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PubMed1979

Ethidium bromide enhancement of frameshift mutagenesis caused by photoactivatable ethidium analogs.

Ethidium azide analogs (3-amino-8-azido-ethidium monoazide and ethidium diazide) have been developed as photosensitive probes in order to analyze directly the reversible in vivo interactions of ethidium bromide. Our preliminary observations [11], relating the mutagenic potential of the monoazide analog of ethidium, have been extended and refined, using the highly purified ethidium azide analogs [5]. A number of physical-chemical studies indicate that the monoazide analog interaction with nucleic acids, prior to photolysis, resembles remarkably the interaction of the parent ethidium (unpublished). It was anticipated, therefore, that competition by ethidium for the ethidium monoazide mutagenic sites in Salmonella TA1538 would be observed when these drugs were used in combination. Previous results in fact showed a decreased production of frameshift mutants when ethidium bromide was added to the ethidium monoazide in the Ames assay [1]. However, more extensive investigations, reported here, have shown that this apparent competition was the result of neglecting the toxic effects of ethidium monoazide and its enhanced toxocity in the presence of ethidium bromide. Conversely, an enhancement of the azide mutagenesis and toxicity for both the mono- and diazide analogs was seen when ethidium bromide was used in combination with these analogs.

Azides↗
PubMed1984

Antimutagenic effects of germanium oxide on Trp-P-2-induced frameshift mutations in Salmonella typhimurium TA98 and TA1538.

A germanium compound, germanium oxide (GeO2) behaved as a potent antimutagen on frameshift-type reverse mutations induced by 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) in strains of Salmonella typhimurium TA98 and TA1538 with and without a plasmid pKM101, respectively. This metal antimutagen seems to work independently of the plasmid, a promotive factor in chemically induced mutagenesis through error-prone DNA repair.

Animals↗
PubMed1988

Antimutagens against spontaneous and induced reversion of a lacZ frameshift mutation in E. coli K-12 strain ND-160.

Isopropyl-beta-D-thiogalactoside (IPTG), at 0.5 or 1.0 mM, is shown to reduce spontaneous, and to virtually abolish caffeine- or quinacrine-induced reversions of the lacZ frameshift mutation in E. coli ND160. Guanosine at 200 micrograms/ml and Co2+ at 15 micrograms/ml had an erratic partial antimutagenic effect on spontaneous lac+ reversions. All 3 agents reduce caffeine-induced (500 micrograms/ml) mutagenesis. Spermine (250 micrograms/ml) also reduces quinacrine-induced Lac+ reversion frequencies in this system.

Caffeine↗
PubMed1986

A frameshift at a mutational hotspot in the polyoma virus early region generates two new proteins that define T-antigen functional domains.

A frameshift mutation, arising from the deletion of any one of nine consecutive cytidines in the region of Py DNA encoding both the midregion of large T-Ag and the C-terminal region of middle T-Ag, yields unstable flat cell revertants that synthesize two novel viral proteins in which shuffling of the different domains of the Py T-Ags has occurred. The first protein (37 kd) is a hybrid containing the N-terminus of large T-Ag and the hydrophobic C-terminus of middle T-Ag. The latter domain is responsible for membrane association, even in the 37 kd hybrid protein. The second protein (43 kd), which contains the N-terminal 75% of middle T-Ag, has an associated protein kinase activity and forms a complex with c-src, but cannot induce a transformed phenotype.

Animals↗
PubMed1993

Frameshifting in the expression of the E. coli trpR gene occurs by the bypassing of a segment of its coding sequence.

The E. coli trpR gene encodes the 108 amino acid long trp repressor. We have previously shown that a +1 frameshifting event occurs during the expression of trpR. Here we show that the transition from the 0 to the +1 frame of trpR occurs by the bypassing of a 55 nt long segment of the trpR+1-lacZ mRNA. This bypassing event is not pretranslational, and it probably takes place during translation. Two adjacent elements are required: a specific sequence of trpR, which must be preceded by a nonspecific 5' end longer than 10 translatable codons. Unique to trpR-lacZ bypassing is that the 55 nt long region must be translated in frame 0 to enable bypassing into the +1 frame. Translational bypassing as a newly discovered mechanism of gene expression is discussed, and the possible existence of translational introns is suggested.

Amino Acid Sequence↗
PubMed1981

Frameshift mutagenesis of 9-aminoacridine derivatives in Salmonella typhimurium.

It has been noted that 9-aminoacridine reverts a his C frameshift but not one in his D in the Salmonella strains used in the Ames test, without metabolic activation. The 2 sites differ in the arrangement of G and C residues present. We show here that a series of 9-aminoacridine derivatives exhibits the same selectivity as 9-aminoacridine provided there is at least one exocyclic amino hydrogen at the central ring position in acridines, or the analogous site in aminoquinolines. The results are consistent with a model derived from NMR experiments on 9-aminoacridine binding to dinucleoside phosphates, in which the N-H group is situated in the duplex so as to participate in a hydrogen bond with one base while excluding its complementary partner, thereby provoking mismatching. We also report a strong difference in the dose-response behavior of 9-aminoacridine, quinacrine and a bifunctional derivative of quinacrine.

Aminoacridines↗
PubMed1981

Nitrated fluorene derivatives are potent frameshift mutagens.

Nitrated derivatives if fluorene are potent frameshift-type mutagens. A reduction of the nitro function is required for the expression of mutagenicity. Hydroxylamines are the presumed key intermediates, which following esterification to electrophiles are capable of forming adducts with cellular DNA. Evidence in support of this mechanism is obtained by the use of tester strains having a functional uvrB gene product or lacking specific nitroreductases. The mutagenic potency of nitrated fluorenes increases upon successive addition of nitro groups reaching a peak at the trisubstituted state. Addition of a 4th nitro group leads to decreased activity.

Fluorenes↗
PubMed1984

Frameshift mutagenicity in Salmonella typhimurium of furocoumarins in the dark.

The dark mutagenicity of 4,5',8-trimethylpsoralen (4,5',8-TMP), 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP), 3-carbethoxypsoralen (3-CPs) and two new pyridopsoralens (PyPs and MePyPs) was tested using the Ames Salmonella plating assay in the absence of metabolic activation. 4,5',8-TMP, 8-MOP and the two pyridopsoralens were found to be weak frameshift mutagens in strain TA1537 whereas 5-MOP and 3-CPs did not demonstrate any significant mutagenic activity. These findings support the notion that the genetic risks of these psoralens in the dark may be considered to be negligible.

Darkness↗
PubMed1986

Potassium chromate potentiates frameshift mutagenesis in E. coli and S. typhimurium.

Possible comutagenic effects of chromate on frameshift mutagenesis were studied in bacterial assays. In these experiments, cells were treated with potassium chromate and 9-aminoacridine either singly or in combination. Results were analyzed to detect synergistic, additive and antagonistic responses. Data from these investigations show a clear potentiation of 9-aminoacridine-induced mutagenesis in the presence of chromate in S. typhimurium strain TA1537. Results from cell viability assays shows that the effect is not due to a toxicity artifact. Similar results are obtained in E. coli strains 343/358 (repair-proficient parental strain), 343/415 (recA-deficient), and 343/435 (mismatch-repair-deficient). These data indicate the neither induction of recA-protein nor inhibition of mismatch repair is involved in the action of chromate. In E. coli strain 343/447 (DNA polymerase I deficient), the potentiation was observed at lower concentrations of chromate. This finding suggests that polymerase I functions in recovery of cells from 9-aminoacridine-induced DNA damage and that its absence allows some of this damage to be dealt with in a manner which promotes mutagenesis in the presence of chromate. One possible explanation of these findings is that chromate and 9-aminoacridine react chemically to produce a unique mutagen and that damage caused by this mutagen is repaired via some excision process. However, no reaction between chromate and 9-aminoacridine could be detected by TLC under conditions similar to those in the bacterial assays, even at very high concentrations of both agents. Thus, it seems most likely that the potentiation is due to some action of chromate on repair and/or replication at sites of 9-aminoacridine intercalation. Chromate appears, then, to have significant comutagenic actions in bacterial systems.

Aminacrine↗
PubMed1987

Base-substitution and frameshift mutagenesis by sodium chloride and potassium chloride in Saccharomyces cerevisiae.

Sodium chloride (NaCl) and potassium chloride (KCl) are both capable of inducing lethality and mutations when each is administered at a molarity of two for different lengths of time to logarithmic phase cells of the yeast Saccharomyces cerevisiae. Analysis of the revertants indicates that the reversions can be base substitutions, of both the transition and the transversion type, as well as frameshift mutations. At equal molarity, with the frequency of mutations as the criterion, KCl and NaCl are equally efficient in inducing all types of mutations.

Cell Survival↗
PubMed1985

Induction of the SOS response by ICR191 does not influence frameshift mutagenesis at the hisC3076 marker of Salmonella typhimurium.

Reversion of the Salmonella typhimurium frameshift marker hisC3076 by ICR191 and 9-aminoacridine in rec+ and recA1 backgrounds was examined using the standard plate-reversion assay. For both compounds, the level of reversion observed in the recA strain is significantly greater than in the rec+ strain. Thus reversion of hisC3076 is not recA-dependent, but is recA-modulated. The ability of a mutagen (or mutagenic treatment) to induce the recA lexA-dependent SOS response does not therefore imply that mutagenic effects will also be recA-dependent.

Aminacrine↗
PubMed1987

Frameshift mutagenesis by chloroquine in Escherichia coli and Salmonella typhimurium.

Chloroquine can be detected as a direct-acting mutagen in plate-incorporation assays using the excision-deficient Salmonella typhimurium strain TA97, but very much more effectively using the repair-proficient Escherichia coli strain DG1669 which carries the lacZ19124 marker. When tested at concentrations of 200-1000 micrograms/plate with strain DG1669, the mutagenicity of chloroquine is enhanced by the addition of Aroclor-induced rat-liver S9. Further experiments indicated that chloroquine-induced reversion frequencies were essentially identical in wild-type, recA, umuC and uvrC derivatives of DG1669, as well as in strains carrying the mutation enhancing plasmid pKM101, over a wide range of doses (0-1200 micrograms/plate). These results suggest that neither excision repair nor SOS-type repair are important in chloroquine-induced frameshift mutagenesis.

Animals↗
PubMed1988

Harman and norharman induce SOS responses and frameshift mutations in bacteria.

Norharman and harman, beta-carboline derivatives with comutagenic activity in Salmonella typhimurium, were examined for their activity to induce SOS responses in S. typhimurium using the umu-test and mutations in Escherichia coli. The inducibility of the umuC gene by norharman and harman was assayed by measuring the levels of beta-galactosidase activity in tester cells harbouring the umuC'-'lacZ fusion gene on a plasmid. In the umu-test, both norharman and harman weakly induced umuC gene expression at 25-100 and 50-150 micrograms/ml, respectively. In the mutation test using reversion from trpE9777 to Trp+, harman was relatively more potent than norharman in inducing the mutations. These results indicate that norharman and harman induce SOS responses as well as reversion of trpE9777 frameshift mutation in bacteria.

Alkaloids↗
PubMed1987

Frameshift mutagenesis by nitracrine analogues in wild-type, uvrB, polA and recA strains of Salmonella typhimurium, with and without plasmid pKM101.

The mutagenic potential of 9-[(3-dimethylaminopropyl)amino]-acridine and its 1-, 2-, 3- and 4-nitro derivatives was studied in several strains of Salmonella typhimurium carrying the frameshift marker hisC3076. The strains all carried deep rough (rfa) mutations, and were either wild-type with respect to DNA repair capacity or carried recA, uvrB, polA1 or polA3 (amber) mutations. Derivatives with and without plasmid pKM101 were also studied. The des-nitro compound resembled 9 aminoacridine and other simple intercalating compounds. Both toxicity and mutagenesis were apparently unaffected by the uvrB and recA mutations or by the presence of plasmid pKM101. However, mutagenicity was reduced by the polA1 mutation, and virtually eliminated by the polA3 mutation. The drug was substantially more toxic in the latter, slightly more toxic in the former, of these polA- strains. Plasmid pKM101 enhanced mutagenesis and protected from toxicity in both polA1- and polA3- strains, although it did not restore either of these parameters to the level in the wild-type strain. The 2-nitro compound was generally similar to the des-nitro compound, except that it was considerably more toxic and apparently non-mutagenic in the recA-bearing strain. By contrast, mutagenicity of the 3- and 4-nitro compounds was enhanced by the uvrB mutation and by the presence of the plasmid. These compounds were highly toxic but non-mutagenic in the recA- strain, and showed some increased toxicity in polA1- and polA3- strains. The 1-nitro compound has been previously found to cross-link DNA. Unlike well-characterised cross-linkers such as mitomycin C it was highly mutagenic in the uvrB- strain, and this mutagenesis was enhanced by plasmid pKM101, but eliminated by the recA mutation. At high doses, where the drug was completely toxic towards uvrB- or recA-carrying strains, it became mutagenic in the DNA-repair-proficient strains. This 'high-dose' mutagenesis was enhanced by plasmid pKM101, but reduced by the polA1 mutation and almost eliminated by the polA3 mutation. Although there are several possible interpretations of these data, they are compatible with the suggestion that the lesion induced by high doses (but not by low doses) of nitracrine is a cross-link, but that this is not the major mutagenic lesion.

Aminoacridines↗
PubMed1988

Frameshift lesions induced by oxazolopyridocarbazoles are recognized by the mismatch repair system in Escherichia coli.

The simple reversible intercalating agent isopropyl-OPC (iPr-OPC) induces frameshift-1 mutations in Salmonella typhimurium and Escherichia coli. The mutagenic responses of S. typhimurium and E. coli wild-type strains are not proportional to the amount of drug intercalated into double-stranded nucleic acids in living bacteria; it occurs only above a minimum level of binding. The fact that mismatch-repair-deficient (mutS) as well as adenine-methylation-deficient (dam) E. coli mutants are hypermutable at low concentrations of iPr-OPC suggests that the majority of mutants induced by this intercalating drug occur as mismatch-repairable mutations (or lesions) in the newly synthesized DNA strand close to the replication fork.

Alkaloids↗
PubMed1989

Distribution of introns in frameshift-suppressor proline-tRNA genes of Saccharomyces cerevisiae.

Mutations in the suf9, suf10, and suf11 genes of yeast suppress + 1 nucleotide (nt) insertions in proline codons. Nucleotide sequence analysis indicates that the suf9 and suf11 genes are members of the proline tRNA(UGG) gene family, which also includes three other previously identified genes, suf7, suf8, and trn1. All five members of this gene family contain introns. The suf9 and suf11 introns are 31 and 30 nt in length, respectively, and are similar but not identical in sequence to other introns within the family. The suf10 gene is identical in sequence to suf2, which was shown previously to encode proline tRNA(IGG). Both members of this gene family lack introns. Alleles of suf9, suf10, and suf11 that confer frameshift suppression were also analyzed. The SUF9-1 allele results in a G----U substitution at nt position 39 in the anticodon stem. The recessive suf11-1 allele is a double mutant containing the same nt position 39 alteration as in SUF9-1 plus a second U----A substitution at nt position 38 in the anticodon loop. The SUF10-1 suppressor mutation corresponds to a +1G insertion in the anticodon loop. Since the nt substitutions in suf11-1 alter the sequence of the 3' exon/intron boundary, the double mutant pre-tRNA was tested for its ability to be cleaved in vitro by tRNA-splicing endonuclease. It was found that suf11-1 pre-tRNA is cleaved with reduced efficiency at the 3' splice junction.

Base Sequence↗
PubMed1990

Evidence for a role of translational frameshifting in the expression of transposition activity of the bacterial insertion element IS1.

The bacterial insertion element IS1 contains two essential open reading frames, insA and insB, arranged in tandem. We have introduced a number of site-specific mutations into the region including the 3'-terminal region of insA, the region between insA and insB, and the ATG codon at the start of insB. Relative transposition activities of mutant and wild-type elements were determined using a modified in vivo cointegration assay. The results support the hypothesis that a translational (-1) frameshift occurring in the 3'-terminal region of insA and linking insB to insA is responsible for the synthesis of the active IS1 transposition enzyme. Further results with IS1 elements containing internal deletions are in agreement with a role of the normally terminated insA product as an inhibitor of transposition.

Amino Acid Sequence↗