Brief Communication abstract
Nature Cell Biology 4, 998 - 1002 (2002)
Published online: 25 November 2002 | doi:10.1038/ncb892
There is a Corrigendum (January 2003) associated with this Brief Communication.
53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer
Richard A. DiTullio, Jr1,2, Tamara A. Mochan1,2, Monica Venere1,2, Jirina Bartkova3, Maxwell Sehested4, Jiri Bartek3 & Thanos D. Halazonetis1,5
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.
- Wistar Institute, Philadelphia, PA 19104-4268, USA
- Cell and Molecular Biology Graduate Group, Biomedical Graduate Studies, University of Pennsylvania, PA19104, USA
- Institute of Cancer Biology, Danish Cancer Society, Copenhagen, DK-2100, Denmark
- Department of Pathology, University Hospital, Copenhagen, DK-2100, Denmark
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, PA 19104, USA
Correspondence to: Jiri Bartek3 e-mail: bartek@biobase.dk
Correspondence to: Thanos D. Halazonetis1,5 e-mail: halazonetis@wistar.upenn.edu
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