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Published online 30 April 2001. doi:10.1083/jcb.153.3.613
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© The Rockefeller University Press, 0021-9525/2001//613 $5.00
The Journal of Cell Biology, Volume 153, Number 3, , 2001 613-620

Original Article

Tumor Suppressor P53 Binding Protein 1 (53bp1) Is Involved in DNA Damage–Signaling Pathways



Irene Rappolda, Kuniyoshi Iwabuchia, Takayasu Dateb, and Junjie Chena

a Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905
b Department of Biochemistry, Kanazawa Medical University, Ishikawa 920-0293, Japan
Guggenheim 1306, Division of Oncology Research, Mayo Clinic, 200 First Street, S.W., Rochester, MN 55905.(507) 284-3906(507) 538-1545

chen.junjie{at}mayo.edu

The tumor suppressor p53 binding protein 1 (53BP1) binds to the DNA-binding domain of p53 and enhances p53-mediated transcriptional activation. 53BP1 contains two breast cancer susceptibility gene 1 COOH terminus (BRCT) motifs, which are present in several proteins involved in DNA repair and/or DNA damage–signaling pathways. Thus, we investigated the potential role of 53BP1 in DNA damage–signaling pathways. Here, we report that 53BP1 becomes hyperphosphorylated and forms discrete nuclear foci in response to DNA damage. These foci colocalize at all time points with phosphorylated H2AX ({gamma}-H2AX), which has been previously demonstrated to localize at sites of DNA strand breaks. 53BP1 foci formation is not restricted to {gamma}-radiation but is also detected in response to UV radiation as well as hydroxyurea, camptothecin, etoposide, and methylmethanesulfonate treatment. Several observations suggest that 53BP1 is regulated by ataxia telangiectasia mutated (ATM) after DNA damage. First, ATM-deficient cells show no 53BP1 hyperphosphorylation and reduced 53BP1 foci formation in response to {gamma}-radiation compared with cells expressing wild-type ATM. Second, wortmannin treatment strongly inhibits {gamma}-radiation–induced hyperphosphorylation and foci formation of 53BP1. Third, 53BP1 is readily phosphorylated by ATM in vitro. Taken together, these results suggest that 53BP1 is an ATM substrate that is involved early in the DNA damage–signaling pathways in mammalian cells.

Key Words: 53BP1 • DNA damage • nuclear foci • {gamma}-H2AX • ATM

© 2001 The Rockefeller University Press

Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; BRCA1, breast cancer susceptibility gene 1; BRCT, BRCA1 COOH terminus; DNA-PK, DNA-dependent protein kinase; 53BP1, binding protein 1; GST, glutathione S-transferase; PI3K, phosphatidylinositol 3–kinase.


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