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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alleles
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Amino Acid Motifs
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Animals
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Binding Sites
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Blotting, Western
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Cells, Cultured
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Centrosome / ultrastructure
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Chromosome Aberrations
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Chromosomes / ultrastructure
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Crosses, Genetic
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DNA Repair
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Female
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Genes, Tumor Suppressor
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Genetic Predisposition to Disease
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In Situ Hybridization, Fluorescence
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Intracellular Signaling Peptides and Proteins / physiology*
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Karyotyping
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Lymphoma / metabolism
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Male
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Mice
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Mice, Transgenic
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Microscopy, Fluorescence
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Neoplasms / genetics*
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Neoplasms / pathology
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Phosphoproteins / physiology*
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Receptors, Antigen / metabolism
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Recombination, Genetic
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Reverse Transcriptase Polymerase Chain Reaction
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Spleen / cytology
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Time Factors
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Translocation, Genetic
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Protein p53 / physiology*
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Tumor Suppressor p53-Binding Protein 1
Substances
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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Receptors, Antigen
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TP53BP1 protein, human
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Tumor Suppressor Protein p53
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Tumor Suppressor p53-Binding Protein 1