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Molecular and Cellular Biology, November 2005, p. 10079-10086, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.10079-10086.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

53BP1 Cooperates with p53 and Functions as a Haploinsufficient Tumor Suppressor in Mice

Irene M. Ward,1 Simone Difilippantonio,2 Kay Minn,1 Melissa D. Mueller,3 Julian R. Molina,3 Xiaochun Yu,1 Craig S. Frisk,4 Thomas Ried,5 Andre Nussenzweig,2 and Junjie Chen1*

Division of Oncology Research, Mayo Clinic and Foundation, Rochester, Minnesota 55905,1 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,2 Department of Medical Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905,3 Department of Comparative Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905,4 Genetics Branch, Center for Cancer Research, NCI, NIH, 50 South Dr., Bethesda, Maryland 208925

Received 3 May 2005/ Returned for modification 6 June 2005/ Accepted 17 August 2005

p53 binding protein 1 (53BP1) is a putative DNA damage sensor that accumulates at sites of double-strand breaks (DSBs) in a manner dependent on histone H2AX. Here we show that the loss of one or both copies of 53BP1 greatly accelerates lymphomagenesis in a p53-null background, suggesting that 53BP1 and p53 cooperate in tumor suppression. A subset of 53BP1–/– p53–/– lymphomas, like those in H2AX–/– p53–/– mice, were diploid and harbored clonal translocations involving antigen receptor loci, indicating misrepair of DSBs during V(D)J recombination as one cause of oncogenic transformation. Loss of a single 53BP1 allele compromised genomic stability and DSB repair, which could explain the susceptibility of 53BP1+/– mice to tumorigenesis. In addition to structural aberrations, there were high rates of chromosomal missegregation and accumulation of aneuploid cells in 53BP1–/– p53+/+ and 53BP1–/– p53–/– tumors as well as in primary 53BP1–/– splenocytes. We conclude that 53BP1 functions as a dosage-dependent caretaker that promotes genomic stability by a mechanism that preserves chromosome structure and number.

* Corresponding author. Mailing address: Guggenheim 1342, Division of Oncology Research, Mayo Clinic and Foundation, Rochester, MN 55905. Phone: (507) 538-1545. Fax: (507) 284-3906. E-mail: junjie.chen{at}mayo.edu.

Molecular and Cellular Biology, November 2005, p. 10079-10086, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.10079-10086.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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