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首页> 外文期刊>Cell biochemistry and function >NBS1 deficiency promotes genome instability by affecting DNA damage signaling pathway and impairing telomere integrity
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NBS1 deficiency promotes genome instability by affecting DNA damage signaling pathway and impairing telomere integrity

机译：NBS1缺乏症通过影响DNA损伤信号传导途径和损害端粒完整性来促进基因组不稳定

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摘要

Studies revealed that Nijmegen Breakage Syndrome protein 1 (NBS1) plays an important role in maintaining genome stability, but the underlying mechanism is controversial and elusive. Our results using clinical samples showed that NBS1 was involved in ataxia-telangiectasia mutated (ATM)-dependent pathway. NBS1 deficiency severely affected the phosphorylation of ATM as well as its downstream targets. BrdU proliferation assay revealed a delay of NBS cells in inhibiting DNA synthesis after Doxorubicin (Dox) treatment. In addition, under higher concentrations of Dox, NBS cells exhibited a much lower level of apoptosis compared to their normal counterparts, indicating a resistance to Dox treatment. Accelerated telomere shortening was also observed in NBS fibroblasts, consistent with an early onset of cellular replicative senescence in vitro. This abnormality may be due to the shelterin protein telomeric binding factor 2 (TRF2) which was found to be upregulated in NBS fibroblasts. The dysregulation of telomere shortening rate and of TRF2 expression level leads to telomere fusions and cellular aneuploidy in NBS cells. Collectively, our results suggest a possible mechanism that NBS1 deficiency simultaneously affects ATM-dependent DNA damage signaling and TRF2-regulated telomere maintenance, which synergistically lead to genomic abnormalities.
机译：研究表明，奈梅亨断裂综合症蛋白1（NBS1）在维持基因组稳定性方面起着重要作用，但其潜在机制尚有争议且难以捉摸。我们使用临床样本得出的结果表明NBS1参与了共济失调-毛细血管扩张突变（ATM）依赖性途径。 NBS1缺乏严重影响ATM及其下游靶点的磷酸化。 BrdU增殖测定揭示了阿霉素（Dox）处理后NBS细胞在抑制DNA合成方面的延迟。另外，在较高的Dox浓度下，NBS细胞与正常的细胞相比，其凋亡水平要低得多，表明对Dox处理具有抗性。在NBS成纤维细胞中也观察到端粒加速缩短，这与体外细胞复制衰老的早发相一致。该异常可能是由于发现在NBS成纤维细胞中上调了防护蛋白端粒结合因子2（TRF2）。端粒缩短速率和TRF2表达水平的失调导致NBS细胞端粒融合和细胞非整倍性。总的来说，我们的结果表明NBS1缺乏症同时影响ATM依赖性DNA损伤信号转导和TRF2调控的端粒维持的可能机制，这协同导致基因组异常。

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