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 of p53 mutations in human cancer, as p53 is a downstream target of Chk2 and ATM.
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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We thank J. Chen, S. J. Elledge, A. Nussenzweig and Y. Shiloh for helpful discussions and communication of unpublished observations.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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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 Biol 4, 998–1002 (2002). https://doi.org/10.1038/ncb892
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DOI: https://doi.org/10.1038/ncb892
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