Accumulation of (5′S)-8,5′-cyclo-2′-deoxyadenosine in organs of Cockayne syndrome complementation group B gene knockout mice
Accumulation of (5′S)-8,5′-cyclo-2′-deoxyadenosine in organs of Cockayne syndrome complementation group B gene knockout mice
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DOI：
10.1016/j.dnarep.2008.09.009
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发表时间：
2009-02-01
期刊：
影响因子：
3.8
通讯作者：
Dizdaroglu, Miral
中科院分区：
文献类型：
--
作者：
Kirkali, Gueldal;de Souza-Pinto, Nadja C.;Dizdaroglu, Miral
柯凯因综合征（CS）是一种人类遗传疾病，其特征是对紫外线辐射敏感，神经退行性变，过早衰老等表型。CS-B互补组（CS-B）基因（csb）编码csb蛋白（csb），该蛋白参与体内基因组DNA氧化损伤的碱基切除修复。我们假设CSB也可能在DNA螺旋扭曲串联损伤(5s)-8,5'-环-2'-脱氧腺苷（S-cdA）的细胞修复中发挥作用。在许多DNA损伤中。S-cdA的独特之处在于它同时对同一核苷的糖和碱基部分造成损害。由于C8-C5'共价键的存在，S-cdA是通过核苷酸切除修复的，而不像大多数其他氧化诱导的DNA损伤是通过碱基切除修复的。为了验证我们的假设，我们从野生型和csb敲除（csb(-/-)）小鼠的大脑、肾脏和肝脏中分离出基因组DNA。实验前动物未受到任何外源性氧化应激。采用同位素稀释液相色谱/质谱法对DNA样品进行分析。在统计上，csb（-/-）小鼠的所有三个器官中S-cdA的背景水平都高于野生型小鼠。这些结果表明，在csb（-/-）小鼠体内，由于缺乏修复，S-cdA在基因组DNA中积累。因此，本研究首次提供了CSB在DNA螺旋扭曲串联损伤S-cdA修复中发挥作用的证据。体内未修复的S-cdA的积累可能与CS相关的病理有关。Elsevier B.V.出版
Cockayne syndrome (CS) is a human genetic disorder characterized by sensitivity to UV radiation, neurodegeneration, premature aging among other phenotypes. CS complementation group B (CS-B) gene (csb) encodes the CSB protein (CSB) that is involved in base excision repair of a number of oxidatively induced lesions in genomic DNA in vivo. We hypothesized that CSB may also play a role in cellular repair of the DNA helix-distorting tandem lesion (5'S)-8,5'-cyclo-2'-deoxyadenosine (S-cdA). Among many DNA lesions. S-cdA is unique in that it represents a concomitant damage to both the sugar and base moieties of the same nucleoside. Because of the presence of the C8-C5' covalent bond, S-cdA is repaired by nucleotide excision repair unlike most of other oxidatively induced lesions in DNA, which are subject to base excision repair. To test our hypothesis, we isolated genomic DNA from brain, kidney and liver of wild type and csb knockout (csb(-/-)) mice. Animals were not exposed to any exogenous oxidative stress before the experiment. DNA samples were analysed by liquid chromatography/mass spectrometry with isotope-dilution. Statistically greater background levels of S-cdA were observed in all three organs of csb(-/-) mice than in those of wild type mice. These results suggest the in vivo accumulation of S-cdA in genomic DNA due to lack of its repair in csb(-/-) mice. Thus, this study provides, for the first time, the evidence that CSB plays a role in the repair of the DNA helix-distorting tandem lesion S-cdA. Accumulation of unrepaired S-cdA in vivo may contribute to the pathology associated with CS. Published by Elsevier B.V.