53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice.
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.
Ward
Irene M
IM
Division of Oncology Research, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Difilippantonio
Simone
S
Minn
Kay
K
Mueller
Melissa D
MD
Molina
Julian R
JR
Yu
Xiaochun
X
Frisk
Craig S
CS
Ried
Thomas
T
Nussenzweig
Andre
A
Chen
Junjie
J
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
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