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 repair1,2,3. 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.
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We thank M. B. Kastan, R. Depinho, P. Coffer, S. Miyamoto, A. J. Fornace Jr. and K. K. Khanna for generously providing reagents. This work was supported in part by R01 grant CA113859 (M.C.-T.H.) from the National Cancer Institute (NCI), National Institutes of Health; grants BCTR0504415 from the Susan G. Komen Breast Cancer Foundation, BC045295 from the U.S. Department of Defense Breast Cancer Research Program, and a grant from the Texas Advanced Research Program (M.C.-T.H.); and Cancer Center Support Grant CA16772 from the NCI. The sponsors had no role in the design, conduct or reporting of the study.
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Tsai, WB., Chung, Y., Takahashi, Y. et al. Functional interaction between FOXO3a and ATM regulates DNA damage response. Nat Cell Biol 10, 460–467 (2008). https://doi.org/10.1038/ncb1709