L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1
L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1
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DOI：
10.1038/emboj.2011.10
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发表时间：
2011-03-02
期刊：
影响因子：
11.4
通讯作者：
Bao, Shideng
中科院分区：
文献类型：
--
作者：
Cheng, Lin;Wu, Qiulian;Bao, Shideng
胶质母细胞瘤（GBM）是一种高度致命的脑肿瘤，由于治疗耐药性，目前的治疗方法仅限于姑息治疗。我们之前证明 GBM 干细胞 (GSC) 优先激活 DNA 损伤检查点，并且对辐射具有相对抵抗力。然而，GSC 中优先检查点反应的分子机制仍不清楚。在这里，我们发现 L1CAM (CD171) 通过 L1CAM 胞内结构域 (L1-ICD) 的核转位来调节 GSC 的 DNA 损伤检查点反应和放射敏感性。通过 RNA 干扰靶向 L1CAM 可减弱 DNA 损伤检查点的激活和修复，并使 GSC 对辐射敏感。 L1CAM 调节 NBS1 的表达，NBS1 是 MRE11-RAD50-NBS1 (MRN) 复合物的关键组成部分，可激活共济失调毛细血管扩张突变 (ATM) 激酶和早期检查点反应。 GSC 中 NBS1 的异位表达挽救了 L1CAM 敲低引起的检查点激活和放射抗性下降，表明 L1CAM 通过 NBS1 发出信号来调节 DNA 损伤检查点反应。从机制上讲，L1-ICD 的核转位通过 c-Myc 介导 NBS1 上调。这些数据表明，L1CAM 通过 L1-ICD 介导的 NBS1 上调和增强的 MRN-ATM-Chk2 信号传导增强了 GSC 的 DNA 损伤检查点激活和放射抗性。 EMBO 杂志 (2011) 30, 800-813。 doi：10.1038/emboj.2011.10； 2011 年 2 月 4 日在线发布
Glioblastomas (GBMs) are highly lethal brain tumours with current therapies limited to palliation due to therapeutic resistance. We previously demonstrated that GBM stem cells (GSCs) display a preferential activation of DNA damage checkpoint and are relatively resistant to radiation. However, the molecular mechanisms underlying the preferential checkpoint response in GSCs remain undefined. Here, we show that L1CAM (CD171) regulates DNA damage checkpoint responses and radiosensitivity of GSCs through nuclear translocation of L1CAM intracellular domain (L1-ICD). Targeting L1CAM by RNA interference attenuated DNA damage checkpoint activation and repair, and sensitized GSCs to radiation. L1CAM regulates expression of NBS1, a critical component of the MRE11-RAD50-NBS1 (MRN) complex that activates ataxia telangiectasia mutated (ATM) kinase and early checkpoint response. Ectopic expression of NBS1 in GSCs rescued the decreased checkpoint activation and radioresistance caused by L1CAM knockdown, demonstrating that L1CAM signals through NBS1 to regulate DNA damage checkpoint responses. Mechanistically, nuclear translocation of L1-ICD mediates NBS1 upregulation via c-Myc. These data demonstrate that L1CAM augments DNA damage checkpoint activation and radioresistance of GSCs through L1-ICD-mediated NBS1 upregulation and the enhanced MRN-ATM-Chk2 signalling. The EMBO Journal (2011) 30, 800-813. doi: 10.1038/emboj.2011.10; Published online 4 February 2011