A 3 milliTesla 60 Hz magnetic field is neither mutagenic nor Co-Mutagenic in the presence of menadione and MNU in a transgenic rat cell line

Suri, Andrew; deBoer, Johan G.; Kusser, Wolfgang; Glickman, Barry W.

doi:10.1016/s0027-5107(96)00105-4

Cited by 30 publications

(9 citation statements)

References 35 publications

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“…2) were similar to those obtained with ''Big Blue'' transgenic mice, where 91% of all MNU mutations sequenced were G:C to A:T transitions, with 71% occurring at the 3Ј G of GpG sequences (23). This was also in keeping with studies in bacteria that indicated that mispairing of O 6-meG with T was the principal mutagenic mechanism of MNU-induced DNA base alkylation (12,(26)(27)(28)(29)(30)(31)(32). MNU-induced mutations of hprt were also dominated by G:C to A:T transitions at A͞GpG sites, further suggesting O 6 -meG as the principal premutagenic lesion stemming from MNU exposure (33,34).…”

Section: Discussionsupporting

confidence: 80%

Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent

Andrew

McKinnon²,

Cheng³

et al. 1998

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

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The mutational response of mismatch repair-deficient animals to the alkylating agent N-methyl-Nnitrosourea was evaluated by using a transgenic lacI reporter system. Although the mutations detected in MSH2 heterozygotes were similar to those of controls, MSH2؊͞؊ animals demonstrated striking increases in mutation frequency in response to this agent. G:C to A:T transitions at GpG sites, as opposed to CpG sites, dominated the mutational spectrum of both MSH2؉͞؉ and MSH2 ؊͞؊ N-methyl-N-nitrosourea -treated animals. Extrapolating to humans with hereditary non-polyposis colorectal cancer, the results suggest that MSH2 heterozygotes are unlikely to be at increased risk of mutation, even when exposed to potent DNA methylating agents. In contrast, mismatch repair-deficient cells spontaneously arising within individuals with hereditary nonpolyposis colorectal cancer would likely exhibit hypermutability in response to such mutagens, an outcome predicted to accelerate the pace of tumorigenesis.Kindreds with hereditary non-polyposis colorectal cancer (HNPCC) carry germ-line mutations in various human orthologs of the bacterial DNA mismatch repair (MMR) genes mutS and mutL (1). The gene most frequently involved in HNPCC, hMSH2, encodes a component required for DNA mismatch recognition (2, 3). Although heterozygosity for hMSH2 confers a high risk of colonic and endometrial neoplasms, malignancies at other sites, such as stomach, ovary, and urinary tract, also occur with increased frequency. Such tumors are accompanied by somatic mutations that inactivate the normal allele. The mutator phenotype arising from the combination of polymerase errors and a lack of MMR is thought to hasten the acquisition of alterations within key growth control genes, thus driving the multistep process that culminates in neoplasia (4).To generate a model of human HNPCC, mice harboring a disruption of the MSH2 locus were generated (5, 6). However, rodents heterozygous for MSH2, unlike humans with HNPCC, failed to show an increased rate of tumor formation. Mice lacking MSH2, on the other hand, developed thymic lymphomas with high frequency. In addition, although small intestinal adenomas and adenocarcinomas were seen, colonic tumors were rarely observed in these mice (5-7). Interestingly, MMR deficiency because of a lack of MSH2 or PMS2 was compatible with normal murine growth and development (5,6,8), despite the presence of an elevated mutation frequency in all tissues evaluated (9, 10). Thus, the restricted spectrum of tumors in MSH2 Ϫ͞Ϫ animals was not attributable solely to differences in tissue-specific spontaneous mutation frequencies.Although mice heterozygous for MSH2 did not demonstrate a mutator phenotype (10), it was conceivable that heterozygous cells might accrue mutations at a higher rate after mutagen exposure, owing to reduced levels of MSH2 protein.To determine whether specific mutagen administration would result in abnormal increases in mutation frequency in MSH2 ϩ͞Ϫ and MSH2 Ϫ͞Ϫ tissues, we investigated the effects of an S N ...

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Section: Discussionsupporting

confidence: 80%

Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent

Andrew

McKinnon²,

Cheng³

et al. 1998

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

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“…Three weeks after ENU treatment, the mice were sacrificed and colons were excised, rinsed with sterile PBS, flash frozen in liquid nitrogen, and stored at Ϫ80°C until needed. Genomic DNA was isolated as previously described (41). lacI transgenes were recovered from purified mouse chromosomal DNA by in vitro packaging (Stratagene, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

p27^kip1 Deficiency Impairs G₂/M Arrest in Response to DNA Damage, Leading to an Increase in Genetic Instability

Payne

Zhang

Tsuchiya

et al. 2008

Molecular and Cellular Biology

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p27kip1 is a cyclin-dependent kinase inhibitor and a tumor suppressor. In some tumors, p27 suppresses tumor growth by inhibition of cell proliferation. However, this is not universally observed, implying additional mechanisms of tumor suppression by p27. p27-deficient mice are particularly susceptibility to genotoxininduced tumors, suggesting a role for p27 in the DNA damage response. To test this hypothesis, we measured genotoxin-induced mutations and chromosome damage in p27-deficient mice. Both p27 ؉/؊ and p27 ؊/؊ mice displayed a higher N-ethyl-N-nitrosourea-induced mutation frequency in the colon than p27 ؉/؉ littermates. Furthermore, cells from irradiated p27-deficient mice exhibited a higher number of chromatid breaks and showed modestly increased micronucleus formation compared to cells from wild-type littermates. To determine if this mutator phenotype was related to the cell cycle-inhibitory function of p27, we measured cell cycle arrest in response to DNA damage. Both normal and tumor cells from p27-deficient mice showed impaired G 2 /M arrest following low doses of ionizing radiation. Thus, p27 may inhibit tumor development through two mechanisms. The first is by reducing the proliferation of cells that have already sustained an oncogenic lesion. The second is by transient inhibition of cell cycle progression following genotoxic insult, thereby minimizing chromosome damage and fixation of mutations.

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“…Colons were removed, rinsed with phosphatebuered saline (PBS),¯ash frozen in liquid nitrogen and stored at 7808C. Genomic DNA was isolated by a dialysis puri®cation procedure (Suri et al, 1996). LacI transgenes were recovered from puri®ed mice chromosomal DNA by in vitro l packaging (Stratagene, La Jolla, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Msh2 DNA mismatch repair gene deficiency and the food-borne mutagen 2-amino-1-methy1-6-phenolimidazo [4,5-b] pyridine (PhIP) synergistically affect mutagenesis in mouse colon

et al. 2001

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A 3 milliTesla 60 Hz magnetic field is neither mutagenic nor Co-Mutagenic in the presence of menadione and MNU in a transgenic rat cell line

Cited by 30 publications

References 35 publications

Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent

Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent

p27^kip1 Deficiency Impairs G₂/M Arrest in Response to DNA Damage, Leading to an Increase in Genetic Instability

Msh2 DNA mismatch repair gene deficiency and the food-borne mutagen 2-amino-1-methy1-6-phenolimidazo [4,5-b] pyridine (PhIP) synergistically affect mutagenesis in mouse colon

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A 3 milliTesla 60 Hz magnetic field is neither mutagenic nor Co-Mutagenic in the presence of menadione and MNU in a transgenic rat cell line

Cited by 30 publications

References 35 publications

Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent

Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent

p27kip1 Deficiency Impairs G2/M Arrest in Response to DNA Damage, Leading to an Increase in Genetic Instability

Msh2 DNA mismatch repair gene deficiency and the food-borne mutagen 2-amino-1-methy1-6-phenolimidazo [4,5-b] pyridine (PhIP) synergistically affect mutagenesis in mouse colon

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p27^kip1 Deficiency Impairs G₂/M Arrest in Response to DNA Damage, Leading to an Increase in Genetic Instability