Journal of Biological Chemistry
Volume 278, Issue 17, 25 April 2003, Pages 14971-14977
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DNA: REPLICATION REPAIR AND RECOMBINATION
Role for the BRCA1 C-terminal Repeats (BRCT) Protein 53BP1 in Maintaining Genomic Stability*

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p53-binding protein-1 (53BP1) is phosphorylated in response to DNA damage and rapidly relocalizes to presumptive sites of DNA damage along with Mre11 and the phosphorylated histone 2A variant, γ-H2AX. 53BP1 associates with the BRCA1 tumor suppressor, and knock-down experiments with small interfering RNA have revealed a role for the protein in the checkpoint response to DNA damage. By generating mice defective in m53BP1(m53BP1tr/tr), we have created an animal model to further explore its biochemical and genetic roles in vivo. We find that m53BP1tr/tr animals are growth-retarded and show various immune deficiencies including a specific reduction in thymus size and T cell count. Consistent with a role in responding to DNA damage, we find thatm53BP1tr/tr mice are sensitive to ionizing radiation (γ-IR), and cells from these animals exhibit chromosomal abnormalities consistent with defects in DNA repair. Thus, 53BP1 is a critical element in the DNA damage response and plays an integral role in maintaining genomic stability.

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Published, JBC Papers in Press, February 10, 2003, DOI 10.1074/jbc.M212484200

*

This work was supported by grants from The Robert A. Welch Foundation (to P. B. C.) and The Ellison Medical Foundation (to P. B. C.) as well as National Institute of Health Grants GM65812-01 (to P. B. C.), DK46207 (to R. E. K.), and 5P30 CA16672 (to W. N. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A fellow of the U. S. Army Breast Cancer Postdoctoral Trainee Award.

**

A Sophie Caroline Steves Distinguished Professor in Cancer Research.

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An investigator with the Howard Hughes Medical Institute, an Ellison Medical Foundation Senior Scholar, and the Welch Professor of Biochemistry.