53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice

Irene M. Ward, Simone Difilippantonio, Kay Minn, Melissa D. Mueller, Julian R Molina, Xiaochun Yu, Craig S. Frisk, Thomas Ried, Andre Nussenzweig, Junjie Chen

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)10079-10086
Number of pages8
JournalMolecular and Cellular Biology
Volume25
Issue number22
DOIs
StatePublished - Nov 2005

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Genomic Instability
V(D)J Recombination
Chromosome Structures
Antigen Receptors
Aneuploidy
Diploidy
Histones
DNA Damage
Lymphoma
Neoplasms
Carrier Proteins
Carcinogenesis
Alleles

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice. / Ward, Irene M.; Difilippantonio, Simone; Minn, Kay; Mueller, Melissa D.; Molina, Julian R; Yu, Xiaochun; Frisk, Craig S.; Ried, Thomas; Nussenzweig, Andre; Chen, Junjie.

In: Molecular and Cellular Biology, Vol. 25, No. 22, 11.2005, p. 10079-10086.

Research output: Contribution to journalArticle

Ward, IM, Difilippantonio, S, Minn, K, Mueller, MD, Molina, JR, Yu, X, Frisk, CS, Ried, T, Nussenzweig, A & Chen, J 2005, '53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice', Molecular and Cellular Biology, vol. 25, no. 22, pp. 10079-10086. https://doi.org/10.1128/MCB.25.22.10079-10086.2005
Ward, Irene M. ; Difilippantonio, Simone ; Minn, Kay ; Mueller, Melissa D. ; Molina, Julian R ; Yu, Xiaochun ; Frisk, Craig S. ; Ried, Thomas ; Nussenzweig, Andre ; Chen, Junjie. / 53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 22. pp. 10079-10086.
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