Effect of target gene CpG content on spontaneous mutation in transgenic mice

Skopek, Thomas R.; Marino, Deborah R.; Kort, Kristy L.; Miller, Judith E.; Trumbauer, Myrna E.; Gopal, Shobhna; Chen, Howard

doi:10.1016/s0027-5107(98)00040-2

Cited by 16 publications

(6 citation statements)

References 17 publications

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“…No significant differences were found. Skopek et al (52) observed a similar response when they generated lacI transgenic mice by using a lacI transgene (mrkII) that had substantially reduced numbers of CpG sequences. The mutation frequency and proportion of GC to AT transitions at CpG sequences did not differ significantly between lacI mice and their modified mrkII transgenic mice.…”

Section: Discussionmentioning

confidence: 84%

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O ⁶ - methylguanine-DNA methyltransferase

Zhou

Manguino

Kewitt

et al. 2001

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

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O 6 -methylguanine (O 6 mG) is a potent mutagenic and procarcinogenic DNA lesion. Organisms have evolved with a DNA repair mechanism that largely ameliorates the deleterious effects of O 6 mG through a direct reversal mechanism by a protein termed O 6 -methylguanine-DNA methyltransferase (MGMT). However, the contribution of O 6 mG to carcinogenesis, in the absence of known exposure to agents that produce it, has not been defined. Nontransgenic C3HeB male mice have a high frequency of spontaneous liver tumors. Transgenic CeHeB͞FeJ mice expressing human MGMT (hMGMT) were generated that had elevated hepatic MGMT activity. The spontaneous development of hepatocellular carcinoma was significantly reduced in those mice expressing hMGMT compared with nontransgenic C3HeB͞FeJ male mice. No differences were detected in spontaneous mutant frequencies in lacI transgenes in mice carrying hMGMT compared with that without hMGMT but the proportion of GC to AT transition mutations was lower in the transgenic mice carrying hMGMT as well as lacI. Tumors that arose in C3HeB͞FeJ transgenic mice were largely deficient in hMGMT protein as determined by immunohistochemistry with a monoclonal antibody directed against hMGMT. Together these data indicate that spontaneous O 6 mG lesions induced hepatocellular carcinogenesis in C3HeB͞FeJ male mice. These transgenic mice represent a rare example of reduced spontaneous carcinogenesis.

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Section: Discussionmentioning

confidence: 84%

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O ⁶ - methylguanine-DNA methyltransferase

Zhou

Manguino

Kewitt

et al. 2001

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

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“…As the lacI gene contains proportionally more CpG sites than mammalian genes, the lacI gene may be an inappropriate mutational target since mutations at this gene could be an overestimate of both spontaneous (31) and chemical mutagenesis in the rat genome. However, recently it was shown that a reduction in the CpG content of the lacI gene did not reduce the rate of spontaneous mutation or the contribution of CpG related events (32). Conversely, if compounds did preferentially bind to CpG sites and mutations at these sites were causal events in tumourigenesis, then the use of a 'sensitive' gene such as lacI in in vivo mutagenesis studies could be a very appropriate target for detecting potential carcinogens.…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen induces G:C->T:A mutations in the cII gene in the liver of lambda/lacI transgenic rats but not at 5'-CpG-3' dinucleotide sequences as found in the lacI transgene

et al. 1999

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Tamoxifen, a rat liver carcinogen, can induce mutations in the lacI gene in the livers of lambda/lacI transgenic rats. However, the presence of persistent tamoxifen adducts on the liver DNA raises the possibility that some contribution to the mutagenesis from ex vivo mutations during the in vitro lacI assay cannot be ruled out. To address this issue, mutagenesis at the cII gene of the transgenic shuttle vector was determined using a selection based assay which is unaffected by the presence of tamoxifen-DNA adducts. Female lambda/lacI transgenic rats were dosed orally with tamoxifen (20 mg/kg body wt) daily for 6 weeks, causing a 3.2-fold increase in the mutant frequency (MF) in the cII gene compared with that obtained with solvent treated animals. This was similar to the MF found previously at the lacI gene and confirms that tamoxifen is mutagenic in vivo. The major class of mutation induced by tamoxifen in the cII gene was G:C-->T:A transversions as was found previously in the lacI gene. However, in the one unreplicated study of mutations in the p53 gene of liver tumours induced by tamoxifen, no G:C-->T:A transversions were found; possible differences between mutagenesis in normal and tumour tissues are explored. The major proportion of the G:C-->T:A transversions occurred at 5'-CpG-3' dinucleotide (CpG) sites in the lacI gene, but not at such sites in the cII gene. The methylation of CpG sites greatly enhances the targeting of deoxyguanosine by carcinogens, thus this finding might be explained by differences in the methylation patterns at their respective CpG sites; however, nothing is known about the methylation status of either the lacI nor the cII gene in this transgenic rat. This study raises the important issue of which target genes (mammalian or transgenic) should be used as endpoints in mammalian mutagenesis assays.

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“…Given the substantial mutant frequency elevations in the MSH6-deficient mice, this result suggested that spontaneous deaminations of 5'-methycytosine residues was not the only pre-mutagenic mechanism involved in generating the high proportion of G:C to A:T changes observed. In this respect, it should be noted that a transgenic mouse containing a lacI gene purged of 86% of its CpG sites did not exhibit a substantial reduction in spontaneous mutation rate (Skopek et al, 1998). Furthermore, Monroe et al (2001) concluded that tissue-to-tissue variation in spontaneous mutant frequencies of lacI transgenic rats could not be correlated with methylation status of CpG sites in the transgene.…”

Section: Mutation Spectramentioning

confidence: 99%

Elevated mutant frequencies and predominance of G:C to A:T transition mutations in Msh6−/− small intestinal epithelium

et al. 2002

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Effect of target gene CpG content on spontaneous mutation in transgenic mice

Cited by 16 publications

References 17 publications

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O ⁶ - methylguanine-DNA methyltransferase

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O ⁶ - methylguanine-DNA methyltransferase

Tamoxifen induces G:C->T:A mutations in the cII gene in the liver of lambda/lacI transgenic rats but not at 5'-CpG-3' dinucleotide sequences as found in the lacI transgene

Elevated mutant frequencies and predominance of G:C to A:T transition mutations in Msh6−/− small intestinal epithelium

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Effect of target gene CpG content on spontaneous mutation in transgenic mice

Cited by 16 publications

References 17 publications

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O 6 - methylguanine-DNA methyltransferase

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O 6 - methylguanine-DNA methyltransferase

Tamoxifen induces G:C->T:A mutations in the cII gene in the liver of lambda/lacI transgenic rats but not at 5'-CpG-3' dinucleotide sequences as found in the lacI transgene

Elevated mutant frequencies and predominance of G:C to A:T transition mutations in Msh6−/− small intestinal epithelium

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Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O ⁶ - methylguanine-DNA methyltransferase

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O ⁶ - methylguanine-DNA methyltransferase