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PubMed1989

Genotoxicity of quinoxaline 1,4-dioxide derivatives in Escherichia coli and Salmonella typhimurium.

The mutagenicities of 5 quinoxaline 1,4-dioxide (QdO) derivatives were tested by 2 bacterial assays using forward mutation with Escherichia coli WP2uvrA/pKM101 and reverse mutation with Salmonella typhimurium TA100 and TA98. Potent mutagenic activities of all QdOs tested were observed in both mutation assays. Mutagenicities of these compounds were varied by addition of S9 mix. Their SOS-inducing activities were examined with a 'Rec-lac test' that has been newly developed by us for detecting genotoxins. A high level of SOS-inducing activity was observed in all samples tested. These results suggest that the mutagenicity of QdOs results from the error-prone repair involved in SOS responses.

Dose-Response Relationship, Drug↗
PubMed1990

The sir locus of Escherichia coli: a gene involved in SOS-independent repair of mitomycin C-induced DNA damage.

A Mud1 (lac Apr) insertion has been isolated in a delta (lac)recA+ lexA3(Ind-)rpoB87 gyrA87 mutant of Escherichia coli resulting in a decrease in mitomycin C tolerance and an increase in post-mitomycin C DNA degradation. The mitomycin C sensitivity of the insertion mutant is not further increased by substituting either the rpoB87 or the gyrA mutation by the respective wild-type alleles. However, when both rpoB87 and gyrA87 mutations are replaced by rpoB+ and gyrA+ the strain becomes hypersensitive to mitomycin C. Inactivation of recA in the insertion mutant has no effect on its mitomycin C sensitivity provided both rpoB87 and gyrA87 are present. When either or both of the mutations is/are replaced by the wild-type allele inactivation of recA renders the strain hypersensitive to mitomycin C. The locus of Mud1 (lac Apr) insertion, designated sir (SOS-independent repair), has been mapped between 57 and 61 min on the E. coli linkage map. Expression of the sir gene seems to be constitutive and not enhanced by mitomycin C. These results are discussed in relation to the SOS-independent repair of mitomycin C-induced DNA damage reported earlier.

Bacteriophage lambda↗
PubMed1991

Human cells (normal and ataxia telangiectasia) transfected with pR plasmid are hypersensitive to DNA strand-breaking agents.

Ataxia telangiectasia (AT) cells are known to be hypersensitive to ionizing radiations and to drugs such as bleomycin and epipodophyllotoxin VP16, a topoisomerase II poison. Both of these produce DNA double-strand breaks even if through different mechanisms. In this work we analyzed the sensitivity to bleomycin and to epipodophyllotoxin of AT cells after transfection with pR plasmid. This plasmid, interacting with bacterial SOS repair pathways, expresses itself in mammalian cells conferring cell resistance to the SOS inducers UV and 4NQO and cell sensitivity to different drugs such as bleomycin. This effect is presumably due to the interaction of pR products with double-strand breaks. Our findings indicate that pR plasmid, in both AT lines tested (AT5BIVA fibroblasts and ATL6 lymphoblasts), expresses itself (increasing UV protection) and amplifies the already enhanced AT cell sensitivity to both bleomycin and VP16.

Ataxia Telangiectasia↗
PubMed1991

Survival of M13mp18 gapped duplex DNA as a function of gap length.

Gaps of various lengths were generated in duplex M13mp18DNA by exonuclease III digestion of nicked DNA. The length of the gap increased essentially linearly with time of digestion. Survival in E. coli, however, was not a linear function of gap length. Similar results were obtained when gaps were produced by stopping the polymerization reaction. The survival (N/No) of the gapped DNA in SOS-induced E. coli cells transformed by electroporation and uninduced cells transformed by the calcium chloride method can be quantitatively accounted for by a kinetic model assuming a single-strand endonucleolytic activity (Pd) in the cell which increases linearly with gap length (L) and a repair activity by a polymerase (Pr) which is independent of gap length (formula 1). With uninduced cells transformed by electroporation the results can be mathematically described if assumptions are made concerning the protection of single-stranded parts of the DNA by single-strand affinic proteins.

Base Sequence↗
PubMed1991

Cross-adaptive response in Escherichia coli caused by pretreatment with H2O2 against formaldehyde and other aldehyde compounds.

A cross-adaptive response (CAR), defined as a reduction of the effects of an agent by pretreatment with another agent, was demonstrated when E. coli WP2 cells were pretreated with hydrogen peroxide (H2O2) followed by challenging treatment with aldehyde compounds. Pretreatment with a sublethal dose (60 microM) of H2O2 for 30 min made WP2 cells resistant to the killing effects of formaldehyde (FA), and 4 other mutagenic aldehydes: glutaraldehyde, glyoxal, methyl glyoxal and chloroacetaldehyde. CAR was also observed in WP2uvrA (uvrA-) and ZA12 (umuC-) cells, but not in ZA60 (recA-) and CM561 (lexA- (Ind-] cells. A role of recA and lexA in CAR was further suggested by the lack of beta-galactosidase induction in recA- and lexA- cells by H2O2. CAR and beta-galactosidase induction, however, were found to be separate events since CAR was recovered by introducing the recA+ gene into lexA- cells, but no induction of beta-galactosidase by H2O2 was observed in cells with the same gene transfer. These results suggest that H2O2 has the capacity to induce a function which reduces the killing effects of aldehydes, and the function is controlled by the recA gene without involvement of SOS response.

Acclimatization↗
PubMed1991

'Rec-lac test' for detecting SOS-inducing activity of environmental genotoxic substance.

beta-Galactosidase activities (beta-GA) of E. coli strains carrying the fusion gene of recA and lacZ, GE94 and its DNA repair-deficient derivatives such as KY946[uvrA], KY945[recA] and KY943[lexA] treated with UV, 4NQO, MNNG and MMC were examined. The beta-GA, reflecting the SOS-inducing activity, of GE94 and KY946 treated with these compounds increased significantly with a clear dose-response relationship, and reached a maximum level within 60 min, while no response was seen in KY945 and KY943. Using KY946 and KY945 as a positive and a negative indicator, respectively, the SOS-inducing activity of oxidative mutagens, i.e., hydrogen peroxide (H2O2), formaldehyde, tert-butyl hydroperoxide, cumene hydroperoxide and streptonigrin, was investigated. Clear dose-dependent increases in beta-GA were observed in KY946 treated with all oxidative mutagens tested, but not in KY945. Significant increases in beta-GA were observed with a lower concentration of H2O2 and a shorter incubation time of 4NQO in this assay than in the umu-test. The assay, called 'Rec-lac test' by us, may be useful to detect environmental genotoxic substances.

4-Nitroquinoline-1-oxide↗
PubMed1992

The lipid peroxidation product 4-hydroxynonenal is a potent inducer of the SOS response.

An important aspect of bacterial mutagenesis by several difunctional carbonyl compounds appears to be the induction of the SOS system. We tested the ability of a series of carbonyl compounds to induce expression of the SOS-regulated umu operon in Salmonella typhimurium TA1535/pSK1002. SOS-inducing potencies varied widely among the carbonyl compounds tested. 4-Hydroxynonenal, a product of lipid peroxidation, was the most potent SOS-inducer, with maximal induction observed at concentrations of 0.1-1 microM. Acrolein, crotonaldehyde and methacrolein induced little increase over background umu expression. Malondialdehyde, another product of lipid peroxidation, was a very weak SOS-inducer with a maximal response induced at a concentration of 28 mM. Substitution at the alpha-position of malondialdehyde, which abolishes frameshift mutagenicity, did not abolish SOS-inducing activity. Substitution of the hydroxyl group of malondialdehyde and alpha-methyl-malondialdehyde by a better leaving group (benzoyloxy) resulted in an approximately 250-fold higher SOS-inducing potency. Comparison of the present results to literature reports on bacterial mutagenicity indicates a poor correlation of the two properties between different classes of difunctional carbonyl compounds and even within the same class of difunctional carbonyl compounds.

Acrolein↗
PubMed1992

Phenotypes conferred by the Bacillus subtilis recM13 mutation and the din23 fusion.

The din23 fusion encodes a B. subtilis SOS-inducible regulatory region fused to the E. coli lacZ gene (Love et al., 1985). A strain encoding the din23 fusion and a recM13 allele showed low-level constitutive beta-galactosidase expression, was induced for beta-galactosidase production by DNA gyrase inhibitors but not by DNA-damaging agents, and was slightly induced by a variety of agents which do not normally induce the SOS regulon. The din23 fusion itself resulted in high levels of spontaneous prophage induction in wild-type, recM- and recA-hosts, despite the fact that the din23recM13 strain was not induced for beta-galactosidase production by DNA-damaging agents. The results suggest that the recM gene may be involved with the regulation of the RecA protease-mediated SOS response, while the din23 gene may be involved with the regulation of an alternative function which results in the cleavage of prophage repressor.

Bacillus subtilis↗
PubMed1993

Recovery of DNA replication in UV-damaged Escherichia coli.

Following exposure to UV light DNA replication stops and then resumes. The SOS response is required for the restoration of replication. Replication recovery occurs in lexA(Ind) cells carrying a high constitutive level of RecA protein. Replication is also affected by UmuCD proteins, photoreactivation, and excision repair. In addition, there is a constitutive and recA independent way to replicate over UV photoproducts associated with the production of gaps in daughter DNA strands. There are two ways to account for the replication in UV-irradiated cells. A stalled replication fork can be reactivated. Alternatively, a replication fork could be destroyed irreparably, with no available way to complete the round of replication. In that case, postirradiation replication could be due exclusively to replication forks assembled de novo at the origin(s). Changes in replication initiation are observed following UV irradiation. Initiations are first inhibited and then stimulated. They become independent of de novo protein synthesis and sometimes do not stop in dnaA(ts) mutants shifted to 42 degrees C. Although the inducible functions are involved in the recovery of replication at different levels of UV damage, some modifications of the replication initiation mechanism appear to be specific to severely damaged cells. Such modifications seem to include the dnaA(ts) independence for initiations and the transient initiation inhibition. RecA protein can be directly involved both in the modification of initiation and in reactivation of the stalled replication forks. Although the restoration of replication depends on the SOS response a synthesis of some protein(s) that do not belong to the LexA regulon seems to be required as well. These proteins can be under RecA control and one of their functions may be to inhibit the rnhA gene. Certain recA mutations may selectively affect different mechanisms of the replication recovery (namely, recA430, recA727, recA718, recA1730). Overproduction of the photoreactivating enzyme in the dark could influence UmuCD activity in replication. The UmuCD function appears to be blocked in strains carrying the dnaE1026 mutation or overproducing the dnaQ protein. For some unknown reason the UmuCD-associated replication mechanism is the only one available for phage with damaged DNA.

DNA Damage↗
PubMed1993

Resistance to cisplatin in an E. coli B/r NalR mutant.

The effects of various mutations in DNA-repair processes have been reported to either enhance or decrease bacterial sensitivity to cis-diamminedichloroplatinum(II) (cis-DDP). In the search for other mutations affecting bacterial sensitivity to this antitumor compound, we tested the E. coli B/r BS80 mutant, which is resistant to nalidixic acid (NalR). This mutation maps in the topoisomerase II gene (gyrA subunit) and leads to cross-resistance to cis-DDP. The mechanism underlying the resistance phenotype was only partly due to decreased DNA platination. BS80 was cross-resistant to mitomycin C and, to a lesser extent, to UV light, while it was normally sensitive to MNNG. The mechanisms involved in cis-DDP and mitomycin C resistance were independent of uvrA (excision repair) and recA (SOS repair and recombination) gene expression. In contrast, UV resistance was dependent upon recA gene expression. Both the reversion to NalS in BS80 and the transduction of NalR in the parental wild type (F26) did not modify cis-DDP toxicity; in addition, platinated plasmids equally survived in BS80 and F26 strains. Hence, it is possible that selection of the NalR phenotype induced other mutation(s) than gyrA responsible for cis-DDP, mitomycin C and UV resistance and/or that lesions with a different toxic potential were introduced by cis-DDP into the BS80 and F26 chromosomes.

Cisplatin↗
PubMed1993

Effect of mutations in SOS genes on UV-induced precise excision of Tn10 in Escherichia coli.

UV treatment increases the frequency of Tn10 precise excision from different sites of the Escherichia coli chromosome. UV induction of Tn10 excision is not evidenced in a lexA3 (ind-) mutant carrying either a recA+ or a recA730 allele. High levels of RecA synthesized by a recA+ gene not repressible by LexA do not relieve the non-inducibility of Tn10 excision in a lexA3 (ind-) background. This indicates that the expression of an SOS gene different from recA is necessary for the induction of Tn10 excision. In contrast to UV induction of point mutations, this induction does not depend on a functional umuC gene since umuC::Tn5 mutants show increased levels of Tn10 excision from leu, thr or gal after irradiation. MucAB+ plasmid pKM101 which renders cells more UV-mutable for point mutations decreases UV-induced Tn10 excision. These results show that UV-induced Tn10 precise excision requires SOS induction and that it involves a pathway different from point mutagenesis.

Bacterial Proteins↗
PubMed1995

Analysis of recA mutants with altered SOS functions.

The Escherichia coli RecA protein has at least three roles in SOS mutagenesis: (1) derepression of the SOS regulon by mediating LexA cleavage; (2) activation of the UmuD mutagenesis protein by mediating its cleavage; and (3) targeting the Umu-like mutagenesis proteins to DNA. Using a combined approach of molecular and physiological assays, it is now possible to determine which of the three defined steps has been altered in any recA mutant. In this study, we have focused on the ability of six particular recA mutants (recA85, recA430, recA432, recA433, recA435 and recA730) to perform these functions. Phenotypically, recA85 and recA730 were similar in that in lexA+ and lexA(Def) backgrounds, they exhibited constitutive coprotease activity towards the UmuD mutagenesis protein. Somewhat surprisingly, in a lexA(Ind-) background, UmuD cleavage was damage inducible, suggesting that the repressed level of the RecA* protein cannot spontaneously achieve a fully activated state. Although isolated in separate laboratories, the nucleotide sequence of the recA85 and recA730 mutants revealed that they were identical, with both alleles possessing a Glu38-->Lys change in the mutant protein. The recA430, recA433 and recA435 mutants were found to be defective for both lambda mutagenesis and UmuD cleavage. lambda mutagenesis was fully restored, however, to the recA433 and recA435 strains by a low copy plasmid expressing the mutagenically active UmuD' protein. In contrast, lambda mutagenesis was only partially restored to a recA430 strain by a high copy UmuD' plasmid, suggesting that RecA430 may also be additionally defective in targeting the Umu proteins to DNA. Sequence analysis of the recA433 and recA435 alleles revealed identical substitutions resulting in Arg243-->His. The recA432 mutation had a complex phenotype in that its coprotease activity towards UmuD depended upon the lexA background: inducible in lexA+ strains, inefficient in lexA(Ind-) cells and constitutive in a lexA(Def) background. The recA432 mutant was found to carry a Pro119-->Ser substitution, a residue believed to be at the RecA subunit interface; thus this complex phenotype may result from alterations in the assembly of RecA multimers.

Bacterial Proteins↗
PubMed1994

Mutagenesis resulting from DNA damage by lipid peroxidation in the supF gene of Escherichia coli.

In vitro incubation of rat microsomal lipids with NADPH and Fe3+ in the presence of cytochrome P450 reductase produces lesions in double-stranded pZ189 plasmid DNA, the mutagenic potential of which was analyzed after transfection into Escherichia coli host cells that had been induced for SOS functions by ultraviolet irradiation. The extent of lipid peroxidation, when monitored by the formation of thiobarbituric acid reaction substances, was increased with increased addition of lipids in the reaction mixture. Mutagenesis was determined with the forward mutation assay using the supF gene of pZ189 as a target. When treated pZ189 DNA was used to transfect host cells, a seven-fold increase in mutation frequency for SOS uninduced hosts and a 12-fold increase in mutation frequency for SOS induced hosts was observed at 50% survival compared to that observed with untreated DNA. Sequence analysis shows that incubation of pZ189 DNA in the lipid peroxidation reaction mixture results mostly in single base substitutions, the most frequent base change being G:C-->C:G transversion, followed by G:C-->T:A transversion. The fact that, in the SOS induced hosts, the spectrum obtained by lipid peroxidation is similar to that of hydrogen peroxide suggests the possible involvement for mutagenesis of superoxide produced during lipid peroxidation, but not lipid peroxidation end products such as aldehyde or alkane. Treatment of pZ189 DNA with increasing extents of lipid peroxidation did not yield increasing formation of 8-hydroxyguanine. The results suggest that the origins of G:C-->C:G and G:C-->T:A transversions may be (an) as yet unidentified lesion(s) generated by lipid peroxidation.

Animals↗
PubMed1994

Effects of the umuDC, mucAB, and samAB operons on the mutational specificity of chemical mutagenesis in Escherichia coli: I. Frameshift mutagenesis.

The specificity of frameshift mutations induced by several classes of chemical mutagens was determined using a collection of mutant E. coli lacZ genes. This collection can detect each of five kinds of specific frameshift events by scoring Lac+ revertant colonies. In addition, the mutational spectra were characterized in backgrounds carrying plasmids that encode the umuDC, mucAB, or samAB operon. 4-Nitroquinoline 1-oxide (4-NQO) and furylfuramide (AF-2) induced efficiently -1G, -2(C-G), and +1A frameshift mutations. 4-NQO and AF-2 differed in the ability for the induction of -1A and +1G frameshifts. +1A and -1A frameshift mutations induced by 4-NQO or AF-2 were enhanced by the introduction of the mucAB plasmid, and, to a lesser extent, the umuDC plasmid. The enhancing effect of the umuDC or mucAB plasmid on -1G and -2(C-G) frameshifts was weak or else not observed. 9-Aminoacridine was a potent inducer of +1G, -1G and -1A frameshifts, whereas ICR-191 induced all types of frameshift mutations. A mutation enhancing effect was observed only on ICR-191-induced +1A frameshift mutations by the introduction of the mucAB plasmid. Mitomycin C caused no appreciable induction of frameshift mutations to the tester strains without plasmid. However, all types of frameshifts, except -1G, were induced in the strains carrying the mucAB plasmid. N-methyl-N'-nitro-N-nitrosoguanidine induced all types of frameshift mutations. The mucAB plasmid enhanced mutagenesis in strains designed to detect the addition or loss of A.T base pair, indicating that the formation of +1A and -1A frameshifts was partly dependent on an error-prone SOS repair. Any frameshift mutagenesis was not affected by the samAB plasmid. In general, frameshifts in adenine runs were enhanced more preferentially by the mucAB and umuDC plasmids than frameshifts at runs of guanine were.

4-Nitroquinoline-1-oxide↗
PubMed1994

Effects of the umuDC, mucAB, and samAB operons on the mutational specificity of chemical mutagenesis in Escherichia coli: II. Base substitution mutagenesis.

Mutational spectra induced by different classes of chemical mutagens including two ultraviolet-mimetic mutagens, an alkylating agent, intercalators, a crosslinking agent, and base analogs were characterized by means of a set of mutant lacZ genes in E. coli. These strains can be used to detect each of two types of transition and four types of transversion, simply by measuring the number of Lac+ revertant colonies. 4-Nitroquinoline 1-oxide induced G.C-->A.T, G.C-->C.G, or G.C-->T.A changes almost equally, whereas furylfuramide and mitomycin C induced only G.C-->A.T transitions and G.C-->T.A transversions, respectively. No base substitutional mutations were detected by the treatment with 9-aminoacridine. A weak stimulation of G.C-->A.T transitions by ICR-191 was observed. Both the G.C-->A.T and A.T-->G.C transitions were induced by N-methyl-N'-nitro-N-nitrosoguanidine and N4-aminocytidine. 5-Azacytidine was a specific inducer of G.C-->C.G transversions. In addition, a comparative study of mutational specificity was performed in the strains bearing either the umuDC, mucAB, or the samAB operon on a multicopy plasmid. Regardless of the kind of mutagen, G.C-->T.A transversions were greatly potentiated by the introduction of plasmids in the order of pGW1700 (mucAB) > pSE117 (umuDC) > or = pYG8011 (samAB). Besides G.C-->T.A transversions, the introduction of pGW1700, but not pSE117 and pYG8011, enhanced the mutations of A.T-->C.G and A.T-->T.A transversions. The mucAB plasmid also enhanced the G.C-->A.T transitions and G.C-->C.G transversions induced by some mutagens.

Aminacrine↗
PubMed1994

Induction of the alkylation-inducible aidB gene of Escherichia coli by cytoplasmic acidification and N-ethylmaleimide.

We have studied the effects of changes in intracellular pH and the influence of thiol reagents on the induction of the DNA damage-inducible genes of Escherichia coli, aidB, alkA, and alkB. Under aerobic conditions in the absence of alkylating agents aidB, but not alkA or alkB, was induced by an acidification of cytoplasm or by treatment with the sulfhydryl reagent N-ethylmaleimide. Alkaline shift and thiosalicyclic acid did not affect the induction of aidB and alkB. The induction of alkA increased under the alkaline shift but not in the case of treatment with reducing agents. Compared with the aidB gene, a component of the SOS system, the sulA (sfiA) gene, responded to changes in cytoplasmic pH and in the level of intracellular thiols in an opposite way. SulA induction was observed under alkaline shift and after treatment with thiosalicylic acid.

Acetates↗
PubMed1996

Constitutive increase of RecA protein: its influence on pyrimidine dimer excision and survival of UV-irradiated Escherichia coli.

Transformation of E. coli with the plasmid pRA containing recA gene increased the constitutive level of RecA protein 50-67 fold. This slightly inhibited pyrimidine dimer excision and reduced cell survival in three investigated, UV-irradiated E. coli strains. Our data support the view that RecA protein prematurely present at a high level may mask the dimers. The masking subsequently reduces the dimer excision and switches off the inducing signal.

DNA, Bacterial↗
PubMed1996

MMS-induced mutagenesis and DNA repair in Escherichia coli dnaQ49: contribution of UmuD' to DNA repair.

dnaQ-encoded epsilon subunit of DNA polymerase III, possesses 3',5' exonuclease (proofreading) activity, and is a fidelity factor of polymerase III holoenzyme. It is assumed that during SOS-induced mutagenesis, UmuD', UmuC, and RecA may suppress DnaQ proofreading activity, and allow for translesional DNA synthesis at the cost of fidelity of replication. In this report SOS-dependent, MMS-induced mutagenesis and DNA repair were tested in E. coli dnaQ49 strains. Bacteria were transformed with various pDNAs harboring compilation of the umuD(D')C genes, and the influence of plasmids on mutagenesis (argE3-->Arg+) and DNA repair was tested. DNA damage and repair were tested in plasmid DNA grown in MMS-treated bacteria and isolated either immediately after MMS treatment, or after starving the cells (MFD conditions) for 30 and 60 min, then nicking activity of Fpg protein on plasmid DNAs was analyzed. It has been found that (i) repair of MMS-induced lesions depends on umuD'C, umuD' (and to much less degree, on umuDC) genes encoded in pDNA; (ii) MMS-induced mutations, in contrast to DNA repair, are highest in the cells transformed with pDNA harboring umuDC, and lowest or zero in cells with plasmids harboring umuD'C. It is postulated that UmuD'C or UmuD' proteins play a role in the repair of damaged DNA and/or in maintenance of DNA integrity. The kinetics of these processes (perhaps due to introducing too many of the lesions) seems to be different in E. coli dnaQ+ and dnaQ cells, and probably this is a reason that (iii) MMS-induced mutations in dnaQ49 strains are not subject to MFD.

Arginine↗