53BP1 Cooperates with p53 and Functions as a Haploinsufficient Tumor Suppressor in Mice

p53 binding protein 1 (53BP1) was identified in a yeast two-hybrid screen as a protein that binds to the central DNA binding domain of the tumor suppressor protein p53 (15). It contains two tightly packed tudor domains and a C-terminal tandem BRCT motif (9, 19). BRCT domains are thought to be protein-protein interaction domains and are found in many DNA damage response proteins (5, 19). The observation that, upon exposure of cells to ionizing radiation (IR), 53BP1 rapidly localizes in a dose-dependent manner to discrete nuclear foci supported the proposed role of 53BP1 in the DNA damage response (2, 16, 25, 29, 36). Moreover, following irradiation, 53BP1 interacts with and becomes phosphorylated by ataxia telangiectasia mutated (ATM), a central kinase in the DNA double-strand break (DSB) response (2, 25, 36). Colocalization of 53BP1 foci with those of phosphorylated histone H2AX and the Mre-11/Nbs1/Rad50 complex mapped the IR-induced accumulation of 53BP1 to regions of DNA DSBs (2, 25, 29). Subsequent studies using small interfering RNAs indicated that 53BP1 is involved in DNA damage checkpoint control by facilitating the phosphorylation of ATM substrates like Chk2 or SMC1 (12, 31). Moreover, 53BP1 was reported to be required for p53 accumulation in response to IR (31). Defects in DNA damage checkpoint control were also observed in cells derived from 53BP1 knockout mice (13); however, the more striking observations obtained with these mice were of sensitivity towards ionizing radiation and greatly impaired class switch recombination (CSR) combined with immunodeficiency and an increased lymphoma predisposition (23, 24, 33, 34). Since CSR involves the generation and rejoining of DNA DSBs, a function of 53BP1 in DSB repair has been proposed (23, 34). It is well established that defects in the joining of DSBs can lead to chromosome translocations and gene amplifications that promote tumorigenesis, particularly in the context in which p53-dependent apoptosis is abrogated (11, 37). In this study, we address how 53BP1 contributes to genomic stability by analyzing tumorigenesis in p53-null mice that express various amounts of 53BP1.