title: 53BP1 is limiting for NHEJ repair in ATM-deficient model systems that are subjected to oncogenic stress or radiation.
abstract: The DNA damage response (DDR) factors ataxia telangiectasia mutated (ATM) and p53 binding protein 1 (53BP1) function as tumor suppressors in humans and mice, but the significance of their mutual interaction to the suppression of oncogenic translocations in vivo has not been investigated. To address this question, the phenotypes of compound mutant mice lacking 53BP1 and ATM (Trp53bp1(-/-)/Atm(-/-)), relative to single mutants, were examined. These analyses revealed that loss of 53BP1 markedly decreased the latency of T-lineage lymphomas driven by RAG-dependent oncogenic translocations in Atm(-/-) mice (average survival, 14 and 23 weeks for Trp53bp1(-/-)/Atm(-/-) and Atm(-/-) mice, respectively). Mechanistically, 53BP1 deficiency aggravated the deleterious effect of ATM deficiency on nonhomologous end-joining (NHEJ)-mediated double-strand break repair. Analysis of V(D)J recombinase-mediated coding joints and signal joints in Trp53bp1(-/-)/Atm(-/-) primary thymocytes is, however, consistent with canonical NHEJ-mediated repair. Together, these findings indicate that the greater NHEJ defect in the double mutant mice resulted from decreased efficiency of rejoining rather than switching to an alternative NHEJ-mediated repair mechanism. Complementary analyses of irradiated primary cells indicated that defects in cell-cycle checkpoints subsequently function to amplify the NHEJ defect, resulting in more frequent chromosomal breaks and translocations in double mutant cells throughout the cell cycle. Finally, it was determined that 53BP1 is dispensable for the formation of RAG-mediated hybrid joints in Atm(-/-) thymocytes but is required to suppress large deletions in a subset of hybrid joints.
  
  
  CONCLUSIONS
  The current study uncovers novel ATM-independent functions for 53BP1 in the suppression of oncogenic translocations and in radioprotection.
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, 1550 Orleans Street, CRB II, Rm#405, Baltimore, MD 21287. sfranco2@jhmi.edu.
authors.forename: Ivana
authors.initials: I
authors.lastname: Rybanska-Spaeder
authors.forename: Taylor L
authors.initials: TL
authors.lastname: Reynolds
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chou
authors.forename: Mansi
authors.initials: M
authors.lastname: Prakash
authors.forename: Tameca
authors.initials: T
authors.lastname: Jefferson
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Stephen
authors.initials: S
authors.lastname: Desiderio
authors.forename: Sonia
authors.initials: S
authors.lastname: Franco
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage; D059766:DNA End-Joining Repair / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000502:physiology*; D005720:Gamma Rays; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D013312:Stress, Physiological / Q000235:genetics; D060168:Thymocytes / Q000378:metabolism / Q000528:radiation effects; D014178:Translocation, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse