Mutagenesis from a Chemical Perspective: Nucleic Acid Reactions, Repair, Translation, and Transcription

Singer, Brett C.

doi:10.1007/978-1-4613-3476-7_1

Cited by 14 publications

(7 citation statements)

References 97 publications

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“…About 60-70% of ENU alkylations are found as ethyl phosphotriesters [37]. Of base alkylations, the most significant pre-mutagenic lesions induced by ENU are O 6 -ethylguanine, O 2 -ethylthymine, and O 4 -ethylthymine.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of the genetic effects of equimolar doses of ENU and MNU: While the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia

Russell

Hunsicker

Russell

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Mutagenic, reproductive, and toxicity effects of two closely related chemicals, ethylnitrosourea (ENU) and methylnitrosourea (MNU), were compared at equimolar and near-equimolar doses in the mouse specific-locus test in a screen of all stages of spermatogenesis and spermiogenesis. In stemcell spermatogonia (SG), ENU is more than an order of magnitude more mutagenic than MNU. During post-SG stages, both chemicals exhibit high peaks in mutation yield when differentiating spermatogonia (DG) and preleptotene spermatocytes are exposed. The mutation frequency induced by 75 mg MNU/kg during this peak interval is, to date, the highest induced by any single-exposure mutagenic treatment -chemical or radiation -that allows survival of the exposed animal and its germ cells, producing an estimated 10 new mutations per genome. There is thus a vast difference between stem cell and differentiating spermatogonia in their sensitivity to MNU, but little difference between these stages in their sensitivity to ENU.During stages following meiotic metaphase, the highest mutation yield is obtained from exposed spermatids, but for both chemicals, that yield is less than one-quarter that obtained from the peak interval. Large-lesion (LL) mutations were induced only in spermatids. Although only a few of the remaining mutations were analyzed molecularly, there is considerable evidence from recent molecular characterizations of the marker genes and their flanking chromosomal regions that most, if not all, mutations induced during the peak-sensitive period did not involve lesions outside the marked loci. Both ENU and MNU treatments of post-SG stages yielded significant numbers of mutants that were recovered as mosaics, with the proportion being higher for ENU than for MNU.Comparing the chemicals for the endpoints studied and additional ones (e.g., chromosome aberrations, toxicity to germ cells and to animals, teratogenicity) revealed that while MNU is generally more effective, the opposite is true when the target cells are SG.

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Section: Discussionmentioning

confidence: 99%

“…MNU produces relatively little alkylation of the phosphate backbone [37]. In bases, MNU, like ENU, is known to induce adducts at the O 2 and O 4 positions of thymine, as well as O 6 -methylguanine which, in contrast to O 4 -methylthymine, is efficiently repaired [40].…”

Section: Discussionmentioning

confidence: 99%

Comparison of the genetic effects of equimolar doses of ENU and MNU: While the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia

Russell

Hunsicker

Russell

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…MMS and MNNG methylate DNA by different mechanisms (16) and produce different spectra of lesions in DNA. MNNG methylates oxygen sites in DNA to high levels relative to nitrogen sites, whereas MMS is relatively poor at oxygen methylation (26). Mutagenesis resulting from treatments with these two methylating agents differs: MNNG mutagenesis is umuDC independent and is due largely to mispairing of 06-methylguarine during replication, whereas MMS mutagenesis appears to be partially due to error-prone, umuDC-dependent processing of lesions that block replication (10,25,39).…”

Section: Resultsmentioning

confidence: 99%

Altered induction of the adaptive response to alkylation damage in Escherichia coli recF mutants

Volkert

1989

J Bacteriol

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Escherichia coli recF mutants are hypermutable when treated with methyl methanesulfonate (G. C. Walker, Mol. Gen. Genet. 152:93-103, 1977). In this study, methylation hypermutability of recF mutant strains was examined, and it was found that recF+ is required for normal induction of the adaptive response to alkylation damage. Although this regulatory effect of recF mutations results in reduced levels of enzymes that specifically repair methyl lesions in DNA, it only partially explains the hypermutability. Further examination showed that methylation hypermutability of recF mutant strains required a functional umuDC operon, a component of the SOS response. These results lead to the hypothesis that methylation hypermutability results from the effects of recF mutations on the induction of both the SOS response and the adaptive response.The adaptive response of Escherichia coli to alkylation damage involves four known genes arranged in three transcriptional units, the ada-alkB operon and the alkA and aidB genes (for a review, see references 18 and 32). This response is induced when cells are treated with alkylating agents (primarily methylating agents) and the induced activities specifically repair alkylation lesions in DNA. This repair is accomplished by enzymes that either remove methyl groups from modified sites or remove methylated bases from DNA. Induction requires a wild-type ada gene (14) and occurs when Ada protein transfers methyl groups from methylphosphotriesters in the DNA backbone to itself. Methylated Ada protein then binds to a sequence adjacent to the promoter and stimulates transcription of the ada-alkB operon, the alkA gene, and presumably also the aidB gene (22,28). The results presented here show that a wild-type recF gene is required for normal induction of adaptive response genes.Mutations in the recF gene are pleiotropic, affecting recombination, DNA repair, expression of the SOS response, and mutagenesis. The effects of recF mutations on chromosomal recombination are seen in recB recC sbc mutants (12); in this genetic background, recombination requires the wild-type recF gene. recF mutations also have effects on DNA metabolism in wild-type cells; recF is required for recombination between plasmids (8, 13) and for mutagenesis and repair of UV damage to DNA (1,4,6,7,11,12,15,23,24,40). Many of the DNA repair defects associated with recF mutations can be ascribed to their effect on induction of the SOS response, a damage-inducible DNA repair response (5,6,21,(33)(34)(35). The SOS response is induced when RecA protein is activated by DNA damage.Activated RecA then stimulates cleavage of LexA protein, thereby derepressing the SOS genes, which are under the control of the LexA repressor protein (19,20,39,41). Mutations in recF decrease the induction of the SOS response and result in increased sensitivity to DNA-damaging agents (6,21,29,34,35). The role of recF in this regulation is, however, not clear at present. Walker (38) noted that the recF143 mutation also affected mutagenesis by methyl methan...

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“…Single-stranded DNA is more labile to mutagenesis by deamination and alkylation than is double-stranded DNA (Singer, 1982). Moreover, damage cannot be repaired while the heavy strand is displaced because of difficulty with nucleotide excision and repair in single-stranded DNA, and because no complementary strand is present to direct nucleotide-specific repair.…”

Section: Phylogenetic Estimatesmentioning

confidence: 99%

Sequence heterogeneity of bovine mitochondrial DNA

Lindberg¹

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Mutagenesis from a Chemical Perspective: Nucleic Acid Reactions, Repair, Translation, and Transcription

Cited by 14 publications

References 97 publications

Comparison of the genetic effects of equimolar doses of ENU and MNU: While the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia

Comparison of the genetic effects of equimolar doses of ENU and MNU: While the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia

Altered induction of the adaptive response to alkylation damage in Escherichia coli recF mutants

Sequence heterogeneity of bovine mitochondrial DNA

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