• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1
【24h】

Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1

机译：脊髓小脑共济失调伴轴突神经病1的DNA单链断裂修复缺陷

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Spinocerebellar ataxia with axonal neuropathy- 1 (SCAN1) is a neurodegenerative disease that results from mutation of tyrosyl phosphodiesterase 1 (TDP1)(1). In lower eukaryotes, Tdp1 removes topoisomerase 1 (top1) peptide from DNA termini during the repair of double-strand breaks created by collision of replication forks with top1 cleavage complexes in proliferating cells(2-4). Although TDP1 most probably fulfils a similar function in human cells, this role is unlikely to account for the clinical phenotype of SCAN1, which is associated with progressive degeneration of post-mitotic neurons. In addition, this role is redundant in lower eukaryotes, and Tdp1 mutations alone confer little phenotype(4-7). Moreover, defects in processing or preventing double-strand breaks during DNA replication are most probably associated with increased genetic instability and cancer, phenotypes not observed in SCAN1 ( ref. 8). Here we show that in human cells TDP1 is required for repair of chromosomal singlestrand breaks arising independently of DNA replication from abortive top1 activity or oxidative stress. We report that TDP1 is sequestered into multi-protein single-strand break repair (SSBR) complexes by direct interaction with DNA ligase IIIalpha and that these complexes are catalytically inactive in SCAN1 cells. These data identify a defect in SSBR in a neurodegenerative disease, and implicate this process in the maintenance of genetic integrity in post-mitotic neurons.
机译：轴突神经病-1（SCAN1）的脊髓小脑共济失调是一种神经退行性疾病，由酪氨酰磷酸二酯酶1（TDP1）（1）突变引起。在低等真核生物中，在复制叉与top1裂解复合物在增殖细胞中碰撞而产生的双链断裂修复过程中，Tdp1从DNA末端去除了拓扑异构酶1（top1）肽（2-4）。尽管TDP1最有可能在人类细胞中履行类似的功能，但这种作用不太可能解释SCAN1的临床表型，这与有丝分裂后神经元的逐步变性有关。此外，这种作用在低等真核生物中是多余的，仅Tdp1突变就不会产生什么表型（4-7）。此外，DNA复制过程中加工或防止双链断裂的缺陷很可能与遗传不稳定性和癌症的增加有关，这是在SCAN1中未观察到的表型（参考文献8）。在这里，我们显示出在人类细胞中，TDP1是修复染色体单链断裂所必需的，而断裂单链断裂独立于DNA复制而不受流产top1活性或氧化应激的影响。我们报告说，TDP1被隔离到多蛋白单链断裂修复（SSBR）复合物通过与DNA连接酶IIIalpha的直接相互作用，并且这些复合物在SCAN1细胞中催化失活。这些数据确定了神经退行性疾病中SSBR的缺陷，并将这一过程暗示在有丝分裂后神经元的遗传完整性维持中。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号