Tsai Wen-Bin, Chung Young Min, Takahashi Yoko, Xu Zhaohui, Hu Mickey C-T
Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Nat Cell Biol. 2008 Apr;10(4):460-7. doi: 10.1038/ncb1709. Epub 2008 Mar 16.
The maintenance of genomic stability in cells is relentlessly challenged by environmental stresses that induce DNA breaks, which activate the DNA-damage pathway mediated by ataxia-telangiectasia mutated (ATM) and its downstream mediators to control damage-induced cell-cycle checkpoints and DNA repair. Here, we show that FOXO3a interacts with ATM to promote phosphorylation of ATM at Ser 1981 and prompting its downstream mediators to form nuclear foci in response to DNA damage. Silencing FOXO3a in cells abrogates the formation of ATM-pS1981 and phospho-histone H2AX foci after DNA damage. Increasing FOXO3a in cells promotes ATM-regulated signalling, the intra-S-phase or G2-M cell-cycle checkpoints, and the repair of damaged DNA, whereas cells lacking FOXO3a did not trigger the DNA-repair mechanism after DNA damage. The carboxy-terminal domain of FOXO3a binds to the FAT domain of ATM, thereby contributing to the activation of ATM. These results suggest that ATM may be regulated directly by FOXO3a in the DNA-damage response.
细胞中基因组稳定性的维持不断受到诱导DNA断裂的环境压力的挑战，DNA断裂会激活由共济失调毛细血管扩张症突变基因（ATM）及其下游介质介导的DNA损伤途径，以控制损伤诱导的细胞周期检查点和DNA修复。在此，我们表明FOXO3a与ATM相互作用，促进ATM在丝氨酸1981处的磷酸化，并促使其下游介质在DNA损伤时形成核灶。在细胞中沉默FOXO3a可消除DNA损伤后ATM-pS1981和磷酸化组蛋白H2AX灶的形成。在细胞中增加FOXO3a可促进ATM调节的信号传导、S期内或G2-M期细胞周期检查点以及受损DNA的修复，而缺乏FOXO3a的细胞在DNA损伤后不会触发DNA修复机制。FOXO3a的羧基末端结构域与ATM的FAT结构域结合，从而有助于ATM的激活。这些结果表明，在DNA损伤反应中，ATM可能直接受FOXO3a调控。
