The role of CSA in the response to oxidative DNA damage in human cells
The role of CSA in the response to oxidative DNA damage in human cells
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DOI：
10.1038/sj.onc.1210232
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发表时间：
2007-06-01
期刊：
影响因子：
8
通讯作者：
Dogliotti, E.
中科院分区：
文献类型：
--
作者：
D'Errico, M.;Parlanti, E.;Dogliotti, E.
Cockayne综合征（CS）是一种罕见的遗传性疾病，其特征是严重的生长，智力低下和明显的恶病质。CS最常见的是由于两个基因CSB和CSA中的任何一个突变。CSB蛋白在氧化性DNA损伤修复中的作用的证据最近已被提供。在这里，我们表明，CSA也参与了对氧化应激的反应。CS-A人类初级成纤维细胞和角质形成细胞显示出对溴酸钾（一种氧化损伤的特异性诱导物）的超敏反应。这与氧化诱导的DNA损伤即8-羟基鸟嘌呤（8-OH-Gua）和（5 ' S）-8，5'-环2 '-脱氧腺苷的修复效率低下有关。在CS-A细胞系CS3 BE中表达野生型CSA显著降低了8-OH-Gua的稳态水平，并增加了氧化剂处理后的修复率。CS-A细胞提取物在体外试验中显示出正常的8-OH-Gua切割活性，而CS-B细胞提取物被确认为有缺陷。我们的数据提供了。第一个体内证据表明CSA蛋白有助于防止各种氧化DNA碱基的积累，并强调了CSB与CSA不共享的特定功能。这些.这些发现支持了这样的假设，即氧化性DNA损伤的修复缺陷与CS患者的临床特征有关。
Cockayne syndrome (CS) is a rare genetic disease characterized by severe growth, mental retardation and pronounced cachexia. CS is most frequently due to mutations in either of two genes, CSB and CSA. Evidence for a role of CSB protein in the repair of oxidative DNA damage has been provided recently. Here, we show that CSA is also involved in the response to oxidative stress. CS-A human primary. fibroblasts and keratinocytes showed hypersensitivity to potassium bromate, a specific inducer of oxidative damage. This was associated with inefficient repair of oxidatively induced DNA lesions, namely 8-hydroxyguanine (8-OH-Gua) and (5 ' S)-8,5 '-cyclo 2 '-deoxyadenosine. Expression of the wild-type CSA in the CS-A cell line CS3BE significantly decreased the steady-state level of 8-OH-Gua and increased its repair rate following oxidant treatment. CS-A cell extracts showed normal 8-OH-Gua cleavage activity in an in vitro assay, whereas CS-B cell extracts were con. firmed to be defective. Our data provide the. first in vivo evidence that CSA protein contributes to prevent accumulation of various oxidized DNA bases and underline specific functions of CSB not shared with CSA. These. findings support the hypothesis that defective repair of oxidative DNA damage is involved in the clinical features of CS patients.