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 损伤引起的转录干扰的直接细胞毒性反应，转录偶联修复（TCR）——一种可以有效去除转录链损伤的特殊途径——得到了发展。 TCR 的遗传缺陷构成了严重神经发育障碍科凯恩综合征 (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 机制及其缺陷与 CS 症状的相关性。我们发现了一种名为 XAB2 的新型蛋白质，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位至核基质。 CSA（CS A 组）的易位需要 CSB（CS B 组）蛋白。在紫外线照射的细胞中，CSA 蛋白与 RNA 聚合酶 II 的过度磷酸化形式共定位，参与转录延伸。 CSA的易位也可以通过用顺铂或过氧化氢处理细胞来诱导，这两种药物都会产生受到TCR影响的损伤，但用硫酸二甲酯处理则不会诱导，而硫酸二甲酯会产生不受TCR影响的损伤。过氧化氢诱导的 CSA 易位也是 CSB 依赖性的。这些发现建立了 TCR 和 CSA 介导的核基质之间的联系。此外，我们报告说，同时缺乏 XPA（A 组色素性干皮病）和 CSB 基因的小鼠在出生后早期就表现出明显的共济失调，并且小脑显示出明显的结构异常。也观察到。这些结果表明XPA和CSB基因缺陷导致影响神经元细胞增殖和存活的神经功能障碍，并且XPA和CSB在发育中的小鼠神经系统中具有附加作用。

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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期刊：
影响因子：
0
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通讯作者：

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。