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
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Abstract |
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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.
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Introduction |
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The genome is continuously damaged by a variety of endogenous and exogenous agents. Repair of such damage is a crucial mechanism for maintaining genomic integrity, which is essential for normal developmental and physiological consequences. A failure in faithful repair causes mutations with an increased risk of cancer. In addition, higher animal cells have a mechanism for eliminating damaged cells called apoptosis. Among the damage, DNA base modifications, such as deamination, alkylation and oxidation, or apurinic/apyrimidinic (AP) sites due to spontaneous depurination arise most frequently (1
,2). These small lesions are mainly repaired through base excision repair (BER) (3,4). BER is initiated by a damage-specific DNA N-glycosylase that removes a modified base, generating an AP site (also arising spontaneously); and AP endonuclease excises the site leaving a 5' deoxyribose-5-phosphate (dRP) residue and a single-strand break (SSB) (5). The following reactions are divided into the short-patch and long-patch pathways (4,6,7). In the short-patch pathway, DNA polymease ß (Polß) inserts a nucleotide into the gap through a nucleotidyltransferase activity generating nicked DNA with a dRP flap (8,9); Polß removes the flap by its dRP lyase activity and the gap is finally sealed by DNA ligase I or a complex of XRCC1/DNA ligase III (10). In the long-patch pathway, Polß or DNA polymerase 
/
along with PCNA adds 2–10 nt into the gap by displacing the dRP residue (often modified by oxidation or reduction) as part of an oligonucleotide flap; this flap is removed by flap endonuclease I, followed by sealing the gap with DNA ligase I (11).
Brain is one of the tissues in mouse which exhibit a high level of Polß activity (12,13), suggesting an important role for the enzyme in development and differentiation of the nervous system. We and others have previously shown that Polß null mice exhibit a reduced size and weight, and die of a respiratory defect immediately after birth (14–16). We have also shown that in Polß-deficient embryos, extensive cell death (apoptosis) occurs in postmitotic neurons in the developing central and peripheral nervous systems and that this apoptosis is closely associated with the period between the onset and cessation of neurogenesis (15). No abnormalities in tissues other than the nervous system have been observed in embryos (15,16). Moreover, we reported that p53 deficiency can rescue the neuronal apoptosis but not lethality, owing to the developmental abnormality in the nervous system (17,18). A recent report shows that Polß overexpressing mice cause severe cortical cataract, suggesting the involvement of Polß in lens epithelial differentiation (19). Taken together, these findings indicate that Polß plays a crucial role specifically in the development of the nervous system, as we have suggested previously (15,17).
The impact of altered Polß levels on mutagenesis has been studied in cultured cells and Polß heterozygous mice. For example, it was reported that CHO cells overexpressing Polß cDNA show a spontaneous mutator phenotype (20). On the contrary, mouse embryonic fibroblast cells null for Polß exhibited a modest increase in spontaneous mutation frequency but a markedly increased frequency following treatment with a DNA alkylating agent methyl methanesulfate compared with wild-type controls (21). Similarly, Polß heterozygous (Polß+/–) mice expressing one-half of the activity in wild-type mice exhibited no increased spontaneous mutation frequency but a more induced frequency by dimethyl sulfate than wild-type mice did (22). However, the relationship between Polß deficiency and in vivo mutagenesis during development and neurogenesis remains unexplored. To study this, we used the in vivo mutation detection system consisting of a plasmid shuttle vector pSSW with the Escherichia coli rpsL reporter gene (23,24). This system relies on a positive detection of rare drug-resistant colonies occurring in a large population of drug-sensitive E.coli and is very facile for sequencing because the rpsL target gene is only 375 bp long. We generated Polß–/– and wild-type (Polß+/+) mice harboring the rpsL transgene and examined mutation frequency and spectrum in these embryos. We find that the mutant frequency in brain from Polß–/– mouse embryos is significantly lower than that from wild-type littermates. We suggest that this decreased mutant frequency may be caused by the elimination of apoptotic neuronal cells generated by unrepaired DNA damage in Polß null brains.
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Materials and methods |
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Transgenic mice
The rpsL transgenic mouse (ssw2-14p) line used in this study is a modified version of the one established originally by Gondo et al. (23
) and harbors 
100 copies of the pSSW shuttle plasmid vector hemizygously in the genome (24). The pSSW carries a replicative origin (ori) from the pUC vector, the kanamycin-resistant (Kmr) gene and the E.coli rpsL gene. The wild-type rpsL gene encodes for the S12 protein, one of the small subunit proteins of E.coli ribosome and confers a dominant streptomycin-sensitive (Sms) phenotype to E.coli. The Kmr gene in pSSW serves to recover all transfectants, while the mutated rpsL gene confers a Sm-resistant (Smr) phenotype. Therefore, mutant frequency can easily be estimated by scoring the number of colonies occurring in plates containing Km alone and Km plus Sm. The transgenic mice were mated with Polß+/– mice (15), in order to generate Polß+/–, Polß+/+ and Polß–/– mice, which were all hemizygous for the rpsL gene. Genotyping of Polß was carried out by PCR as described previously (15). Noon of the day on which the vaginal plug was detected in the morning was designated as embryonic day (E) 0.5. All mice were maintained in a pathogen-free environment under the guidelines of Kihara Institute for Biological Research, Yokohama City University for laboratory animals.
rpsL mutation assay
Brain and liver tissues were isolated from E18.5 embryos and quickly stored in frozen conditions below –80°C. The rpsL mutation assay was performed according to the procedures described previously (23,24). Briefly, genomic DNA was isolated from the frozen tissues, digested with restriction enzyme BanII (Takara, Kyoto, Japan), which excises the integrated shuttle vectors at a unit size. The digested DNA sample was then treated with T4 DNA ligase to self-circularize the transgene. An aliquot of 20 µl of the competent E.coli DH10B strain were mixed with 1 ng of the ligated DNA sample and transferred into an electroporation cell; then, electroporation was conducted at 1.4 kV/mm (BTX, San Diego, CA) according to the manufacturer's instructions. The mixture was transferred into 1 ml of SOC medium and incubated at 27°C with vigorous shaking for 70 min. Aliquots of the cultures were spread on to Luria–Bertani (LB) agar plates containing Km (50 µg/ml) alone or both Km (50 µg/ml) and Sm (100 µg/ml), and were incubated at 27°C for 36 h. Resulting colonies were counted, and mutant frequency was calculated as the ratio of the number of colonies detected on the plates containing Km plus Sm to the number of colonies on the plates containing Km alone as described (23). Assays were repeated with the same DNA samples with reproducible results.
Individual colonies were picked from the above Km- and Sm-containing plates after the colony number was scored and incubated in 2 ml of LB with 50 µg/ml Km alone at 27°C for overnight. Plasmid DNA was then extracted by the alkaline lysis method and suspended in 30 µl of TE [10 mM Tris–HCl and 1 mM EDTA (pH 8.0)]. An aliquot of 1 µl of the DNA sample (diluted 100-fold) was used as a template for PCR with a pair of primers, EcoR (5'-TTCCCGGTTTGACTGGTC-3') and R3 (5'-GTACTCAGTTTAAGCTGGCC-3'), for the sequences flanking upstream and downstream, respectively, of the rpsL gene in pSSW. The PCR condition was 25 cycles of incubation at 95°C for 30 s, at 60°C for 30 s and at 72°C for 1 min. PCR products were purified with a PCR Clean-up System (Promega Japan, Tokyo), and sequenced using a Multi-capillary DNA Sequencer CEQ8000 (Beckman Coulter, Fullerton, CA). The sequence primers (F1 and R1) for the sense and antisense strands of the rpsL gene were described previously (24).
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Results |
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Mutant frequency in brain and liver from Polß–/– embryonic mice
We established Polß+/– mice carrying the E.coli rpsL gene by mating Polß+/– mice with rpsL transgenic mice (rpsL hemizygotes). Polß+/– mice with the transgene were then mated with Polß+/– mice, and Polß–/– and Polß+/+ (wild-type) mice carrying the reporter gene were generated. These mice were represented at ratios close to the Mendelian law during the prenatal stage (N. Niimi, N. Sugo, Y. Aratani, Y. Gondo, M. Katsuki and H. Koyama, unpublished data). Genomic DNA was extracted from brain and liver tissues recovered from mice at embryonic day 18.5 (E18.5) and subjected to the rpsL mutation analysis as described in the Materials and methods section. As shown in Table I, the mean mutant frequency in brains from wild-type mice was 3.12 ± 0.83 x 10–5 (n = 8). Unexpectedly, the frequency in brains from Polß–/– littermates was 1.63 ± 0.67 x 10–5 (n = 10). Therefore, the frequency in Polß–/– brains was 2-fold lower than that in wild-type controls, and the difference was statistically significant (t-test, P < 0.001). To examine whether the decrease occurred specifically in brains, we examined mutant frequency in livers of the respective wild-type and Polß–/– mice (Table II). The mean mutant frequency in the corresponding wild-type livers was 0.71 ± 0.31 x 10–5 (n = 7), and the frequency slightly increased in Polß–/– livers (0.92 ± 0.38 x 10–5) (n = 8), although the difference was not fully significant (P = 0.20).
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Mutation spectra in brain and liver from Polß–/– embryonic mice
We carried out sequence analysis of a rpsL gene in Kmr Smr clones obtained with genomic DNA from wild-type and Polß–/– brains at E18.5 and examined their mutational spectra (Figure 1 and Table III). Interestingly, in wild-type brains, single-base deletions were almost completely detected (33/36, 92%), except for one transition and two large deletions (2 or more base losses). In addition, the mutation sites fell within runs of 2–6 identical bases distributing evenly in the rpsL sequence and a TA repeat at positions 110–118. Similarly, in Polß–/– brains, all the mutations were exclusively single-base deletions (38/38). Interestingly, 55% of the sites (21/38) in Polß–/– brains fell into a run of six consecutive adenine residues at positions 127–132, whereas in wild-type brains, the deletions at this run accounted for only 14% (5/36) (Figure 1). This difference in the mutation sites was found to be highly significant by
2-analysis (P < 0.001). The remaining sites (17/38) in Polß–/– brains were also observed at the runs of two or more identical bases and the TA repeat, as seen in the wild-type brains.
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We also examined mutational spectra in livers from wild-type and Polß–/– embryos (Figure 2 and Table III). We found
60% of single-base deletions in livers with both genotypes; but the remaining mutations in wild-type livers were base substitutions (4/16, 25%) including one transition and three transversions, and large deletions (3/16, 19%), whereas those in Polß–/– liver were base substitutions (3/25, 12%) including one transition and two transversions and large deletions (6/25, 24%). These data indicate that there are no significant differences in the mutational spectra between the livers from wild-type and Polß–/– embryos (P > 0.10, by 2-analysis). In addition, the significant difference in frequencies of single-base deletions between Polß–/– brains versus livers and between wild-type brains versus livers was found by 2-analysis (P < 0.005 and P < 0.001, respectively).
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Discussion |
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In this study, we examined mutations occurring spontaneously in Polß–/– and wild-type mice, by using the transgenic mutation detection system consisting of a pSSW shuttle vector carrying the rspL gene of E.coli. We have found that the mutant frequency in brain from Polß–/– mice at E18.5 is significantly lower than that from wild-type controls. In contrast, we have found no such difference between the corresponding Polß–/– and wild-type livers. Interestingly, mutation spectrum analysis revealed the occurrence of single-base deletions almost exclusively in brains from embryos with both genotypes, but the considerably uneven distribution of the deletion sites in Polß–/– brains, compared with those in wild-type controls. To our knowledge, the present data are the first report concerning spontaneous mutagenesis in Polß null mice.
In the BER pathway, repair of damaged DNA bases is initiated by a variety of DNA glycosylases generating AP sites which are also generated spontaneously by depurination (3,4). Then, AP endonuclease excises the sites, generating SSBs as BER intermediates. Since the Polß-dependent, short-patch BER is predominant and proceeds very efficiently, these lesions unlikely accumulate in wild-type tissues. However, in Polß-deficient cells, loss of Polß would leave such unrepaired lesions, resulting in the accumulation of the AP sites and SSBs. Since p53 levels are controlled by a variety of such DNA damage including SSBs and double-strand breaks occurring in cells, the increased damage would stabilize and/or activate p53, leading to its enhanced levels (25). Consequently, this enhancement can trigger the p53-dependent cell cycle arrest by the checkpoint mechanism and, if the damage is too much and is left unrepaired, may lead to apoptosis during postmitotic neuronal cells in Polß–/– brains. In fact, we found a marked increase in the level of p53 protein in E13.5 Polß–/– brains (17). Therefore, we suggest that the low mutant frequency observed in Polß–/– embryonic brains compared with wild-type ones (Table I) may be caused by the elimination of neuronal cells carrying abundant, unrepaired DNA damage through apoptosis. Our previous findings that livers in Polß–/– embryos do not display apoptosis (15) support the above explanation. We have seen a slight (but not fully significant) increase in the mutant frequency in Polß–/– livers versus wild-type controls (Table II); this frequency is less than the decreased frequency in the corresponding Polß–/– brains. Therefore, the level of unrepaired damage occurring in Polß–/– livers would be insufficient for the induction of apoptosis. Rockwood et al. (26) reported 1.6-fold lower mutant frequencies of brain and liver from mice deficient in Ku80, the key factor for non-homologous end-joining in DSB repair, as compared with those in wild-type controls. Similar to Polß–/– embryos, Ku80–/– embryos exhibit neuronal apoptosis in brains (27), although Ku80–/– mice can survive after birth. It was suggested that the lowered frequency observed in Ku80 null mice results from the elimination of cells with unrepaired damage by apoptosis.
The mutation spectra in brains from both Polß–/– and wild-type embryos were almost exclusively single-base deletions, whose sites were frequently found at the runs of two or more identical bases in the rpsL sequence (Figure 1 and Table III). On the other hand, in livers with two genotypes, both single-base deletions and base substitutions were detected (Figure 2 and Table III). We found these mutation types at a similar frequency in spleens of 8-week-old, wild-type mice (N. Niimi, N. Sugo, Y. Aratani, Y. Gondo, M. Katsuki and H. Koyama, unpublished data), consistent with the data reported previously (23,24). Therefore, it seems that the deletions observed in brains occur in a tissue-specific manner. DNA replication is known to cause base deletions or additions (frameshifts) by slippage errors arising preferentially at repeated base sequences, and these errors can be repaired by the mismatch repair pathway (28,29). Despite the presence or absence of Polß, the higher levels of single-base deletions in wild-type and Polß–/– brains might be attributable to the occurrence of higher levels of replication errors or lower levels of the mismatch repair activity, although there is no evidence for supporting these at present. Moreover, translesional synthesis of abasic DNA by DNA ploymerase 
, a member of the DNA polymerase X family like Polß, would contribute to the formation of single-base deletions (30,31). These possibilities are now under study.
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Acknowledgments |
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We thank Miss A.Oonuma for animal care. N.S. is a recipient of Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists. This work is supported in part by Grant-in-Aid (C) for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Notes |
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* To whom correspondence should be addressed. Tel: +81 45 820 2440; Fax: +81 45 820 1901; Email: koyama{at}yokohama-cu.ac.jp
4 Present address: Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan 
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Received on October 15, 2005; revised on December 4, 2005; accepted on December 5, 2005.
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