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DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1

Abstract

Activation of the ataxia telangiectasia mutated (ATM) kinase triggers diverse cellular responses to ionizing radiation (IR), including the initiation of cell cycle checkpoints1. Histone H2AX, p53 binding-protein 1 (53BP1) and Chk2 are targets of ATM-mediated phosphorylation2,3,4,5, but little is known about their roles in signalling the presence of DNA damage. Here, we show that mice lacking either H2AX or 53BP1, but not Chk2, manifest a G2–M checkpoint defect close to that observed in ATM−/− cells after exposure to low, but not high, doses of IR. Moreover, H2AX regulates the ability of 53BP1 to efficiently accumulate into IR-induced foci. We propose that at threshold levels of DNA damage, H2AX-mediated concentration of 53BP1 at double-strand breaks is essential for the amplification of signals that might otherwise be insufficient to prevent entry of damaged cells into mitosis.

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Figure 1: H2AX is required for low-dose IR-induced G2 arrest.
Figure 2: 53BP1 regulates the G2–M checkpoint.
Figure 3: Chk2 phosphorylation in ATM−/−, H2AX−/− and 53BP1−/− cells and G2–M checkpoint in Chk2−/− cells.
Figure 4: H2AX regulates IR-induced 53BP1 foci formation.

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References

  1. Shiloh, Y. Biochem. Soc. Trans. 29, 661–666 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. J. Biol. Chem. 273, 5858–5868 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Burma, S., Chen, B. P., Murphy, M., Kurimasa, A. & Chen, D. J. J. Biol. Chem. 276, 42462–42467 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Anderson, L., Henderson, C. & Adachi, Y. Mol. Cell. Biol. 21, 1719–1729 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rappold, I., Iwabuchi, K., Date, T. & Chen, J. J Cell Biol 153, 613–620 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jongmans, W. et al. Mol. Cell. Biol. 17, 5016–5022 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yamazaki, V., Wegner, R. D. & Kirchgessner, C. U. Cancer Res. 58, 2316–2322 (1998).

    CAS  PubMed  Google Scholar 

  8. Girard, P. M., Riballo, E., Begg, A. C., Waugh, A. & Jeggo, P. A. Oncogene 21, 4191–4199 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Buscemi, G. et al. Mol. Cell. Biol. 21, 5214–5222 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Antoccia, A., Ricordy, R., Maraschio, P., Prudente, S. & Tanzarella, C. Int. J. Radiat. Biol 71, 41–49 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Hirao, A. et al. Mol. Cell. Biol. 22, 6521–6532 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Takai, H. et al. EMBO J. 21, 5195–5205 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Celeste, A. et al. Science 296, 922–927 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bassing, C. H. et al. Proc. Natl Acad. Sci. USA 99, 8173–8178 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xu, B., Kim, S. & Kastan, M. B. Mol. Cell. Biol. 21, 3445–3450 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhou, B. B. et al. J. Biol. Chem. 275, 10342–10348 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Schultz, L. B., Chehab, N. H., Malikzay, A. & Halazonetis, T. D. J. Cell Biol. 151, 1381–1390 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhou, B. B. & Elledge, S. J. Nature 408, 433–439 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Wang, B., Matsuoka, S., Carpenter, P. B. & Elledge, S. J. Science Online (cited 3 October 2002) C10.1126/science.1076182 (2002).

    Google Scholar 

  20. Matsuoka, S., Huang, M. & Elledge, S. J. Science 282, 1893–1897 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Science 286, 1162–1166 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Paull, T. T. et al. Curr. Biol. 10, 886–895 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Bartek, J., Falck, J. & Lukas, J. Nature Rev. Mol. Cell Biol. 2, 877–886 (2001).

    Article  CAS  Google Scholar 

  24. Barlow, C. et al. Cell 86, 159–171 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Ward, I. et al. Mol. Cell. Biol. (submitted).

  26. Ward, I. M., Wu, X. & Chen, J. J. Biol. Chem. 276, 47755–47758 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Iwabuchi, K. et al. J. Biol. Chem. 273, 26061–26068 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Canman, C. E. et al. Science 281, 1677–1679 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

These studies were in part motivated by discussions with T. Halazonetis, who suggested examining the effects of low-dose IR, and we thank T. Halazonetis for sharing unpublished results. We also thank M. Lichten, J. Chung, A. Lee, S. Petersen and A. Singer for critical comments on the manuscript, and M. Kruhlack for assistance with microscopy. P.B.C was supported by a grant from The Robert Welch Foundation.

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Correspondence to André Nussenzweig.

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The authors declare no competing financial interests.

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Supplementary Figure

Figure S1. Phosphorylation of 53BP1 serine residue (S25) in vitro and in vivo in response to IR. (PDF 43 kb)

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Fernandez-Capetillo, O., Chen, HT., Celeste, A. et al. DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol 4, 993–997 (2002). https://doi.org/10.1038/ncb884

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