Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice
Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice
复制标题
DOI：
10.1016/s1568-7864(02)00188-x
复制
发表时间：
2003-01-02
期刊：
影响因子：
3.8
通讯作者：
van der Horst, GTJ
中科院分区：
文献类型：
--
作者：
de Waard, H;de Wit, J;van der Horst, GTJ
CSB基因突变导致Cockayne综合征(CS)，这是一种罕见的遗传性疾病，其特征是对紫外线敏感，严重的神经发育和孕激素症状。CSB在核苷酸切除修复(NER)的转录偶联修复(TCR)亚途径中发挥作用，负责从活性基因的转录链中移除紫外线诱导的和其他螺旋扭曲的损伤。有几条证据支持这样的观点，即CSB TCR缺陷延伸到其他非NER类型的转录阻断损伤，特别是各种氧化损伤，这可能为部分严重的CS表型提供解释。我们使用基因定义的小鼠模型来研究CSB缺陷与不同细胞类型和完整生物体水平上的氧化损伤敏感性之间的关系。主要结论如下：(1)CSB-/-小鼠胚胎成纤维细胞(MEF)对电离辐射表现出明显的超敏反应，将遗传异质性的人CSB成纤维细胞的研究结果推广到其他物种。(2)CSB-/-MEF对百草枯高度敏感，表明细胞毒性增加是由于氧化损伤所致。(3)高敏感度与遗传背景无关，与CSB缺陷直接相关，在完全缺乏NER的XPA MEF中未观察到。(4)野生型胚胎干细胞对电离辐射的敏感性高于成纤维细胞。令人惊讶的是，CSB缺陷对ES细胞对氧化损伤的敏感性只有非常微小的额外影响，与XPA缺陷相当，表明TCR和NER对细胞存活的贡献因细胞类型而异。(5)与ES细胞相似，CSB和XPA小鼠对全身X射线照射都表现出轻微的敏感性。这表明，一个完整的有机体对辐射的反应在很大程度上取决于干细胞的敏感性，而不是分化的细胞。这些发现确立了转录偶联修复在抵抗氧化损伤中的作用，并揭示了这一修复途径对CS和XP临床表型的特定细胞和器官影响。(C)2002 Elsevier Science B.V.保留所有权利。
Mutations in the CSB gene cause Cockayne syndrome (CS), a rare inherited disorder, characterized by UV-sensitivity, severe neurodevelopmental and progeroid symptoms. CSB functions in the transcription-coupled repair (TCR) sub-pathway of nucleotide excision repair (NER), responsible for the removal of UV-induced and other helix-distorting lesions from the transcribed strand of active genes. Several lines of evidence support the notion that the CSB TCR defect extends to other non-NER type transcription-blocking lesions, notably various kinds of oxidative damage, which may provide an explanation for part of the severe CS phenotype. We used genetically defined mouse models to examine the relationship between the CSB defect and sensitivity to oxidative damage in different cell types and at the level of the intact organism. The main conclusions are: (1) CSB-/- mouse embryo fibroblasts (MEFs) exhibit a clear hypersensitivity to ionizing radiation, extending the findings in genetically heterogeneous human CSB fibroblasts to another species. (2) CSB-/- MEFs are highly sensitive to paraquat, strongly indicating that the increased cytotoxicity is due to oxidative damage. (3) The hypersenstivity is independent of genetic background and directly related to the CSB defect and is not observed in totally NER-deficient XPA MEFs. (4) Wild type embryonic stem (ES) cells display an increased sensitivity to ionizing radiation compared to fibroblasts. Surprisingly, the CSB deficiency has only a very minor additional effect on ES cell sensitivity to oxidative damage and is comparable to that of an XPA defect, indicating cell type-specific differences in the contribution of TCR and NER to cellular survival. (5) Similar to ES cells, CSB and XPA mice both display a minor sensitivity to whole-body X-ray exposure. This suggests that the response of an intact organism to radiation is largely determined by the sensitivity of stem cells, rather than differentiated cells. These findings establish the role of transcription-coupled repair in resistance to oxidative damage and reveal a cell- and organ-specific impact of this repair pathway to the clinical phenotype of CS and XP. (C) 2002 Elsevier Science B.V All rights reserved.