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Functional interaction between FOXO3a and ATM regulates DNA damage response

Nature Cell Biology volume 10, pages 460–467 (2008)Cite this article

A Corrigendum to this article was published on 01 November 2009

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Abstract

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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Figure 1: Silencing FOXO3a results in defective intra-S-phase and G2–M phase cell-cycle checkpoints.
Figure 2: FOXO3a may be colocalized with γ-H2AX and ATM-pS1981 to form nuclear foci in cells treated with ionizing radiation or CPT.
Figure 3: FOXO3a is colocalized with ATM-pSer1981 or γ-H2AX in primary tumour tissues in vivo, associated with these phospho-proteins in the nucleus in cells treated with CPT, and involved in ATM autophosphorylation of Ser 1981.
Figure 4: FOXO3a promotes the repair of damaged DNA.
Figure 5: The carboxy-terminal domain of FOXO3a binds to the FAT domain of ATM in vitro and in vivo.

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Change history

  • 01 October 2009

    In the version of this article initially published, the top left panel in Fig. 4c was incorrect. This error has been corrected in the HTML and PDF versions of the article.

References

  1. Zhou, B. B. & Elledge S. J. The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439 (2000).

    Article  CAS  Google Scholar 

  2. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003).

    Article  CAS  Google Scholar 

  3. Kastan, M. B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    Article  CAS  Google Scholar 

  4. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995).

    Article  CAS  Google Scholar 

  5. Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).

    Article  CAS  Google Scholar 

  6. Bakkenist, C. J. & Kastan, M. B. Initiating cellular stress responses. Cell 118, 9–17 (2004).

    Article  CAS  Google Scholar 

  7. Celeste, A. et al. Genomic instability in mice lacking histone H2AX. Science 296, 922–927 (2002).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. Lee, J. H. & Paull, T. T. ATM activation by DNA double-strand breaks through the Mre11–Rad50–Nbs1 complex. Science 308, 551–554 (2005).

    Article  CAS  Google Scholar 

  10. Burgering, B. M. & Kops, G. J. Cell cycle and death control: long live Forkheads. Trends Biochem. Sci. 27, 352–360 (2002).

    Article  CAS  Google Scholar 

  11. Tran, H., Brunet, A., Griffith, E. C. & Greenberg, M. E. The Many Forks in FOXO's Road. Sci. STKE re5 (2003).

  12. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).

    Article  CAS  Google Scholar 

  13. Accili, D. & Arden, K. C. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117, 421–426 (2004).

    Article  CAS  Google Scholar 

  14. Hu, M. C. -T. et al. IκB kinase promotes tumourigenesis through inhibition of Forkhead FOXO3a. Cell 117, 225–237 (2004).

    Article  CAS  Google Scholar 

  15. Kops, G. J. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316–321 (2002).

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. Essers, M. A. et al. Functional interaction between ß-catenin and FOXO in oxidative stress signaling. Science 308, 1181–1184 (2005).

    Article  CAS  Google Scholar 

  18. Goldberg, M. et al. MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature 421, 952–956 (2003).

    Article  CAS  Google Scholar 

  19. d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    Article  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. Niida, H. & Nakanishi, M. DNA damage checkpoints in mammals. Mutagenesis 21, 3–9 (2006).

    Article  CAS  Google Scholar 

  23. Tran, H. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530–534 (2002).

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. Bosotti, R., Isacchi, A. & Sonnhammer, E. L. FAT: a novel domain in PIK-related kinases. Trends Biochem. Sci. 25, 225–227 (2000).

    Article  CAS  Google Scholar 

  26. Fernandez-Capetillo, O. et al. DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1. Nature Cell Biol. 4, 993–997 (2002).

    Article  CAS  Google Scholar 

  27. 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).

    Article  CAS  Google Scholar 

  28. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumourigenesis. Nature 434, 864–870 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

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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Authors and Affiliations

  1. Departments of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, TX, USA

    Wen-Bin Tsai, Young Min Chung, Yoko Takahashi, Zhaohui Xu & Mickey C.-T. Hu

  2. Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, TX, USA

    Mickey C.-T. Hu

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  1. Wen-Bin Tsai
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  2. Young Min Chung
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Contributions

W.B.T. performed the majority of experiments, including the cell-cycle checkpoint, siRNA knockdown, coimmunoprecipitation, immunoblotting, immunofluorescence confocal microscopy, tumour staining, GST pulldown, immunocomplex kinase assays and data analysis. Y.M.C. performed all the analysis of DNA damage by the comet assays and quantification of immunofluorescence images. Y.T. conducted quantitative real-time PCR analyses, mammalian and yeast two-hybrid assays. Z.X. provided crucial assistance in generating DNA constructs, cell lines, GST fusion proteins and performing luciferase and PCR analyses. M.C.-T.H. generated DNA constructs and cell lines, designed and coordinated all experimental approaches, drafted and revised the entire manuscript.

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Correspondence to Mickey C.-T. Hu.

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Supplementary Figures S1, S2, S3, S4, S5, S6 and Supplementary Text (PDF 2664 kb)

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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

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