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.

Abstract

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

Substances

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