53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

p53-binding protein 1 (53BP1) participates in the cellular response to DNA double-stranded breaks where it associates with various DNA repair/cell cycle factors including the H2AX histone variant. Mice deficient for 53BP1 (53BP1 ^-/-) are sensitive to ionizing radiation and immunodeficient because of impaired Ig heavy chain class switch recombination. Here we show that, as compared with p53^-/- mice, 53BP1^-/-/p53^-/- animals more rapidly develop tumors, including T cell lymphomas and, at lower frequency, B lineage lymphomas, sarcomas, and teratomas. In addition, T cells from animals deficient for both 53BP1 and p53 (53BP1^-/-/p53 ^-/-) display elevated levels of genomic instability relative to T cells deficient for either 53BP1 or p53 alone. In contrast to p53^-/- T cell lymphomas, which routinely display aneuploidy but not translocations, 53BP1^-/-/p53^-/- thymic lymphomas fall into two distinct cytogenetic categories, with many harboring clonal translocations (40%) and the remainder showing aneuploidy (60%). We propose that 53BP1, in the context of p53 deficiency, suppresses T cell lymphomagenesis through its roles in both cell-cycle checkpoints and double-stranded break repair.