Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation?
Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation?
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DOI：
10.1038/sj.emboj.7601885
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发表时间：
2007-11-14
期刊：
影响因子：
11.4
通讯作者：
Boerkoel, Cornelius F.
中科院分区：
文献类型：
--
作者：
Hirano, Ryuki;Interthal, Heidrun;Boerkoel, Cornelius F.
Tyrosyl-DNA磷酸二酯酶1(Tdp1)断裂了DNA 3‘端和拓扑异构酶I(Topo I)之间的磷酸二酯键。Topo I在DNA链断裂时的停滞是由内源性DNA损伤和Topo I特异性抗癌药物喜树碱(CPT)诱导的。Tdp1基因H493R突变导致神经退行性疾病脊髓小脑性共济失调伴轴索神经病(SCAN1)。与SCAN1源于催化失活的Tdp1的假设相反，Tdp1(-/-)小鼠在生理、组织学、行为和电生理上与野生型小鼠没有区别。然而，与野生型小鼠相比，Tdp1(-/-)小鼠对CPT和博莱霉素过敏，但对依托泊苷不敏感。与早期的体外研究一致，我们表明，在CPT处理SCAN1细胞后，H493R Tdp1突变蛋白保持了残余活性，并成为共价捕获在DNA上。这一结果为Tdp1修复体内Topo I共价损伤提供了直接证据，并提示SCAN1是由隐性新形性突变H493R引起的。这是一种新的疾病机制，因为新形性突变通常是显性的。
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) cleaves the phosphodiester bond between a covalently stalled topoisomerase I (Topo I) and the 3 ' end of DNA. Stalling of Topo I at DNA strand breaks is induced by endogenous DNA damage and the Topo I-specific anticancer drug camptothecin (CPT). The H493R mutation of Tdp1 causes the neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy (SCAN1). Contrary to the hypothesis that SCAN1 arises from catalytically inactive Tdp1, Tdp1(-/-) mice are indistinguishable from wild-type mice, physically, hiwstologically, behaviorally, and electrophysiologically. However, compared to wild-type mice, Tdp1(-/-) mice are hypersensitive to CPT and bleomycin but not to etoposide. Consistent with earlier in vitro studies, we show that the H493R Tdp1 mutant protein retains residual activity and becomes covalently trapped on the DNA after CPT treatment of SCAN1 cells. This result provides a direct demonstration that Tdp1 repairs Topo I covalent lesions in vivo and suggests that SCAN1 arises from the recessive neomorphic mutation H493R. This is a novel mechanism for disease since neomorphic mutations are generally dominant.