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

为了抵消由DNA损伤引起的转录干扰的即时和细胞毒性反应，转录偶联修复（TCR），一种有效地去除转录链损伤的专门途径，已经发展。TCR的遗传缺陷形成了严重神经发育障碍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机制及其缺陷与CS症状的相关性。我们发现了一种名为XAB 2的新蛋白，它与CSA、CSB和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移位到核基质中。CSA（CS group A）的易位需要CS B（CS group B）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的易位也通过用顺铂或过氧化氢处理细胞而诱导，这两种物质都产生受到TCR的损伤，但不通过用硫酸二甲酯处理而诱导，硫酸二甲酯产生不受到TCR的损伤。that.is过氧化氢诱导的CSA易位也依赖于CSA。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，小鼠缺乏XPA（A组着色性干皮病）和CSB基因表现出明显的共济失调，从出生后早期的年龄和显示显着的结构异常，小脑的神经发生减少和增加的凋亡细胞死亡小脑外颗粒层也被观察到。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相加作用。

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.