title: Genetic interaction between DNA polymerase beta and DNA-PKcs in embryogenesis and neurogenesis.
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.
authors.affiliation: Kihara Institute for Biological Research and Graduate School of Integrated Science, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Niimi
authors.forename: N
authors.initials: N
authors.lastname: Sugo
authors.forename: Y
authors.initials: Y
authors.lastname: Aratani
authors.forename: H
authors.initials: H
authors.lastname: Koyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D003433:Crosses, Genetic; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020964:Embryo Loss / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D009420:Nervous System / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D019951:DNA Polymerase beta