Age-associated increase of spontaneous mutant frequency and molecular nature of mutation in newborn and old lacZ-transgenic mouse

Ono, Tetsuya; Ikehata, Hironobu; Nakamura, Shingo; Saito, Yûsuke; Hosoi, Yoshio; Takai, Yoshihiro; Yamada, Satoshi; Onodera, Junichi; Yamamoto, Kazuo

doi:10.1016/s0027-5107(99)00200-6

Cited by 87 publications

(87 citation statements)

References 52 publications

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“…The effect of age on these classes of mutations appears to be strongly tissue-dependent. In certain tissues, such as brain and testis, the mutant frequency remains fairly constant (33)(34)(35). In contrast, for liver and bladder, mutant cell frequency increases with age similar to what has been observed for the pancreas in these studies (33)(34)(35).…”

Section: Discussionsupporting

confidence: 83%

“…In certain tissues, such as brain and testis, the mutant frequency remains fairly constant (33)(34)(35). In contrast, for liver and bladder, mutant cell frequency increases with age similar to what has been observed for the pancreas in these studies (33)(34)(35). It is interesting to speculate that for tissues in which spontaneous mutations accumulate with age, mutagenic exposures during adult life may have a greater influence on cancer risk.…”

Section: Discussionsupporting

confidence: 75%

“…Other mouse models, including BigBlue (33,34), MutaMouse (35), and LacZ (36), have been used to examine changes in the frequency of point mutations and small deletions with age. The effect of age on these classes of mutations appears to be strongly tissue-dependent.…”

Section: Discussionmentioning

confidence: 99%

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Age-dependent accumulation of recombinant cells in the mouse pancreas revealed byin situfluorescence imaging

Wiktor-Brown

Hendricks²,

Olipitz³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Mitotic homologous recombination (HR) is critical for the repair of double-strand breaks, and conditions that stimulate HR are associated with an increased risk of deleterious sequence rearrangements that can promote cancer. Because of the difficulty of assessing HR in mammals, little is known about HR activity in mammalian tissues or about the effects of cancer risk factors on HR in vivo. To study HR in vivo, we have used fluorescent yellow direct repeat mice, in which an HR event at a transgene yields a fluorescent phenotype. Results show that HR is an active pathway in the pancreas throughout life, that HR is induced in vivo by exposure to a cancer chemotherapeutic agent, and that recombinant cells accumulate with age in pancreatic tissue. Furthermore, we developed an in situ imaging approach that reveals an increase in both the frequency and the sizes of isolated recombinant cell clusters with age, indicating that both de novo recombination events and clonal expansion contribute to the accumulation of recombinant cells with age. This work demonstrates that aging and exposure to a cancer chemotherapeutic agent increase the frequency of recombinant cells in the pancreas, and it also provides a rapid method for revealing additional factors that modulate HR and clonal expansion in vivo.aging ͉ homologous recombination ͉ mutation ͉ chemotherapy C ells are constantly exposed to endogenous and exogenous DNA-damaging agents that can lead to double-strand breaks, either by causing breaks in both strands of DNA or by causing replication fork breakdown (1). Homologous recombination (HR) is critical for repairing double-strand breaks in mammalian cells. By using homologous DNA sequences present on the sister chromatid or homologous chromosome, damage can be repaired accurately without loss of sequence information (2, 3). Thus, the frequency of HR reflects both the levels of double-strand breaks and the ability of cells to use HR during DNA repair.Although HR is generally error-free, recombination between misaligned sequences can cause insertions, deletions, and translocations. Furthermore, recombination between homologous chromosomes can lead to loss of heterozygosity (4), and HR has been estimated to be the underlying cause of loss of heterozygosity 25-80% of the time in mammalian cells (e.g., see ref. 5). Germ-line mutations in genes that modulate the frequency of HR are associated with an increased risk of cancer. For example, inherited mutations in the HR helicases BLM and WRN lead to increased rates of HR (6, 7) and increase the risk of cancer (8).Whereas too much HR can be problematic, too little HR can also destabilize the genome, possibly as a result of nonhomologous end-joining of DNA ends created at broken replication forks (4, 9). In the pancreas, inherited mutations in BRCA1 (8), BRCA2 (10), and FANCC (11) increase the risk of pancreatic cancer, and loss of function of these genes suppresses HR (12-14), causing an increased frequency of tumorigenic sequence rearrangements (15,16). Although these findings sug...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 75%

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Age-dependent accumulation of recombinant cells in the mouse pancreas revealed byin situfluorescence imaging

Wiktor-Brown

Hendricks²,

Olipitz³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, splenic and hepatic DNA from different transgenic mice showed increased spontaneous mutation with age (35) and a highly elevated mutation frequency was also observed in the lymphocytes of senescence-accelerated mice (36). More recently, old transgenic Big-Blue and Mutra mice were shown to contain elevated mutation frequencies (37,38). In humans, age-related increases in mutation frequency have been found in the hprt gene of peripheral blood lymphocytes and kidney epithelial cells (39,40).…”

Section: Discussionmentioning

confidence: 99%

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Chang¹,

Jin

Yoon

et al. 2008

Molecular Cancer Research

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DNA damage and mutations in the genome increase with age. To determine the potential mechanisms of senescence-dependent increases in genomic instability, we analyzed DNA mismatch repair (MMR) efficiency in young and senescent human colonic fibroblast and human embryonic lung fibroblast. It was found that MMR activity is significantly reduced in senescent cells. Western blot and immunohistochemistry analysis revealed that hMSH2 and MSH6 protein (MutSA complex), which is a known key component in the MMR pathway, is markedly down-regulated in senescent cells. Moreover, the addition of purified MutSA to extracts from senescent cells led to the restoration of MMR activity. Semiquantitative reverse transcription-PCR analysis exhibited that MSH2 mRNA level is reduced in senescent cells. In addition, a decrease in E2F transcriptional activity in senescent cells was found to be crucial for MSH2 suppression. E2F1 small interfering RNA expression reduced hMSH2 expression and MMR activity in young human primary fibroblast cells. Importantly, expression of E2F1 in quiescent cells restored the MSH2 expression as well as MMR activity, whereas E2F1-infected senescent cells exhibited no restoration of MSH2 expression and MMR activity. These results indicate that the suppression of E2F1 transcriptional activity in senescent cells lead to stable repression of MSH2, followed by a induction of MutSA dysfunction, which results in a reduced cellular MMR capacity in senescent cells. (Mol Cancer Res 2008;6(6):978 -89)

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“…These results show that the activity derived from TDG is probably lost in the (−/−) embryos. In mammals, the most frequent type of spontaneous mutation observed is a base substitution of G:C to A:T in the DNA sequence 5′CG3′ (de Boer et al 1998;Ono et al 2000). This type of mutation is assumed to be created through the following process; spontaneous deamination of 5-methylcytosine in the 5′CG3′sequence results in the formation of T, and a T:G mispairing instead of C:G; and replication of DNA leads to T:A and C:G pairings (Gonzalgo and Jones 1997).…”

Section: Spontaneous Mutation Frequencies In Tdg Homozygous Embryosmentioning

confidence: 99%

Embryonic Lethality in Mice Lacking Mismatch-Specific Thymine DNA Glycosylase Is Partially Prevented by DOPS, a Precursor of Noradrenaline

Saito

Ono

Takeda

et al. 2012

Tohoku J. Exp. Med.

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Thymine DNA glycosylase (TDG) is involved in the repair of G:T and G:U mismatches caused by hydrolytic deamination of 5-methylcytosine and cytosine, respectively. Recent studies have shown that TDG not only has G-T/U glycosylase activities but also acts in the maintaining proper epigenetic status. In order to investigate the function of TDG in vivo, mice lacking Tdg, Tdg (−/−), were generated. Tdg mutant mice died in utero by 11.5 days post coitum (dpc), although there were no significant differences in the spontaneous mutant frequencies between wild type and Tdg (−/−) embryos. On the other hand, the levels of noradrenaline in 10.5 dpc whole embryos, which is necessary for normal embryogenesis, were dramatically reduced in Tdg (-/-) embryos. Consequently, we tested the effect of D, L-threo-3, 4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline, on the survival of the Tdg (−/−) embryos. DOPS was given to pregnant Tdg (+/−) mice from 6.5 dpc through drinking water. Most of the Tdg (−/−) embryos were alive at 11.5 dpc, and they were partially rescued up to 14.5 dpc by the administration of DOPS. In contrast, the administration of L-3, 4-dihydroxyphenylalanine (L-DOPA) had marginal effects on Tdg (−/−) embryonic lethality. No embryo was alive without DOPS beyond 11.5 dpc, suggesting that the lethality in (−/−) embryos is partially due to the reduction of noradrenaline. These results suggest that embryonic lethality in Tdg (−/−) embryos is due, in part, to the reduction of noradrenaline levels.

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Age-associated increase of spontaneous mutant frequency and molecular nature of mutation in newborn and old lacZ-transgenic mouse

Cited by 87 publications

References 52 publications

Age-dependent accumulation of recombinant cells in the mouse pancreas revealed byin situfluorescence imaging

Age-dependent accumulation of recombinant cells in the mouse pancreas revealed byin situfluorescence imaging

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Embryonic Lethality in Mice Lacking Mismatch-Specific Thymine DNA Glycosylase Is Partially Prevented by DOPS, a Precursor of Noradrenaline

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