

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Hiroko Miyauchi-Hashimoto, Kazue Kuwamoto, Yoshihiro Urade, Kiyoji Tanaka and Takeshi Horio: "Carcinogen-induced inflammation and immunosuppression are enhanced in xerodenna pigmentosum group A (XPA) model mice associated with hyperproduction of prostagla

Hiroko Miyauchi-Hashimoto、Kazue Kuwamoto、Yoshihiro Urade、Kiyoji Tanaka 和 Takeshi Horio：“致癌物诱导的炎症和免疫抑制在 A 组着色性干皮病 (XPA) 模型小鼠中增强，与前列腺素过度生成有关

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Takatoshi Ishikawa, Fumio Ide, Xiusheng Qin, Shaomin Zhang, Yoshihisa Takahashi, Mutsuo Sekiguchi, Kiyoji Tanaka and Yoko Nakatsuru: "Importance of DNA repair in carcinogenesis : evidence from trarisgenic and gene targeting studies"Mutation Research. 477.

Takatoshi Ishikawa、Fumio Ide、Xiusheng Qing、Shaomin Zhang、Yoshihisa Takahashi、Mutsuo Sekiguchi、Kiyoji Tanaka 和 Yoko Nakatsuru：“DNA 修复在致癌作用中的重要性：来自遗传和基因靶向研究的证据”突变研究。