Mutagenesis Advance Access originally published online on January 6, 2006
Mutagenesis 2006 21(1):55-59; doi:10.1093/mutage/gei074
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Decreased mutant frequency in embryonic brain of DNA polymerase ß null mice
1Kihara Institute for Biological Research and Graduate School of Integrated Science, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan, 2Population and Quantitative Genomics Team, Bioinformatics Group, RIKEN GSC, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan and 3National Institute for Basic Biology, Nishigonaka 38, Myodaiji, Okazaki 444-8585, Japan
DNA polymerase ß (Polß) 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 Polß deficiency and mutagenesis during development and neurogenesis, we examined spontaneous mutations in Polß null (Polß–/–) and wild-type (Polß+/+) 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 Polß–/– brain (1.63 ± 0.67 x 10–5) compared with wild-type controls (3.12 ± 0.83 x 10–5) (P < 0.001). In contrast, no such difference was found between livers from Polß–/– (0.92 ± 0.38 x 10–5) and wild-type (0.71 ± 0.31 x 10–5) 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 Polß deficiency, we suggest that the lower mutant frequency observed in Polß–/– embryonic brain may be caused by the elimination of neuronal cells with unrepaired DNA damage through apoptosis.
4 Present address: Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
* To whom correspondence should be addressed. Tel: +81 45 820 2440; Fax: +81 45 820 1901; Email: koyama{at}yokohama-cu.ac.jp
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