title: 53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice.
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.
authors.affiliation: Division of Oncology Research, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ward
authors.forename: Simone
authors.initials: S
authors.lastname: Difilippantonio
authors.forename: Kay
authors.initials: K
authors.lastname: Minn
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Mueller
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yu
authors.forename: Craig S
authors.initials: CS
authors.lastname: Frisk
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Andre
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002478:Cells, Cultured; D018385:Centrosome / Q000648:ultrastructure; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000648:ultrastructure; D003433:Crosses, Genetic; D004260:DNA Repair; D005260:Female; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D007621:Karyotyping; D008223:Lymphoma / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000502:physiology*; D011946:Receptors, Antigen / Q000378:metabolism; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011946:Receptors, Antigen; C498301:TP53BP1 protein, human; D016159:Tumor Suppressor Protein p53; D000071857:Tumor Suppressor p53-Binding Protein 1