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Nesprin-1 role in DNA damage response

机译：Nesprin-1在DNA损伤反应中的作用

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Nuclear envelope (NE) proteins have fundamental roles in maintaining nuclear structure, cell signaling, chromatin organization, and gene regulation, and mutations in genes encoding NE components were identified as primary cause of a number of age associated diseases and cancer. Nesprin-1 belongs to a family of multi-isomeric NE proteins that are characterized by spectrin repeats. We analyzed NE components in various tumor cell lines and found that Nesprin-1 levels were strongly reduced associated with alterations in further NE components. By reducing the amounts of Nesprin-1 by RNAi mediated knockdown, we could reproduce those alterations in mouse and human cell lines. In a search for novel Nesprin-1 binding proteins, we identified MSH2 and MSH6, proteins of the DNA damage response pathway, as interactors and found alterations in the corresponding pathways in cells with lower Nesprin-1 levels. We also noticed increased number of γH2AX foci in the absence of exogenous DNA damage as was seen in tumor cells. The levels of phosphorylated kinases Chk1 and 2 were altered in a manner resembling tumor cells and the levels of Ku70 were low and the protein was not recruited to the DNA after hydroxyurea (HU) treatment. Our findings indicate a role for Nesprin-1 in the DNA damage response pathway and propose Nesprin-1 as novel player in tumorigenesis and genome instability.
机译：核被膜（NE）蛋白在维持核结构，细胞信号传导，染色质组织和基因调控中具有基本作用，编码NE成分的基因突变被鉴定为许多与年龄相关的疾病和癌症的主要原因。 Nesprin-1属于以血影蛋白重复序列​​为特征的多异构NE蛋白家族。我们分析了各种肿瘤细胞系中的NE成分，发现Nesprin-1的水平与其他NE成分的改变有关而大大降低。通过RNAi介导的敲低减少Nesprin-1的量，我们可以在小鼠和人类细胞系中复制这些改变。在寻找新型Nesprin-1结合蛋白时，我们鉴定了DNA损伤反应途径的蛋白MSH2和MSH6作为相互作用物，并发现Nesprin-1水平较低的细胞中相应途径的改变。我们还注意到在没有外源性DNA损伤的情况下，如在肿瘤细胞中所见，γH2AX病灶数量增加。磷酸化激酶Chk1和2的水平以类似于肿瘤细胞的方式改变，Ku70的水平较低，并且在羟基脲（HU）处理后该蛋白未募集到DNA中。我们的发现表明Nesprin-1在DNA损伤反应途径中的作用，并建议Nesprin-1作为肿瘤发生和基因组不稳定性的新参与者。

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