53BP1 is limiting for NHEJ repair in ATM-deficient model systems that are subjected to oncogenic stress or radiation

Ivana Rybanska-Spaeder, Taylor L. Reynolds, Jeremy Chou, Mansi Prakash, Tameca Jefferson, David L. Huso, Stephen Desiderio, Sonia Franco

Research output: Research - peer-reviewArticle

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 NHEJdefect, 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. Implications: The current study uncovers novel ATM-independent functions for 53BP1 in the suppression of oncogenic translocations and in radioprotection.

LanguageEnglish (US)
Pages1223-1234
Number of pages12
JournalMolecular Cancer Research
Volume11
Issue number10
DOIs
StatePublished - 2013

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Ataxia Telangiectasia
Radiation
Joints
Thymocytes
VDJ Recombinases
Chromosome Breakage
Genetic Translocation
Cell Cycle Checkpoints
DNA Damage
Lymphoma
Cell Cycle
Carrier Proteins
Phenotype
Survival
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

53BP1 is limiting for NHEJ repair in ATM-deficient model systems that are subjected to oncogenic stress or radiation. / Rybanska-Spaeder, Ivana; Reynolds, Taylor L.; Chou, Jeremy; Prakash, Mansi; Jefferson, Tameca; Huso, David L.; Desiderio, Stephen; Franco, Sonia.

In: Molecular Cancer Research, Vol. 11, No. 10, 2013, p. 1223-1234.

Research output: Research - peer-reviewArticle

Rybanska-Spaeder I, Reynolds TL, Chou J, Prakash M, Jefferson T, Huso DL et al. 53BP1 is limiting for NHEJ repair in ATM-deficient model systems that are subjected to oncogenic stress or radiation. Molecular Cancer Research. 2013;11(10):1223-1234. Available from, DOI: 10.1158/1541-7786.MCR-13-0252-T
Rybanska-Spaeder, Ivana ; Reynolds, Taylor L. ; Chou, Jeremy ; Prakash, Mansi ; Jefferson, Tameca ; Huso, David L. ; Desiderio, Stephen ; Franco, Sonia. / 53BP1 is limiting for NHEJ repair in ATM-deficient model systems that are subjected to oncogenic stress or radiation. In: Molecular Cancer Research. 2013 ; Vol. 11, No. 10. pp. 1223-1234
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