Genetic interaction between DNA polymerase beta and DNA-PKcs in embryogenesis and neurogenesis

Cell Death Differ. 2005 Feb;12(2):184-91. doi: 10.1038/sj.cdd.4401543.


DNA polymerase beta (Polbeta) has been implicated in base excision repair. Polbeta knockout mice exhibit apoptosis in postmitotic neuronal cells and die at birth. Also, mice deficient in nonhomologous end-joining (NHEJ), a major pathway for DNA double-strand break repair, cause massive neuronal apoptosis. Severe combined immunodeficiency (SCID) mice have a mutation in the gene encoding DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the component of NHEJ, and exhibit defective lymphogenesis. To study the interaction between Polbeta and DNA-PKcs, we generated mice doubly deficient in Polbeta and DNA-PKcs. Polbeta(-/-)DNA-PKcs(scid/scid) embryos displayed greater developmental delay, more extensive neuronal apoptosis, and earlier lethality than Polbeta(-/-) and DNA-PKcs(scid/scid) embryos. Furthermore, to study the involvement of p53 in the phenotype, we generated Polbeta(-/-)DNA-PKcs(scid/scid)p53(-/-) triple-mutant mice. The mutants did not exhibit apoptosis but were lethal with defective neurulation at midgestation. These results suggest a genetic interaction between Polbeta and DNA-PKcs in embryogenesis and neurogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Crosses, Genetic
  • DNA Polymerase beta / genetics
  • DNA Polymerase beta / metabolism*
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryo Loss / genetics
  • Embryonic Development / genetics
  • Embryonic Development / physiology*
  • Female
  • Heterozygote
  • Homozygote
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, SCID
  • Nervous System / embryology*
  • Nervous System / metabolism
  • Nervous System / pathology
  • Phenotype
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology


  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • DNA-Activated Protein Kinase
  • Protein Serine-Threonine Kinases
  • DNA Polymerase beta