Decreased mutant frequency in embryonic brain of DNA polymerase beta null mice.
DNA polymerase beta (Polbeta) knockout mouse embryos exhibit extensive apoptosis in postmitotic neuronal cells and die immediately after birth. In contrast, no apoptosis has been observed in other tissues as well as liver in the mutant embryos. To study the relationship of Polbeta deficiency and mutagenesis during development and neurogenesis, we examined spontaneous mutations in Polbeta null (Polbeta-/-) and wild-type (Polbeta+/+) mouse embryos, by using the transgenic mutation detection system consisting of a pSSW shuttle vector with the Escherichia coli rpsL reporter gene. Unexpectedly, we found a significant decrease in the mutant frequency of Polbeta-/- brain (1.63+/-0.67x10(-5)) compared with wild-type controls (3.12+/-0.83x10(-5)) (P<0.001). In contrast, no such difference was found between livers from Polbeta-/- (0.92+/-0.38x10(-5)) and wild-type (0.71+/-0.31x10(-5)) embryos. Analysis of mutation spectra revealed that mutations in brains from the two genotypes were almost exclusively single-base deletions and that these sites fell within runs of 2-6 identical bases and a two base repeat in the rpsL sequence, while mutations in the corresponding livers contained base substitutions as well as single-base deletions. Taken together with the extensive neuronal apoptosis associated with Polbeta deficiency, we suggest that the lower mutant frequency observed in Polbeta-/- embryonic brain may be caused by the elimination of neuronal cells with unrepaired DNA damage through apoptosis.
Niimi
Naoko
N
Kihara Institute for Biological Research and Graduate School of Integrated Science, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan.
Sugo
Noriyuki
N
Aratani
Yasuaki
Y
Gondo
Yoichi
Y
Katsuki
Motoya
M
Koyama
Hideki
H
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001921:Brain / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000235:genetics; D029968:Escherichia coli Proteins; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D005822:Genetic Vectors; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins / Q000235:genetics
D029968:Escherichia coli Proteins; D005819:Genetic Markers; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins; C000717190:RpsI protein, E coli; C506766:RpsL protein, E coli; D019951:DNA Polymerase beta