Mutant Cockayne syndrome group B protein inhibits repair of DNA topoisomerase I-DNA covalent complex
Mutant Cockayne syndrome group B protein inhibits repair of DNA topoisomerase I-DNA covalent complex
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DOI：
10.1111/j.1365-2443.2010.01467.x
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发表时间：
2011-01-01
期刊：
影响因子：
2.1
通讯作者：
Tanaka, Kiyoji
中科院分区：
文献类型：
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作者：
Horibata, Katsuyoshi;Saijo, Masafumi;Tanaka, Kiyoji
由于CSB基因的纯合零突变，两名具有轻度光敏性且未检测到体细胞异常的紫外线敏感综合征患者缺乏可检测到的Cockayne综合征B组（CSB）蛋白。相比之下，CS-B患者的Cockayne综合征和光敏性的严重体细胞异常产生突变的CSB蛋白。已知piggyBac转座元件衍生3整合在CSB内含子5内，CSB-piggyBac转座元件衍生3融合（CPFP） mRNA是通过选择性剪接产生的。我们发现CPFP或源自CPFP mRNA的截短的CSB蛋白在CS-B患者中稳定产生，并且野生型CSB、CPFP和截短的CSB蛋白与DNA拓扑异构酶i相互作用。我们还发现CPFP抑制喜树碱诱导的拓扑异构酶I-DNA共价复合物的修复。这种抑制作用被野生型CSB的存在所抑制，与柯凯因综合征的常染色体隐性遗传一致。这些结果表明，DNA拓扑异构酶I-DNA共价复合物因CSB蛋白截短而修复减少参与了CS-B的发病机制。
Two UV-sensitive syndrome patients who have mild photosensitivity without detectable somatic abnormalities lack detectable Cockayne syndrome group B (CSB) protein because of a homozygous null mutation in the CSB gene. In contrast, mutant CSB proteins are produced in CS-B patients with the severe somatic abnormalities of Cockayne syndrome and photosensitivity. It is known that the piggyBac transposable element derived 3 is integrated within the CSB intron 5, and that CSB-piggyBac transposable element derived 3 fusion (CPFP) mRNA is produced by alternative splicing. We found that CPFP or truncated CSB protein derived from CPFP mRNA was stably produced in CS-B patients, and that wild-type CSB, CPFP, and truncated CSB protein interacted with DNA topoisomerase I. We also found that CPFP inhibited repair of a camptothecin-induced topoisomerase I-DNA covalent complex. The inhibition was suppressed by the presence of wild-type CSB, consistent with the autosomal recessive inheritance of Cockayne syndrome. These results suggested that reduced repair of a DNA topoisomerase I-DNA covalent complex because of truncated CSB proteins is involved in the pathogenesis of CS-B.