The Mre11 complex is required for ATM activation and the G2/M checkpoint
The Mre11 complex is required for ATM activation and the G2/M checkpoint
复制标题
DOI：
10.1093/emboj/cdg630
复制
发表时间：
2003-12-15
期刊：
影响因子：
11.4
通讯作者：
Weitzman, MD
中科院分区：
文献类型：
--
作者：
Carson, CT;Schwartz, RA;Weitzman, MD
维持基因组完整性需要对多种类型的 DNA 损伤做出快速、特异性的反应。保守且相关的 PI3 样蛋白激酶、共济失调毛细血管扩张突变 (ATM) 和 ATM-Rad3 相关 (ATR)，协调信号转导途径以响应基因组损伤，例如 DNA 双链断裂 (DSB)。目前尚不清楚哪些蛋白质能够识别 DSB 并激活这些途径，但 Mre11/Rad50/NBS1 复合物已被认为可以充当损伤传感器。在这里，我们发现缺乏 E4 区域的腺病毒感染也会诱导细胞 DNA 损伤反应，并激活 ATM 和 ATR。野生型病毒通过病毒 E1b55K/E4orf6 蛋白降解 Mre11 复合物来阻断这种信号传导。使用这些病毒蛋白，我们表明 Mre11 复合物是 ATM 激活和响应 DSB 的 ATM 依赖性 G(2)/M 检查点所必需的。这些结果表明，Mre11 复合物可以作为哺乳动物细胞中 ATM/ATR 信号上游的损伤传感器。
The maintenance of genome integrity requires a rapid and specific response to many types of DNA damage. The conserved and related PI3-like protein kinases, ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR), orchestrate signal transduction pathways in response to genomic insults, such as DNA double-strand breaks (DSBs). It is unclear which proteins recognize DSBs and activate these pathways, but the Mre11/Rad50/NBS1 complex has been suggested to act as a damage sensor. Here we show that infection with an adenovirus lacking the E4 region also induces a cellular DNA damage response, with activation of ATM and ATR. Wild-type virus blocks this signaling through degradation of the Mre11 complex by the viral E1b55K/E4orf6 proteins. Using these viral proteins, we show that the Mre11 complex is required for both ATM activation and the ATM-dependent G(2)/M checkpoint in response to DSBs. These results demonstrate that the Mre11 complex can function as a damage sensor upstream of ATM/ATR signaling in mammalian cells.