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Nature Cell Biology
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53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer

Nature Cell Biologyvolume 4, pages998–1002 (2002)Cite this article

ACorrigendum to this article was published on 01 January 2003

Abstract

53BP1 is a conserved nuclear protein that is implicated in the DNA damage response. After irradiation, 53BP1 localizes rapidly to nuclear foci, which represent sites of DNA double strand breaks1,2,3,4, but its precise function is unclear. Using small interference RNA (siRNA), we demonstrate that 53BP1 functions as a DNA damage checkpoint protein. 53BP1 is required for at least a subset of ataxia telangiectasia-mutated (ATM)-dependent phosphorylation events at sites of DNA breaks and for cell cycle arrest at the G2–M interphase after exposure to irradiation. Interestingly, in cancer cell lines expressing mutant p53, 53BP1 was localized to distinct nuclear foci and ATM-dependent phosphorylation of Chk2 at Thr 68 was detected, even in the absence of irradiation. In addition, more than 50% of Chk2 was phosphorylated at Thr 68 in surgically resected lung and breast tumour specimens from otherwise untreated patients. We conclude that the constitutive activation of the DNA damage checkpoint pathway may be linked to the high frequency ofp53 mutations in human cancer, as p53 is a downstream target of Chk2 and ATM.

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Figure 1: 53BP1 regulates ATM-dependent phosphorylation events in response to IR.
Figure 2: Cell cycle checkpoint defects in cells transfected with 53BP1 siRNA.
Figure 3: Constitutive activation of the DNA DSB checkpoint in human cancer cell lines.
Figure 4: Chk2 phosphorylation at Thr 68 in cancer and model of 53BP1 function.

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References

  1. 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 

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

    Article CAS PubMed PubMed Central  Google Scholar 

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

    Article CAS PubMed PubMed Central  Google Scholar 

  4. Xia, Z., Morales, J. C., Dunphy, W. G. & Carpenter, P. B.J. Biol. Chem.276, 2708–2718 (2001).

    Article CAS PubMed  Google Scholar 

  5. Shiloh, Y. & Kastan, M. B.Adv. Cancer Res.83, 209–254 (2001).

    Article CAS PubMed  Google Scholar 

  6. Weinert, T. A. & Hartwell, L. H.Science241, 317–322 (1988).

    Article CAS PubMed  Google Scholar 

  7. Vialard, J. E., Gilbert, C. S., Green, C. M. & Lowndes, N. F.EMBO J.17, 5679–5688 (1998).

    Article CAS PubMed PubMed Central  Google Scholar 

  8. Sun, Z., Hsiao, J., Fay, D. S. & Stern, D. F.Science281, 272–274 (1998).

    Article CAS PubMed  Google Scholar 

  9. Schwartz, M. F., Duong, J. K., Sun, Z., Morrow, J. S., Pradhan, D. & Stern, D. F.Mol. Cell9, 1055–1065 (2002).

    Article CAS PubMed  Google Scholar 

  10. 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 

  11. Rogakou, E. P., Boon, C., Redon, C. & Bonner, W. M.J. Cell Biol.146, 905–916 (1999).

    Article CAS PubMed PubMed Central  Google Scholar 

  12. Abraham, R. T.Genes Dev.15, 2177–2196 (2001).

    Article CAS PubMed  Google Scholar 

  13. Kim, S. T., Xu, B. & Kastan, M. B.Genes Dev.16, 560–570 (2002).

    Article CAS PubMed PubMed Central  Google Scholar 

  14. Yazdi, P. T., Wang, Y., Zhao, S., Patel, N., Lee, E. Y. & Qin, J.Genes Dev.16, 571–582 (2002).

    Article CAS PubMed PubMed Central  Google Scholar 

  15. Andegeko, Y., Moyal, L., Mittelman, L., Tsarfaty, I., Shiloh, Y. & Rotman, G.J. Biol. Chem.276, 38224–38230 (2001).

    CAS PubMed  Google Scholar 

  16. Xu, B., Kim, S. T., Lim, D. S. & Kastan, M. B.Mol. Cell. Biol.22, 1049–1059 (2002).

    Article CAS PubMed PubMed Central  Google Scholar 

  17. Vogelstein, B., Lane, D. & Levine, A. J.Nature408, 307–310 (2000).

    Article CAS PubMed  Google Scholar 

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

    Article CAS  Google Scholar 

  19. McGowan, C. H.Bioessays24, 502–511 (2002).

    Article CAS PubMed  Google Scholar 

  20. Bell, D. W. et al.Science286, 2528–2531 (1999).

    Article CAS PubMed  Google Scholar 

  21. Meijers-Heijboer, H. et al.Nature Genet.31, 55–59 (2002).

    Article CAS PubMed  Google Scholar 

  22. Lukas, C. et al.Cancer Res.61, 4990–4993 (2001).

    CAS PubMed  Google Scholar 

  23. Boulton, S. J. et al.Science295, 127–131 (2002).

    Article CAS PubMed  Google Scholar 

  24. Saka, Y., Esashi, F., Matsusaka, T., Mochida, S. & Yanagida, M.Genes Dev.11, 3387–3400 (1997).

    Article CAS PubMed PubMed Central  Google Scholar 

  25. Wang, B., Matsuoka, S., Carpenter, P. B. & Elledge, S. J.Science online (cited 3 October 2002) 10.1126-science.1076182 (2002).

  26. Bartkova, J et al.Cancer Res.55, 949–956 (1995).

    CAS PubMed  Google Scholar 

  27. Falck, J., Mailand, N., SyljuÂsen, R. G., Bartek, J. & Lukas, J.Nature410, 842–847 (2001).

    Article CAS PubMed  Google Scholar 

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Acknowledgements

We thank J. Chen, S. J. Elledge, A. Nussenzweig and Y. Shiloh for helpful discussions and communication of unpublished observations. We also thank L. Schultz for her early contribution to this project. This work was supported by grants CA76367 and CA25874 (T.D.H.) and CA09171 (Wistar Institute Training Grant - T.A.M.) from the National Cancer Institute and by grants from the Danish Cancer Society and the European Commission (J.B., M.S. and J.B.).

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Authors and Affiliations

  1. Wistar Institute, Philadelphia, 19104-4268, PA, USA

    Richard A. DiTullio Jr, Tamara A. Mochan, Monica Venere & Thanos D. Halazonetis

  2. Cell and Molecular Biology Graduate Group, Biomedical Graduate Studies, University of Pennsylvania, PA19104, USA

    Richard A. DiTullio Jr, Tamara A. Mochan & Monica Venere

  3. Institute of Cancer Biology, Danish Cancer Society, Copenhagen, DK-2100, Denmark

    Jirina Bartkova & Jiri Bartek

  4. Department of Pathology, University Hospital, Copenhagen, DK-2100, Denmark

    Maxwell Sehested

  5. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 19104, PA, USA

    Thanos D. Halazonetis

Authors
  1. Richard A. DiTullio Jr

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  2. Tamara A. Mochan

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  3. Monica Venere

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  4. Jirina Bartkova

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  5. Maxwell Sehested

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  6. Jiri Bartek

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  7. Thanos D. Halazonetis

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Corresponding authors

Correspondence toJiri Bartek orThanos D. Halazonetis.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

Figure S1 Suppression of 53BP1 protein levels by siRNA does not affect the cell cycle profile of non-irradiated cells. (PDF 116 kb)

Figure S2 Suppression of 53BP1 protein levels by siRNA does not affect the γ-H2AX foci present in non-irradiated SAOS2 cells.

Figure S3 Specificity of the immunohistochemistry assay for Chk2 phosphorylation at Thr68.

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DiTullio, R., Mochan, T., Venere, M.et al. 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer.Nat Cell Biol4, 998–1002 (2002). https://doi.org/10.1038/ncb892

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