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.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 IRinduced 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 co...

The sodium-iodide symporter (NIS) is primarily a thyroid protein, providing for the accumulation of iodide for biosynthesis of thyroid hormones. Native NIS expression has made possible the use of radioactive iodide to image and treat thyroid disease successfully. The current study, using adult male beagle dogs, was carried out in preparation for a Phase I clinical trial of adenovirus-mediated NIS gene (approved symbol SLC5A5) therapy for prostate cancer. Direct intraprostatic injection of virus (Ad5/CMV/NS) was followed by iv injection of 3 mCi 123I and serial image acquisition. The dogs were then given a therapeutic dose of 131I (116 mCi/m2) and observed for 7 days. SPECT/CT fusion imaging revealed clear images of the NIS-transduced prostates. Dosimetry calculations revealed an average absorbed dose to the prostate of 23 +/- 42 cGy/mCi 131I, with acceptably low radiation doses to other organs. This study demonstrated the successful introduction of localized NIS expression in the prostate gland of dogs, with no vector-related toxicity observed. None of the animals experienced any surgical complications, and serum chemistry panels showed no significant change following therapy. The results presented provide further evidence of the safety and efficacy of NIS as a therapeutic gene and support translation of this work into the clinical setting.

No abstract

No abstract