Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
Genes Cells. 2011 Jan;16(1):101-14. doi: 10.1111/j.1365-2443.2010.01467.x. Epub 2010 Dec 9.
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.
两名对紫外线敏感的综合征患者表现出轻度光敏感性，但没有可检测到的躯体异常，这是由于 Cockayne 综合征 B 型（CSB）基因的纯合缺失突变导致无法检测到 CSB 蛋白。相比之下，具有 Cockayne 综合征和光敏感性严重躯体异常的 CS-B 患者会产生突变的 CSB 蛋白。已知源自 piggyBac 转座子的 3 被整合到 CSB 内含子 5 中，并且通过选择性剪接产生 CSB-piggyBac 转座子衍生的 3 融合（CPFP）mRNA。我们发现 CPFP 或源自 CPFP mRNA 的截断 CSB 蛋白在 CS-B 患者中稳定产生，并且野生型 CSB、CPFP 和截断 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。野生型 CSB 的存在抑制了抑制作用，这与 Cockayne 综合征的常染色体隐性遗传一致。这些结果表明，由于截断的 CSB 蛋白，DNA 拓扑异构酶 I-DNA 共价复合物的修复减少参与了 CS-B 的发病机制。
