Spontaneous mutagenesis: the roles of DNA repair, replication, and recombination

Sargentini, Neil J.; Smith, Kendric C.

doi:10.1016/0165-1110(85)90007-7

Cited by 71 publications

(23 citation statements)

References 215 publications

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“…However, there has been controversy regarding the ability of radl defects to enhance spontaneous mutagenesis (43). Previously, detection of the mutator effect apparently depended on the assay system and the particular radl allele used, suggesting that the mutator phenotype might be obscured by its own specificity or by leakiness of individual radl alleles.…”

Section: Discussionmentioning

confidence: 99%

“…It should also be considered that the radl mutator effect could be unrelated to spontaneous damage (26,43). One possible explanation would be that defects in the RADI gene might somehow reduce the accuracy of DNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Recent findings suggest that the RADI gene product also plays a role in mitotic intrachromosomal recombination and in integration of linear DNA molecules into homologous genomic sequences (2,17,44). In addition to these various properties, defects in RADl confer a mutator phenotype (35,43,47). Both enhanced locus reversion to prototrophy and forward mutation to suppression and canavanine resistance have been reported, but neither the precise mutational changes involved nor the specificity of the mutator effect has been elucidated.…”

mentioning

confidence: 99%

“…mutation, perhaps by somehow reducing the fidelity. of DNA replication (43) or the efficiency of correcting replication errors (26). Alternatively, the products of some repair genes might play a regulatory role (7,16) so that modulation of processes other than DNA repair could be responsible for the mutator phenotypes of certain repair-deficient mutants.…”

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confidence: 99%

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Specificity of the mutator effect caused by disruption of the RAD1 excision repair gene of Saccharomyces cerevisiae

et al. 1990

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The product of the RADI gene of the yeast Saccharomyces cerevisiae is believed to function at the incision step of excision repair of DNA damage (9). Thus, it is not surprising that defects in this gene increase sensitivity to a variety of DNA-damaging agents, including UV, the UV-mimetic chemical 4-nitroquinoline-1-oxide, mono-and bifunctional alkylating agents,.and photoactivated psoralens (6,8,9,40,41,49). As well, the RADI gene product is required for the repair of NM-methyladenine (13). Not only do RADI deficiencies sensitize cells to the lethal effects of certain genotoxic agents, but also they enhance UV and 4-nitroquinoline-1-oxide-induced mutagenesis (27, 40) and UV-induced mitotic interchromosomal recombination (45). Recent findings suggest that the RADI gene product also plays a role in mitotic intrachromosomal recombination and in integration of linear DNA molecules into homologous genomic sequences (2,17,44). In addition to these various properties, defects in RADl confer a mutator phenotype (35,43,47). Both enhanced locus reversion to prototrophy and forward mutation to suppression and canavanine resistance have been reported, but neither the precise mutational changes involved nor the specificity of the mutator effect has been elucidated.To account for the association between repair defects and enhanced spontaneous mutagenesis in yeast cells, von Borstel and colleagues (12, 42) have invoked the repair channeling hypothesis (5, 10). According to this hypothesis, impairment of a specific repair pathway results in channeling of damage normally repaired by that pathway along other, competitive pathways. In a similar fashion, shunting of spontaneous DNA lesions through mutagenic repair pathways might account for elevated spontaneous tnutation in repair-deficient strains. However, the nature of these errorprone pathways has remained obscure, and generally the magnitudes of the mutator effects in yeast cells are relatively small. Consequently, it has been suggested that repair defects might have a more indirect influence on spontaneous * Corresponding author. mutation, perhaps by somehow reducing the fidelity. of DNA replication (43) or the efficiency of correcting replication errors (26). Alternatively, the products of some repair genes might play a regulatory role (7,16) so that modulation of processes other than DNA repair could be responsible for the mutator phenotypes of certain repair-deficient mutants.Characterization of the locations and types of DNA sequence alteration occurring spontaneously within a single gene in a radl background would provide valuable infoi-mation about the specificity of the radl mutator effect. In turn, this could yield important clues about the mechanism(s) of enhanced spontaneous mutagenesis in excision repair-deficient strains. To examine mutational specificity, we previously developed a system for the DNA sequence analysis of forward mutations in the yeast tRNA suppressor gene . In this system, all types of base pair substitution as well as deletions, duplications, in...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Specificity of the mutator effect caused by disruption of the RAD1 excision repair gene of Saccharomyces cerevisiae

et al. 1990

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“…Spontaneaus mutagenesis in microorganisms has been of interest for many decades and the genetic approach has provided valuable insight into the types of mutations occurring, such as replication errors, recombination errors, and repair errors (review by Sargentini and Smith, 1985).…”

Section: Genetic Instabilitymentioning

confidence: 99%

Endogenous genotoxic agents and processes as a basis of spontaneous carcinogenesis

Lutz

1990

Mutation Research/Reviews in Genetic Toxicology

124

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SummaryA list ofendogenaus DNA·damaging agents and processes is given. Endogenaus e/ectrophiles are found with the cosubstrates of physiological transfer reactions (S-adenosylrnethionine for methylation, A TP for phosphorylation, NAD + for ADP-ribosylation, acetyl CoA for acetylation). Aldehyde groups (glyceraldehyde-3-phosphate, formaldehyde, open forms of reducing sugars, degradation products of peroxidation) or alkylating degradation products derived from endogenaus nitrose compounds represent additional possibilities. Radical-forming reactions include leakage of the superoxide anion radical from terminal cytochromes and redox cycles, hydroxyl radical formation by the Fenton reaction from endogenaus hydrogen peroxide, and the formation of lipid peroxides. Genetic instability by spontaneaus deaminations and depurinations as well as replicative instability by tautomer errors andin the presence of mutagenic metal ions represent a third important dass of endogenaus genotoxic processes. The postulated endogenaus genotoxicity could form the mechanistic basis for what is called 'spontaneous' tumor incidence and explain the possibility of an increased tumor incidence after treatment of animals with non-genotoxic compounds exhibiting tumor-promoting activity only. Individual differences are expected to be seen also with endogenaus DNA damage. The presence of endogenaus DNA darnage implies that exogenaus DNAcarcinogen adducts give rise to an incremental darnage which is expected to be proportional to the carcinogen dose at lowest Ievels. An increased tumor risk due to exposure to exogenaus genotoxic carcinogens could therefore be assessed in terms of the background DNA damage~ for instance in multiples of the mean Ievel or of the interindividual variability in a population. bind covalently to DNA of target cells. If these DNA-carcinogen adducts are not repaired before the DNA replicates, a mutation in a daughter strand can result. lf this occurs in a critical gene, a heritable step towards malignant transformation· of the cell could be taken. In an attempt to correlate carcinogenic potency with genotoxic potency (Lutz, 1979), a number of carcinogens were identified which did not bind covalently to 0165-1110/90/$03.50

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Mutagenesis

Crueger

1992

Biotechnology

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Spontaneous mutagenesis: the roles of DNA repair, replication, and recombination

Cited by 71 publications

References 215 publications

Specificity of the mutator effect caused by disruption of the RAD1 excision repair gene of Saccharomyces cerevisiae

Specificity of the mutator effect caused by disruption of the RAD1 excision repair gene of Saccharomyces cerevisiae

Endogenous genotoxic agents and processes as a basis of spontaneous carcinogenesis

Mutagenesis

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