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At least 343 records · Page 19Linked to original sources
PubMed1996

[Co-genotoxic potential of PCB mixtures from pediatric fatty tissue].

In the present study a mixture containing the 11 PCB major components identified in fatty tissues of children was examined for its potency to enhance the toxification of pregenotoxicants (cogenotoxicity) in the liver. As a basis for the study GC/MS PCB analyses of 207 fatty tissue samples of children were used. The PCB mixture was produced on this basis. As a model for the identification of the cogenotoxic potency of the PCB mixtures an in vivo/in vitro enzyme induction assay was developed. The goal of the study was to clarify the question, whether the in vivo pretreatment of rats with a complex PCB pattern derived from children led to a synergism of cogenotoxicants and pregenotoxicants with regard to the enhancement of the in vitro toxification of benzo[a]pyrene (B[a]P) and 2-aminoanthracene (2-AA) to DNA reactive metabolites. Using the SOS-Chromotest as the in vitro part of the induction assay, all liver enzyme fractions of PCB pretreated rats (S9PCB) showed an increase of the toxification of the pregenotoxicants B[a]P and 2-AA in comparison to enzyme factions of untreated animals (S9(0)). With regard to the reactivity pattern it may be supposed that the PCB mixture probably induced cytochrome P450-dependent oxigenases of the subclasses CYP1A1 and CYP1A2. Additionally, it seems to be of interest that the use of S9(0) fractions did not lead to any or only to weak toxification of B[a]P and 2-AA. Thus, a synergism of cogenotoxicants and pregenotoxicants could be confirmed. PCB could be identified in fatty tissues of children in amounts up to 1 mg/kg. Additionally, pregenotoxicants like polycyclic aromates, mycotoxins and/or aminocontaining compounds, are available in almost all environmental sources. Therefore, from the present point of view, a genetic risk caused by PCB in humans (children) cannot be excluded.

Adipose Tissue↗
PubMed1989

Induction of SOS repair by monofunctional methanesulphonates in various Escherichia coli strains. Structure-activity relationships in comparison with mutagenicity in Salmonella typhimurium.

Seventeen monofunctional alkylmethanesulphonates of widely varying structures were investigated in the SOS Chromotest using the Escherichia coli strains PM21, PQ37 and GC4798. As a measure of the SOS-inducing activity, the beta-galactosidase enzyme units (Up/mumol) were determined. Strains PM21 and PQ37 gave similar results in spite of the presence of different genetic markers. In general, the SN1 type secondary compounds (O-alkylation) induced higher SOS repair than the SN2 type primary compounds (N-alkylation). However, methylmethanesulphonate exerted the highest SOS induction of all tested strains, presumably due to its extremely high SN2 reactivity. In general, strain GC4798, which lacks 3-alkyladenine-DNA glycosylases I and II, was more sensitive towards monofunctional alkylating compounds and in particular towards the SN2 type compounds. A good correlation was found between the SOS repair response in the E. coli strains PM21 and PQ37 and the mutagenicity in Salmonella typhimurium TA100. There was, however, little correspondence when comparing the two measures used for the SOS-inducing activity in this work, the SOSIP (SOS-inducing potency) and the specific beta-galactosidase activity (Up/mumol). This effect was explained by the different toxicity corrections used for the calculation of the two measures. Whereas for the SOSIP value the single constitutive enzyme alkaline phosphatase is used, for the Up/mumol the absorbance at 600 nm, which indicates the growth delay (overall toxicity), is utilized. The influence of the toxicity corrections is discussed in more detail.

Alkylating Agents↗
PubMed1988

Chloramphenicol: magic bullet or double-edge sword?

The genetic and genotoxic potentials of chloramphenicol are reviewed and analyzed. Although this widely used antimicrobial agent appears to cause chromosomal effects in somatic cells, in view of the consistent absence of other genetic effects, these cytogenetic abnormalities are ascribed to non-genotoxic causes. It is pointed out that despite its widespread use in human medicine, chloramphenicol has not been systematically tested for genotoxicity.

Animals↗
PubMed1995

Cloning, sequence and regulation of expression of the lexA gene of Aeromonas hydrophila.

The lexA gene of Aeromonas hydrophila (Ah) has been isolated by using a specific one-step cloning system. The Ah LexA repressor is able to block Escherichia coli (Ec) SOS gene expression and is likely to be cleaved by the activated RecA protein of this bacterial species after DNA damage. Ah lexA would encode a protein of 207 amino acids (aa), which is 75% identical to the LexA repressor of Ec. Two Ec-like SOS boxes have been located upstream from Ah lexA, the distance between them being 4 bp, whereas this same distance in Ec lexA is 5 bp. The structure and sequence of the DNA-binding domain of the LexA repressor of Ec, as well as the region at which its hydrolysis occurs, are highly conserved in Ah LexA. Moreover, a residue of the region implicated in the specific cleavage reaction, and which is present in all known RecA-cleavable repressors, is changed in the Ah LexA. Expression of Ah lexA is DNA-damage inducible in both the Ah and Ec genetic backgrounds to the same extent. In contrast, Ec lexA is poorly induced in DNA-injured Ah cells.

Aeromonas hydrophila↗
PubMed1994

Isolation and characterization of novel plasmid-encoded umuC mutants.

Most inducible mutagenesis in Escherichia coli is dependent upon the activity of the UmuDC proteins. The role of UmuC in this process is poorly understood, possibly because of the limited number of genetically characterized umuC mutants. To better understand the function of the UmuC protein in mutagenic DNA repair, we have isolated several novel plasmid-encoded umuC mutants. A multicopy plasmid that expressed UmuC at physiological levels was constructed and randomly mutagenized in vitro by exposure to hydroxylamine. Mutated plasmids were introduced into the umu tester strain RW126, and 16 plasmids that were unable to promote umuC-dependent spontaneous mutator activity were identified by a colorimetric papillation assay. Interestingly, these plasmid mutants fell into two classes: (i) 5 were expression mutants that produced either too little or too much wild-type UmuC protein, and (ii) 11 were plasmids with structural changes in the UmuC protein. Although hydroxylamine mutagenesis was random, most of the structural mutants identified in the screen were localized to two regions of the UmuC protein; four mutations were found in a stretch of 30 amino acids (residues 133 to 162) in the middle of the protein, while four other mutations (three of which resulted in a truncated UmuC protein) were localized in the last 50 carboxyl-terminal amino acid residues. These new plasmid umuC mutants, together with the previously identified chromosomal umuC25, umuC36, and umuC104 mutations that we have also cloned, should prove extremely useful in dissecting the genetic and biochemical activities of UmuC in mutagenic DNA repair.

Bacterial Proteins↗
PubMed2006

[The genetic activity of NO-containing agents is regulated by complex formation with intracellular iron].

This work is a part of a directional search for new crystal donors of nitric oxide (NO), which are promising for complex chemotherapy. The relationships between the physico-chemical properties of NO donors, their genotoxic and mutagenic activities, and the dependence on intracellular iron were studied. New crystal NO donors (di- and trinitrosyl iron complexes with synthetic ligands) were examined for the first time and compared with known NO donors containing natural ligands. All but one compound induced expression of the Escherichia coli sfiA gene belonging to the SOS regulon and exerted a mutagenic effect on Salmonella typhimurium TA1535. These effects were fully or significantly inhibited by the iron(II)-chelating agent o-phenanthrolin, depending on the mono- or binuclear structure of the ligands. The rate of donating free NO in solution did not positively correlate with the genotoxic activity of the crystal NO donors. The genetic activity of all NO donors proved to depend on intracellular iron.

Escherichia coli↗
PubMed1988

Genetic analysis of bacterial cell division.

A relatively small number of cell division genes have been identified in Escherichia coli. The available evidence, however, suggests that several of these genes play a crucial role in the process.

Bacteria↗
PubMed1992

A umuDC-independent SOS pathway for frameshift mutagenesis.

The chemical carcinogen N-acetoxy-N-2-acetylaminofluorene induces mainly frameshift mutations, which occur within two types of sequences (mutation hot spots): -1 frameshift mutations within contiguous guanine sequences and -2 frameshift mutations within alternating GC sequences such as the NarI and BssHII restriction site sequences. We have investigated the genetic control of mutagenesis at these sequences by means of a reversion assay using plasmids pW17 and pX2, which contain specific targets for contiguous guanine and alternating GC sequences, respectively. Our results suggest that mutations at these hot spot sequences are generated by two different genetic pathways, both involving induction of SOS functions. The two pathways differ both in their LexA-controlled gene and RecA protein requirements. In the mutation pathway that acts at contiguous guanine sequences, the RecA protein participates together with the umuDC gene products. In contrast, RecA is not essential for mutagenesis at alternating GC sequences, except to cleave the LexA repressor. The LexA-regulated gene product(s), which participate in this latter mutational pathway, do not involve umuDC but another as yet uncharacterized inducible function. We also show that wild-type RecA and RecA430 proteins exert an antagonistic effect on mutagenesis at alternating GC sequences, which is not observed either in the presence of activated RecA (RecA*), RecA730 or RecA495 proteins, or in the complete absence of RecA as in recA99. It is concluded that the -1 mutation pathway presents the same genetic requirements as the pathway for UV light mutagenesis, while the -2 mutation pathway defines a distinct SOS pathway for frameshift mutagenesis.

Acetoxyacetylaminofluorene↗
PubMed1996

Damage inducible mutagenesis: recent insights into the activities of the Umu family of mutagenesis proteins.

Despite our advances, much remains to be elucidated about the molecular mechanisms of damage inducible mutagenesis. Although some aspects of the intricate protein interactions that lead to the formation of the mutasome have been determined, the precise nature of the interactions between pol III and the UmuD'C-RecA proteins remains entirely speculative. Further progress will depend on the development of a completely reconstituted, cell free lesion bypass system in vitro, as well as structural modelling of the mutasome in its entirety before we understand how error prone translesion DNA synthesis is achieved. Even if a structural homologue of the Escherichia coli mutasome does not exist in higher organisms, it seems quite likely that a functionally homologous mutagenic pathway will indeed be found. Such an active mutagenic process in animal cells would certainly have significant implications for our understanding of the mechanisms of genetic instability, as well as of human carcinogenesis and other pathologies associated with the formation of mutations in DNA.

Bacterial Proteins↗
PubMed2006

PBP3 inhibition elicits adaptive responses in Pseudomonas aeruginosa.

Adaptive evolution depends on both the genetic variability in a population of organisms and the selection of the better adapted genotypes. However, for the fittest variants to be selected they must survive over a sufficient period under the new conditions. Bacteria are often exposed to different types of stress in nature, including antibiotics. We analysed the global expression profiles of the opportunistic pathogen Pseudomonas aeruginosa in response to ceftazidime, a PBP3 inhibitor, at different concentrations and times. PBP3 inhibition exerts a global impact on the transcription of a large number of genes. From an adaptive perspective, it is noteworthy the induction of several SOS genes, as well as adaptation, protection and antibiotic resistance genes. Intriguingly, transcription of pyocin genes, previously described as SOS-regulated, was repressed upon PBP3 inhibition. Ciprofloxacin, an SOS inducer, produced transcriptional induction of pyocins. Our results indicate that: (i) the SOS responses resulting from treatments with these two antibiotics cause only partially overlapping transcription profiles; (ii) PBP3 and DNA-gyrase inhibition produce opposite effects on transcription of pyocin genes. Consequently, ceftazidime decreases ciprofloxacin toxicity; (iii) error-prone DNA-polymerase DinB is induced by PBP3 inhibition but not by DNA-gyrase inhibition; (iv) PBP3 inhibition causes induced mutagenesis; (v) ceftazidime upregulates several antibiotic-resistance and adaptation genes; and (vi) ceftazidime concentrations thought previously to be lethal are not, as most cells treated with ceftazidime remain alive and recover their capacity to form colonies. Thus, transcriptional changes demonstrated in this work are likely to be adaptively relevant to cells that survive.

Adaptation, Physiological↗
PubMed1991

Constitutive and UV-mediated activation of RecA protein: combined effects of recA441 and recF143 mutations and of addition of nucleosides and adenine.

The recF143 mutant of Escherichia coli is deficient in certain functions that also require the RecA protein: cell survival after DNA damage, some pathways of genetic recombination, and induction of SOS genes and temperate bacteriophage through cleavage of the LexA and phage repressors. To characterize the role of RecF in SOS induction and RecA activation, we determined the effects of the recF143 mutation on the rate of RecA-promoted cleavage of LexA, the repressor of the SOS genes. We show that RecA activation following UV irradiation is delayed by recF143 and that RecF is specifically involved in the SOS induction pathway that requires DNA replication. At 32 degrees C, the recA441 mutation partially suppresses the defect of recF mutants in inducing the SOS system in response to UV irradiation (A. Thomas and R. G. Lloyd, J. Gen. Microbiol. 129:681-686, 1983; M. R. Volkert, L. J. Margossian, and A. J. Clark, J. Bacteriol. 160:702-705, 1984); we find that this suppression occurs at the earliest detectable phase of LexA cleavage and does not require protein synthesis. Our results support the idea that following UV irradiation, RecF enhances the activation of RecA into a form that promotes LexA cleavage (A. Thomas and R. G. Lloyd, J. Gen. Microbiol. 129:681-686, 1983; M. V. V. S. Madiraju, A. Templin, and A. J. Clark, Proc. Natl. Acad. Sci. USA 85:6592-6596, 1988). In contrast to the constitutive activation phenotype of the recA441 mutant, the recA441-mediated suppression of recF is not affected by adenine and nucleosides. We also find that wild-type RecA protein is somewhat activated by adenine in the absence of DNA damage.

Adenine↗
PubMed1989

UV induction of coliphage 186: prophage induction as an SOS function.

Our results show that UV induction of the 186 prophage depends upon the phage function Tum, with the mutant phenotype of turbid plaques on mitomycin plates and the expression of which is controlled by the host LexA protein. Tum function, encoded near the right-hand end of the coliphage 186 chromosome, is under the control of promoter p95. This promoter is overlapped by a sequence closely related to the consensus sequence of the LexA-binding site. It is proposed that inactivation of LexA after UV irradiation (or by genetic means) leads to prophage induction by permitting expression of Tum which, by unknown means, induces prophage. This mechanism is basically different from that seen with the UV-inducible lambdoid coliphages, which are not regulated by LexA.

Base Sequence↗
PubMed1994

RecN SOS gene and induced precise excision of Tn10 in Escherichia coli.

A mutant defective in the induced excision of Tn10 was isolated by decreased papillation on MacConkey-galactose plates with mitomycin C. The mutation involved was characterized as recN by genetic mapping and complementation. This mutant, as well as a previously characterized recN mutant (recN262), showed a markedly decreased frequency of excision of Tn10 after treatment with UV or mitomycin C. These observations indicate that recN is involved in the induced excision of Tn10.

DNA Repair↗
PubMed1990

[Solution of genetic problems of ecology using the automated system "Bioscreen C" (SOS-Chromotest program)].

Comparative experiments on the use of the automated system Bioscreen C (SOS-chromotest program) and the Eims tests for estimating the SOS-inducing and mutagenic activity of chemical compounds belonging to 5 different classes showed that the system was obviously promising and safe in rapid screening of environmental mutagens and carcinogens. Advantages of the system use as well as its prospects, specificity and limitations were revealed.

Aziridines↗
PubMed2006

Meningococcal genome dynamics.

Neisseria meningitidis (the meningococcus) is an important commensal, pathogen and model organism that faces up to the environment in its exclusive human host with a small but hyperdynamic genome. Compared with Escherichia coli, several DNA-repair genes are absent in N. meningitidis, whereas the gene products of others interact differently. Instead of responding to external stimuli, the meningococcus spontaneously produces a plethora of genetic variants. The frequent genomic alterations and polymorphisms have profound consequences for the interaction of this microorganism with its host, impacting structural and antigenic changes in crucial surface components that are relevant for adherence and invasion as well as antibiotic resistance and vaccine development.

Antigenic Variation↗
PubMed1995

cAMP-dependent SOS induction and mutagenesis in resting bacterial populations.

The inducible SOS system increases the survival of bacteria exposed to DNA-damaging agents by increasing the capacity of error-free and error-prone DNA repair systems. The inducible mutator effect is expected to contribute to the adaptation of bacterial populations to these adverse life conditions by increasing their genetic variability. The evolutionary impact of the SOS system would be even greater if it was also induced under conditions common in nature, such as in resting bacterial populations. The results presented here show that SOS induction and mutagenesis do occur in bacteria in aging colonies on agar plates. The observed SOS induction and mutagenesis are controlled by the LexA repressor and are RecA- and cAMP-dependent.

Bacterial Proteins↗
PubMed1992

Oxygen species and the genotoxicity of quercetin.

Quercetin has been extensively studied in various short-term assays for genotoxicity. The patterns of genotoxicity of quercetin for different genetic endpoints are subject to a variety of factors (pH, antioxidants, metabolism) whose precise role in each test remains unclear. In the present study we report on the possible effect of oxygen-derived species on the activity of quercetin in the Ames assay and in the SOS chromotest. Our results seem to suggest that superoxide dismutase (SOD) does not account for the levels of mutagenicity detected in the presence of S9 or S100. The latter may, however, contain other factors of antioxidant defense which may prevent the oxidative degradation of quercetin. Since this degradation occurs at pH values above neutrality and the SOS-inducing activity is higher at pH 6.0, it is concluded that the response of quercetin in the SOS chromotest is due to quercetin itself at acidic pH. The SOS-inducing activity at pH 7.4 is enhanced by SOD, but it cannot be unambiguously concluded that this effect in the SOS chromotest might only be due to protection against the oxidative degradation of quercetin.

Animals↗
PubMed2006

Role of Pseudomonas aeruginosa dinB-encoded DNA polymerase IV in mutagenesis.

Pseudomonas aeruginosa is a human opportunistic pathogen that chronically infects the lungs of cystic fibrosis patients and is the leading cause of morbidity and mortality of people afflicted with this disease. A striking correlation between mutagenesis and the persistence of P. aeruginosa has been reported. In other well-studied organisms, error-prone replication by Y family DNA polymerases contributes significantly to mutagenesis. Based on an analysis of the PAO1 genome sequence, P. aeruginosa contains a single Y family DNA polymerase encoded by the dinB gene. As part of an effort to understand the mechanisms of mutagenesis in P. aeruginosa, we have cloned the dinB gene of P. aeruginosa and utilized a combination of genetic and biochemical approaches to characterize the activity and regulation of the P. aeruginosa DinB protein (DinB(Pa)). Our results indicate that DinB(Pa) is a distributive DNA polymerase that lacks intrinsic proofreading activity in vitro. Modest overexpression of DinB(Pa) from a plasmid conferred a mutator phenotype in both Escherichia coli and P. aeruginosa. An examination of this mutator phenotype indicated that DinB(Pa) has a propensity to promote C-->A transversions and -1 frameshift mutations within poly(dGMP) and poly(dAMP) runs. The characterization of lexA+ and DeltalexA::aacC1 P. aeruginosa strains, together with in vitro DNA binding assays utilizing cell extracts or purified P. aeruginosa LexA protein (LexA(Pa)), indicated that the transcription of the dinB gene is regulated as part of an SOS-like response. The deletion of the dinB(Pa) gene sensitized P. aeruginosa to nitrofurazone and 4-nitroquinoline-1-oxide, consistent with a role for DinB(Pa) in translesion DNA synthesis over N2-dG adducts. Finally, P. aeruginosa exhibited a UV-inducible mutator phenotype that was independent of dinB(Pa) function and instead required polA and polC, which encode DNA polymerase I and the second DNA polymerase III enzyme, respectively. Possible roles of the P. aeruginosa dinB, polA, and polC gene products in mutagenesis are discussed.

Bacterial Proteins↗