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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Zhou, B. B. & Elledge S. J. The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439 (2000).
Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003).
Kastan, M. B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).
Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995).
Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).
Bakkenist, C. J. & Kastan, M. B. Initiating cellular stress responses. Cell 118, 9–17 (2004).
Celeste, A. et al. Genomic instability in mice lacking histone H2AX. Science 296, 922–927 (2002).
Fernandez-Capetillo, O., Celeste, A. & Nussenzweig, A. Focusing on foci: H2AX and the recruitment of DNA-damage response factors. Cell Cycle 2, 426–427 (2003).
Lee, J. H. & Paull, T. T. ATM activation by DNA double-strand breaks through the Mre11–Rad50–Nbs1 complex. Science 308, 551–554 (2005).
Burgering, B. M. & Kops, G. J. Cell cycle and death control: long live Forkheads. Trends Biochem. Sci. 27, 352–360 (2002).
Tran, H., Brunet, A., Griffith, E. C. & Greenberg, M. E. The Many Forks in FOXO's Road. Sci. STKE re5 (2003).
Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).
Accili, D. & Arden, K. C. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117, 421–426 (2004).
Hu, M. C. -T. et al. IκB kinase promotes tumourigenesis through inhibition of Forkhead FOXO3a. Cell 117, 225–237 (2004).
Kops, G. J. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316–321 (2002).
Furukawa-Hibi, Y., Yoshida-Araki. K., Ohta, T., Ikeda, K. & Motoyama, N. FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J. Biol. Chem. 277, 26729–26732 (2002).
Essers, M. A. et al. Functional interaction between ß-catenin and FOXO in oxidative stress signaling. Science 308, 1181–1184 (2005).
Goldberg, M. et al. MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature 421, 952–956 (2003).
d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).
Wu, Z. H., Shi, Y., Tibbetts, R. S. & Miyamoto, S. Molecular linkage between the kinase ATM and NF-κB signaling in response to genotoxic stimuli. Science 311, 1141–1146 (2006).
Frescas, D,, Valenti, L. & Accili D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J. Biol. Chem. 280, 20589–20595 (2005).
Niida, H. & Nakanishi, M. DNA damage checkpoints in mammals. Mutagenesis 21, 3–9 (2006).
Tran, H. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530–534 (2002).
Matijasevic, Z., Precopio, M. L., Snyder, J. E. & Ludlum, D. B. Repair of sulfur mustard-induced DNA damage in mammalian cells measured by a host cell reactivation assay. Carcinogenesis 22, 661–664 (2001).
Bosotti, R., Isacchi, A. & Sonnhammer, E. L. FAT: a novel domain in PIK-related kinases. Trends Biochem. Sci. 25, 225–227 (2000).
Fernandez-Capetillo, O. et al. DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1. Nature Cell Biol. 4, 993–997 (2002).
Osborn, A. J., Elledge, S. J. & Zou, L. Checking on the fork: the DNA-replication stress-response pathway. Trends Cell Biol. 12, 509–516 (2002).
Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumourigenesis. Nature 434, 864–870 (2005).
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.
About this article
Cite this article
Tsai, W., 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
Cancer and Metastasis Reviews (2020)
DNA Repair (2020)
Genome Instability & Disease (2020)
Indian Journal of Medical and Paediatric Oncology (2019)