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首页> 外文期刊>Molecular and Cellular Biology >The sensitivity of Cockayne's syndrome cells to DNA-damaging agents is not due to defective transcription-coupled repair of active genes.
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The sensitivity of Cockayne's syndrome cells to DNA-damaging agents is not due to defective transcription-coupled repair of active genes.

机译：Cockayne综合征细胞对DNA破坏剂的敏感性不是由于活性基因的转录偶联修复缺陷引起的。

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Two of the hallmarks of Cockayne's syndrome (CS) are the hypersensitivity of cells to UV light and the lack of recovery of the ability to synthesize RNA following exposure of cells to UV light, in spite of the normal repair capacity at the overall genome level. The prolonged repressed RNA synthesis has been attributed to a defect in transcription-coupled repair, resulting in slow removal of DNA lesions from the transcribed strand of active genes. This model predicts that the sensitivity of CS cells to another DNA-damaging agent, i.e., the UV-mimetic agent N-acetoxy-2-acetylaminofluorene (NA-AAF), should also be associated with a lack of resumption of RNA synthesis and defective transcription-coupled repair of NA-AAF-induced DNA adducts. We tested this by measuring the rate of excision of DNA adducts in the adenosine deaminase gene of primary normal human fibroblasts and two CS (complementation group A and B) fibroblast strains. High-performance liquid chromatography analysis of DNA adducts revealed that N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF) was the main adduct induced by NA-AAF in both normal and CS cells. No differences were found between normal and CS cells with respect to induction of this lesion either at the level of the genome overall or at the gene level. Moreover, repair of dG-C8-AF in the active adenosine deaminase gene occurred at similar rates and without strand specificity in normal and CS cells, indicating that transcription-coupled repair does not contribute significantly to repair of dG-C8-AF in active genes. Yet CS cells are threefold more sensitive to NA-AAF than are normal cells and are unable to recover the ability to synthesize RNA. Our data rule out defective transcription-coupled repair as the cause of the increased sensitivity of CS cells to DNA-damaging agents and suggest that the cellular sensitivity and the prolonged repressed RNA synthesis are primarily due to a transcription defect. We hypothesize that upon treatment of cells with either UV or NA-AAF, the basal transcription factor TFIIH becomes involved in nucleotide excision repair and that the CS gene products are involved in the conversion of TFIIH back to the transcription function. In this view, the CS proteins act as repair-transcription uncoupling factors. If the uncoupling process is defective, RNA synthesis will stay repressed, causing cellular sensitivity. Since transcription is essential for transcription-coupled repair, the CS defect will affect those lesions whose repair is predominantly transcription coupled, i.e., UV-induced cyclobutane pyrimidine dimers.
机译：尽管在整个基因组水平上具有正常的修复能力，但科卡恩综合症（CS）的两个标志是细胞对紫外线过敏，以及细胞暴露于紫外线后缺乏恢复RNA合成能力的能力。长时间抑制的RNA合成被归因于转录偶联修复的缺陷，导致从活性基因的转录链中缓慢清除DNA损伤。该模型预测CS细胞对另一种DNA破坏剂（即紫外线模拟剂N-乙酰氧基-2-乙酰氨基芴）的敏感性也应与RNA合成缺乏恢复和缺陷有关。 NA-AAF诱导的DNA加合物的转录偶联修复。我们通过测量主要正常人成纤维细胞和两个CS（互补组A和B）成纤维细胞株的腺苷脱氨酶基因中DNA加合物的切除率来测试这一点。 DNA加合物的高效液相色谱分析显示，N-（脱氧鸟苷-8-基）-2-氨基芴（dG-C8-AF）是NA-AAF在正常细胞和CS细胞中诱导的主要加合物。在基因组整体水平或基因水平上，在正常和CS细胞之间就该病变的诱导均未发现差异。此外，在正常和CS细胞中，活性腺苷脱氨酶基因中dG-C8-AF的修复以相似的速率发生且无链特异性，这表明转录偶联修复对活性基因中dG-C8-AF的修复没有显着贡献。然而，CS细胞对NA-AAF的敏感性是正常细胞的三倍，并且无法恢复合成RNA的能力。我们的数据排除了转录偶联修复缺陷是CS细胞对DNA损伤剂敏感性增加的原因，并表明细胞敏感性和长时间抑制的RNA合成主要是由于转录缺陷引起的。我们假设在用UV或NA-AAF处理细胞后，基础转录因子TFIIH参与核苷酸切除修复，而CS基因产物参与TFIIH转换回转录功能。按照这种观点，CS蛋白充当修复转录解偶联因子。如果解偶联过程有缺陷，RNA合成将被抑制，从而引起细胞敏感性。由于转录对于转录偶联的修复是必不可少的，因此CS缺陷会影响那些修复主要是转录偶联的损伤，即紫外线诱导的环丁烷嘧啶二聚体。

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