Myc is required for activation of the ATM-dependent checkpoints in response to DNA damage.
Myc is required for activation of the ATM-dependent checkpoints in response to DNA damage.
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DOI：
10.1371/journal.pone.0008924
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发表时间：
2010-01-27
期刊：
影响因子：
3.7
通讯作者：
Frisan T
中科院分区：
文献类型：
--
作者：
Guerra L;Albihn A;Tronnersjö S;Yan Q;Guidi R;Stenerlöw B;Sterzenbach T;Josenhans C;Fox JG;Schauer DB;Thelestam M;Larsson LG;Henriksson M;Frisan T
MYC 蛋白控制细胞功能，例如分化、增殖和凋亡。为了响应基因毒剂，过度表达 MYC 的细胞会发生凋亡。然而，作用于线粒体凋亡途径上游的 MYC 调节效应器仍然未知。在这项研究中，我们证明，在暴露于电离辐射（IR）或细菌细胞致死膨胀毒素（CDT）的大鼠细胞系中，Myc的表达是激活共济失调毛细血管扩张突变（ATM）依赖性DNA损伤检查点反应所必需的。与 myc 阳性 TGR-1 和 HOmyc3 细胞相比，ATM 激酶及其下游效应器（例如组蛋白 H2AX）的磷酸化在 myc 无效细胞系 HO15.19 中受损。奈梅亨断裂综合征 (Nbs) 1 蛋白的核灶形成对于有效 ATM 激活至关重要，在 myc 缺失的情况下也会减少。在人细胞系 HCT116 中，通过 siRNA 敲低 MYC 的内源水平，导致响应辐射的 ATM 和 CHK2 磷酸化减少。相反，紫外线照射诱导的细胞死亡（已知会激活 ATR 依赖性检查点）在所有细胞系中都是相似的，与 myc 状态无关。这些数据表明，MYC 有助于激活 ATM 依赖性检查点反应，导致细胞因特定基因毒性刺激而死亡。
The MYC protein controls cellular functions such as differentiation, proliferation, and apoptosis. In response to genotoxic agents, cells overexpressing MYC undergo apoptosis. However, the MYC-regulated effectors acting upstream of the mitochondrial apoptotic pathway are still unknown. In this study, we demonstrate that expression of Myc is required to activate the Ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses in rat cell lines exposed to ionizing radiation (IR) or the bacterial cytolethal distending toxin (CDT). Phosphorylation of the ATM kinase and its downstream effectors, such as histone H2AX, were impaired in the myc null cell line HO15.19, compared to the myc positive TGR-1 and HOmyc3 cells. Nuclear foci formation of the Nijmegen Breakage Syndrome (Nbs) 1 protein, essential for efficient ATM activation, was also reduced in absence of myc. Knock down of the endogenous levels of MYC by siRNA in the human cell line HCT116 resulted in decreased ATM and CHK2 phosphorylation in response to irradiation. Conversely, cell death induced by UV irradiation, known to activate the ATR-dependent checkpoint, was similar in all the cell lines, independently of the myc status. These data demonstrate that MYC contributes to the activation of the ATM-dependent checkpoint responses, leading to cell death in response to specific genotoxic stimuli.
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影响因子：
4.8
作者：
Cortes-Bratti, X;Karlsson, C;Frisan, T
通讯作者：
Frisan, T
影响因子：
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Dalla-Favera, Riccardo
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影响因子：
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作者：
Albihn, Ami;Loven, Jakob;Henriksson, Marie
通讯作者：
Henriksson, Marie
影响因子：
5.3
作者：
Adachi, S;Obaya, AJ;Sedivy, JM
通讯作者：
Sedivy, JM