Mutagenesis Advance Access published online on January 6, 2006
Mutagenesis, doi:10.1093/mutage/gei074
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1 Kihara Institute for Biological Research and Graduate School of Integrated Science, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan
* To whom correspondence should be addressed. DNA polymerase
Received October 15, 2005
Revised December 4, 2005
Accepted December 5, 2005
Original article
Decreased mutant frequency in embryonic brain of DNA polymerase
Naoko Niimi 1,
Noriyuki Sugo 2,
Yasuaki Aratani 1,
Yoichi Gondo 3,
Motoya Katsuki 4,
and
Hideki Koyama 1 *
null mice
2 Kihara Institute for Biological Research and Graduate School of Integrated Science, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan; Present address: Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
3 Population and Quantitative Genomics Team, Bioinformatics Group, RIKEN GSC, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
4 National Institute for Basic Biology, Nishigonaka 38, Myodaiji, Okazaki 444-8585, Japan
Hideki Koyama, E-mail: koyama{at}yokohama-cu.ac.jp
Abstract 
(Pol) 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 Pol deficiency and mutagenesis during development and neurogenesis, we examined spontaneous mutations in Pol null (Pol-/-) and wild-type (Pol+/+) 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 Pol-/- 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 Pol-/- (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 Pol deficiency, we suggest that the lower mutant frequency observed in Pol-/- embryonic brain may be caused by the elimination of neuronal cells with unrepaired DNA damage through apoptosis.
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