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PubMed1979

[Biochemical mutants of Actinomyces griseus, a producer of the antibiotic grisin. The isolation of the mutants and a study of the level of grisin antibiotic synthesis].

Biochemical mutants of Actinomyces griseus producing grisin were obtained under the action of chemical mutagens. The mutants were divided into 2 groups. The mutants with impaired synthesis of amino acids of the aspartic acid family, i.e. lysine, homoserine and methionine were included into the 1st group. The 2nd group included the mutants with impaired synthesis of the other amino acids, i.e. histidine, arginine, tyrosine, phenylalanine and valine. The antibiotic production level in the biochemical mutants was studied. It was found that the level of the antibiotic production was decreased in most of the biochemical mutants. A necessity for increased fonds of lysine and arginine for biosynthesis of grisin was shown.

Amino Acids↗

PubMed1977

[Mutants of Pichia guilliermondii yeasts with multiple sensitivity to antibiotics and antimetabolites. I. The selection and properties of the mutants].

Riboflavin deficient mutant Pichia guilliermondii MS1 which requires approximately 1000-fold lower concentration of exogenous vitamin B2 for growth when compared with a non-adapted riboflavin deficient mutants of this species was isolated by means of of UV-irradiation. The growth of the mutant was strongly inhibited by actinomycin D and L-canavanine. The revertant MS8 and MS14 which synthesized riboflavin were selected from the strain MS1. These revertants posses a multiple sensitivity to actinomycin D, rifamycin, euflavine, mitomycin C, antimycin A, 8-azaadenine, 8-azaguanine, L-canavanine and 7-methyl-8-trifluoromethyl-10-(1'-D-ribityl)isoalloxazine. The ability to utilized glycerol and ethanol as a sole carbon source for growth was impaired in these mutants. The mutants which can utilize glycerol were isolated from the strain MS14. Such mutants were resistant to actonomycin D. Mutation (s) which determines a multiple sensitivity and inability to utilized glycerol was recessive.

Anti-Bacterial Agents↗

PubMed1979

Formate dehydrogenase mutants of Salmonella typhimurium: a new medium for their isolation and new mutant classes.

We have designed a new medium for the differentiation of mutants of Salmonella typhimurium defective in the ability to reduce nitrate with formate, and have characterized 24 formate dehydrogenase (FDH) mutants isolated on this medium. The mutants were assayed for the ability to use formate to reduce benzyl viologen and phenazine methosulfate, and were mapped by means of conjugation and P22-mediated transduction. Mutants lacking the ability to reduce either dye were found to map at three distinct sites: at a site co-transducible with xyl (presumably fdhA), at a site or sites between 13U and 33U, but not co-transducible with aroA, bio, purB, pyrC, or pyrD (near, but not identical with fdhB), and at asite 10-20% co-transducible with pyrE, for which we suggest the designation fdhC. Six mutant isolates reduced benzyl viologen, but not phenazine methosulfate. They retained the ability to produce nitrite during growth with nitrate. They mapped between 83U and 89U, but no co-transduction was found with metE, glnA, metB, or argH. The combined biochemical and genetic data suggest the existence of a gene in this area which is essential for the reduction of nitrate with formate, but not for formate hydrogenlyase activity or for nitrate reductase activity.

Aldehyde Oxidoreductases↗

PubMed1976

Thiolutin resistant mutants of Escherichia coli are they RNA chain initiation mutants?

Four mutants of Escherichia coli KL16 resistant to the antibiotic Thiolutin have been isolated. This drug was earlier reported to be an inhibitor of RNA chain elongation. The first mutant, TLrI, is resistant only in rich or partially rich media: it can, however, grow in minimal medium containing the drug with a very long doubling time. The other mutants TLrII, TLrIIIa and TLrIIIb are resistant in rich as well as minimal media. beta-galactosidase could not be induced in TLrI and TLrII in the presence of thiolutin whereas the enzyme is constitutively synthesised in TLrIIIa and TLrIIIb irrespective of the drug. The mutants do not support the development of phage T4 in presence of the drug, if the drug is added along with the phage, but "escape" the inhibition if phage development is allowed to proceed for some time before the addition of the drug. The time of this escape is characteristic of the mutant. Even in a sensitive strain, T7 growth escapes inhibition very soon after infection, around the time the phage-specific RNA polymerase is synthesized. In the parent strain the kinetics of inhibition of beta-galactosidase induction resembles more the inhibition caused by rifampicin than by streptolydigin. It is proposed that thiolutin could be an inhibitor of RNA chain initiation and resistance might be due to mutation in the subunit(s)/factor(s) involved in initiation.

Anti-Bacterial Agents↗

PubMed1977

Temperature-sensitive mutants of Streptococcus pneumoniae. I. Preparation and characterization in vitro of temperature-sensitive mutants of type I S. pneumoniae.

After exposure of type I Streptococcus pneumoniae to nitrosoguanidine, 13 temperature-sensitive (ts) mutants were selected that were restricted in capacity to form colonies on blood agar at 38 C. Whereas colony formation by the type I parent (ts+) was unaffected by a temperature of as high as 39 C, the ts mutants exhibited a spectrum of temperature sensitivity in which colony formation was inhibited significantly at 36 C, 37 C, 38 C, or 39 C. Growth of ts mutants at 38 C in broth was reduced or delayed relative to that of ts organisms under identical conditions. In general, there was a direct correlation between degree of temperature sensitivity and genetic stability. Mutants grown at a permissive temperature resembled the ts+ type I parent in colonial morphology and properties of alpha-hemolysis, bile solubility, optochin sensitivity, and antibiotic sensitivity. Moreover, in vitro studies indicated that the mutants retained capsules of immunochemically reactive type I capsular polysaccharide.

Bile↗

PubMed1977

Biological and biochemical studies of cells transformed by simian virus 40 temperature-sensitive gene A mutants and A mutant revertants.

The growth properties of hamster cells transformed by wild-type Simian virus 40 (SV40), by early SV40 temperature-sensitive mutants of the A complementation group, and by spontaneous revertants of these mutants were studied. All of the tsA mutant-transformed cells were temperature sensitive in their ability to form clones in soft agar and on monolayers of normal cells except for CHLA-30L1, which was not temperature sensitive in the latter property. All cells transformed by stable revertants of well-characterized tsA mutants possessed certain growth properties in common with wild-type-transformed cells at both temperatures. Virus rescued from tsA transformants including CHLA30L1 was temperature sensitive for viral DNA replication, whereas that rescued from revertant and wild-type transformants was not thermolabile in this regard. T antigen present in crude extracts of tsA-transformed cells including CHLA30L1, grown at 33 degreeC, was temperature sensitive by in vitro immunoassay, whereas that from wild-type-transformed cells was relatively stable. T antigen from revertant transformants was more stable than the tsA protein. Partially purified T antigen from revertant-transformed cells was nearly as stable as wild-type antigen in its ability to bind DNA after heating at 44 degrees C, whereas T antigen from tsA30 mutant-transformed cells was relatively thermolabile. These results further indicate that T antigen is a product of the SV40 A gene. Significantly more T antigen was found in extracts of CHLA30L1 grown to high density at the nonpermissive temperature than in any other tsA-transformed cell similarly grown. This is consistent with the suggestion that the amount of T antigen synthesized in CHLA30L1 is large enoughto allow partial expression of the transformed phenotype at the restrictive temperature. Alternatively, the increase in T antigen concentration may be secondary to one or more genetic alterations that independently affect the transformed phenotype of these cells.

Animals↗

PubMed1976

[Murine model for experimental studies on attenuated mutants of a Pasteurella multocida strain with pathogenicity for the calf. 1. Isolation and biological characterization of streptomycin-dependent mutants (Sm-d) and their examination for immunogenicity in comparison with thermally inactivated pathogens].

An experimental study was conducted into the immunisation of mice to a strain of Pasteurella multocida with pathogenicity for calf. Here are the results: (a) Stable Sm-d mutants were isolated. (b) The genetic stability of this mutant type was established by unsubstantiable reversion up to the magnitude of 10(-8) or - in cases in which 20 Sm-id revertants maximum occurred in 10(-8) Sm-d germs--by prolongation of the generation period of these suppressor mutants which can be defined also as minus mutants. (c) Stable attenuation of selected Sm-d mutants has been established in mice by intraperitoneal application of 108 germs. (d) Live germs with restricted reproduction exhibited more immunogenicity to thermally inactivated antigen.

Animals↗

PubMed1978

[Transmission of bacteriophage T4 amber mutants. I. Temperature sensitivity of gene 26 T4 phage mutant amN131 multiplication in Escherichia coli B cells].

When studying the single cycle of the multiplication of gene 26 mutant amN131 of phage T4, like in temperature shift experiments, the yield of this mutant in non-permissive host depends greatly on the temperature. The burts size of phage in Escherichia coli B is found to be 3.3 phage particles at 25 degrees C, 1.6 at 30 degrees C, 0.051 at 37 degrees C and 0.0007 at 41 degrees C. In the case of permissive host (E. coli CR-63) the burst size per cell decreases from 158 to 49 phage particles at the same temperature interval. The results of the single-burst experiments indicate, that when the incubation temperature increases, the number of E. coli B cells, in which the phage particles maturate, also decreases. It results in the dependence of the transmission coefficient value on the temperature. The transmission coefficient in the conditions favourable for the maturation of the phage is found to be 0.80. It is shown by several methods that the temperature sensitivity of the multiplication of the mutant amN131 in bacterial cells is entirely due to amber mutation in genome of the phage. Therefore the amber mutants having high temperature sensitivity when maturating in non-permissive host cells exist among ordinary amber mutants of phage T4.

Coliphages↗

PubMed1978

[Rhodosporidium Banno: dose-effect relations, mutagenic efficiency, and spectrum of mutants in the induction of auxotrophic mutants by ultraviolet light and N-methyl-N'-nitro-N-nitrosoguanidine].

The kinetics, efficiency, and specificity of induction of forward mutations to auxotrophy by ultraviolet light (UV) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was examined in stationary phase cells of Rhodosporidium (Rhodotorula) wild strain Rg1. In comparison to the spontaneous level the frequency of auxotrophic mutants was increased more than 1000 times by both mutagens, however, the mutagenic efficiency of MNNG was higher than that of UV. We found that the forward mutation rate is a linear function of the applicated UV and MNNG doses in the range to 600 J m-2 or 25 mM X min, respectively. The 35 studied biosynthetic pathways to amino acids, purines, pyrimidines, and vitamins are genetically blocked at different frequencies, but there is not any significant difference between UV and MNNG induced frequencies of mutants with a specific requirement. However, in difference to the approximately equal distribution of the MNNG-induced nic mutants among the genetic blocks of the tryptophan-nicotinamide pathway, UV-induced nic mutants occurred with a higher frequency in the genes of the tryptophan pyrrolase and the 3-hydroxykynureninase than in the genes of the other enzymes of the pathway.

Amino Acids↗

PubMed1977

Improved electrophoretic and immunochemical techniques for the identification and characterization of mutant proteins, applied to ribosomal protein S8 in Escherichia coli mutants.

The ribosomal proteins of 11 mutants which are sensitive to starvation at elevated temperature and of 36 transductants derived from them were studied with several electrophoretic, immunochemical and proteinchemical methods. The following results were obtained: (1) Ribosomal protein S8 is altered in three of these mutants. (2) The amino acid exchange in proteins S8 of mutant N4128 is Glu leads to Lys in position 59 of the protein chain. (3) Temperature sensitivity and inability to recover from starvation at elevated temperatures are caused by the same mutational event which is, however, unrelated to the alteration in protein S8. Several electrophoretic and immunological procedures were applied during the characterization of these mutants. A modified immunoelectrophoresis on cellulose acetate gels was developed, and proved to be the most applicable procedure for the detection of mutationally altered ribosomal proteins. This procedure may gain general importance for detecting mutational alterations in other proteins.

Amino Acid Sequence↗

PubMed1978

Uvm mutants of Escherichia coli K12 deficient in UV mutagenesis. I. Isolation of uvm mutants and their phenotypical characterization in DNA repair and mutagenesis.

Selection for defective reversion induction, after UV treatment of E. coli K 12, yielded uvm mutants. These mutants exhibited highly reduced or no UV mutability for all loci tested although they were moderately and normally mutable by X-rays and EMS, respectively. Uvm mutations confer only a slight sensitivity to killing by UV and X-rays and no clear sensitivity to the lethal effect of HN2, EMS or MMS. Growth and viability of untreated uvm cells were normal. The properties of uvm mutants are discussed in relation to those of other relevant mutant types and to some actual problems of induced mutagenesis.

DNA Repair↗

PubMed1978

Synthesis of tryptophanase in Escherichia coli: isolation and characterization of a structural-gene mutant and two regulatory mutants.

A mutant of E. coli has been isolated that is temperature-sensitive in respect of tryptophanase. When incubated at 60 degrees C, cell-free extracts of the mutant suffer inactivation of enzyme activity much more rapidly than similar extracts of the wild type. After lysogeny with a specialized transducing phage carrying the wild-type tryptophanase gene, the mutant is able to synthesize tryptophanase that is wild-type in its response to treatment at 60 degrees C. It is concluded that the mutation lies in the structural gene for the enzyme. Two further mutants have been isolated that synthesize tryptophanase constitutively. One mutation renders synthesis of the enzyme indifferent to the presence of inducer; the other mutation allows synthesis of the enzyme in the absence of inducer at about 35% of the fully induced wild-type rate. Neither mutation alleviates catabolite repression. Genetic mapping shows that the constitutive mutations lie very close to the structural-gene mutation, on the side of the structural gene distant from bglR.

Coliphages↗

PubMed1978

Nuclear suppressors of the [poky] cytoplasmic mutant in Neurospora crassa. III. Effects on other cytoplasmic mutants and on mitochondrial ribosome assembly in [poky].

We have previously isolated six non-allelic, nuclear mutations (sui loci) that partially suppress the growth, respiratory and cytochrome abnormalities of the extranuclear [poky] mutant. A comparison of the mitochondrial ribosome profiles of suppressed and unsuppressed [poky] strains revealed that five of the six suppressors alleviate at least partially the deficiency of mitochondrial small ribosomal subunits that is associated with the [poky] genotype. Six independently isolated Group 1 extranuclear mutants, namely [exn-1], [exn-2], [exn-4-a1, [stp-b1], [SG-1] and [SG-3-A1, which have growth and cytochrome phenotypes similar to [poky] also were found to be deficient in small subunits of mitochondrial ribosomes. Using cytochrome aa3 and b production as a criterion for mitochondrial protein synthesis, it could be shown that the nuclear su I suppressors of [poky] also suppress the other six Group I extranuclear mutants. However, differences in the efficiencies of suppression by suI suppressors suggest that at least some of Group I extrachromosomal mutants are not simply re-isolates of [poky], but represent distinct extranuclear mutations.

DNA, Mitochondrial↗

PubMed2026

Retrotransposable element derepression distinguishes DNMT3A-mutant from TET2-mutant clonal haematopoiesis.

Clonal haematopoiesis (CH) is driven by somatic mutations in haematopoietic stem cells that generate clonal populations detectable in peripheral blood and is present in 10-20% of individuals over the age of 65. Mutations in DNMT3A and TET2 are the most common drivers and have been linked to inflammatory phenotypes and increased risk of haematologic and cardiovascular disease. However, the cell-intrinsic mechanisms connecting these mutations to inflammatory signalling remain incompletely understood. Because retrotransposable elements (RTEs) are epigenetically regulated and can activate innate immune pathways when derepressed, we hypothesised that RTE reactivation may represent a mutation-specific mechanism linking clonal haematopoiesis driver mutations to inflammatory pathways. We analysed RTE expression and clonal burden in peripheral blood mononuclear cell (PBMC) samples from 56 individuals with CH and 12 non-CH controls using integrated genomic and transcriptomic approaches, with complementary validation by TARGET-seq across haematopoietic lineages. High variant allele frequency (VAF; > 10%) DNMT3A-mutant clones exhibited widespread derepression of RTEs, particularly LINE and LTR families, whereas TET2-mutant clones showed a trend towards reduced RTE expression relative to controls. Transcriptomic analyses revealed that DNMT3A high-variant allele frequency clones with elevated RTE expression were enriched for inflammatory signalling pathways, including TNF-α/NF-κB signalling, interferon responses, and senescence-associated signatures. In contrast, TET2-mutant clones lacked these RTE-associated inflammatory signatures and instead showed enrichment of oxidative phosphorylation, reactive oxygen species signalling, and a mechanistic target of rapamycin complex 1 pathway. These findings were reproduced in an independent cohort. Collectively, our results highlight mutation-specific inflammatory mechanisms in clonal haematopoiesis and provide a foundation for future functional and preclinical studies to determine whether modulation of RTE activity can influence the inflammatory phenotype of DNMT3A-mutant CH and represent a potential therapeutic strategy.

DNMT3A↗

PubMed1976

Specific action of 4-nitropyridine 1-oxide on Excherichia coli K-12 pro+ strains leading to the isolation of proline-requiring mutants: isolation and characterization of pro-mutants.

A specific action of 4-nitropyridine 1-oxide on Escherichia coli K-12 Pro(+) strains leading to highly efficient, selective isolation of Pro(-) mutants is described. Incubation of Pro(+) cells with a sublethal concentration of 4-nitropyridine 1-oxide in Penassay broth gave Pro(-) mutants, which lacked either the biosynthetic pathway of proline from glutamic acid to glutamyl gamma-phosphate (proB(-)) or the pathway from glutamyl gamma-phosphate to glutamic gamma-semialdehyde (proA(-)) or both. Pro(-) mutants, which have the metabolic block between Delta(1) pyrroline-5-carboxylate (the cyclized dehydration product of glutamic gamma-semialdehyde) and proline (proC(-)) were not found among survivors. Treatment of Pro(+) cells with N-methyl-N'-nitro-N-nitrosoguanidine led to isolation of all three types of Pro(-) mutants, suggesting that the action of 4-nitropyridine 1-oxide on Pro(+) cells is apparently distinct from the action of N-methyl-N'-nitro-N-nitrosoguanidine. F-duction and interrupted mating experiments led to determination of the correlation between proline loci and the biosynthetic pathway of proline from glutamic acid.

Culture Media↗

PubMed1976

RNA- temperature-sensitive mutants of vesicular stomatitis virus: L-protein thermosensitivity accounts for transcriptase restriction of group I mutants.

In vitro transcriptase activity of three group I temperature-sensitive (ts) mutants of vesicular stomatitis virus restricted at 39 C was restored by L-protein fractions derived from wild-type (wt) vesicular stomatitis virion nucleo-capsids. Soluble NS protein from wt nucleocapsids did not reconstitute restricted transcriptions of the group I RNA-ts mutants. NS protein activity, but not L protein activity, was purified from the group I ts mutants; this NS fraction always displayed the wt phenotype in reconstitution assays. Neither the L nor the NS protein was capable of restoring the defective transcriptive activity of the group IV vesicular stomatitis virus mutant ts W16B.

Capsid↗

PubMed1976

Conditional lethal mutants of adenovirus type 2-simian virus 40 hybrids. II. Ad2+ND1 host-range mutants that synthesize fragments of the Ad2+ND1 30K protein.

Adenovirus type 2 (Ad2) grows 1,000 times less well in monkey cells than in human cells. This defect can be overcome, not only upon co-infection of cells with simian virus 40 (SV40), but also when the relevant part of the SV40 genome is integrated into the adenovirus genome to form an adenovirus-SV40 hybrid virus. We have used the nondefective Ad2-SV40 hybrid virus Ad2+ND1, which contains an insertion of 17% of the SV40 genome, to isolate host-range mutants which are defective in growth on monkey cells although they grow normally on human cells. Like Ad2, these mutants are defective in the synthesis of late proteins in monkey cells. A 30,000-molecular-weight protein (30K), unique to Ad2+ND1-infected cells, can be synthesized in vitro, using Ad2+ND1 mRNA that contains SV40 sequences. 30K is not seen in cells infected with those host-range mutants that are most defective in growth on monkey cells, and translation in vitro of SV40-specific mRNA from these cells produces new unique polypeptides, instead of 30K. Genetic and biochemical analyses indicate that these mutants carry point mutations rather than deletions.

Adenoviridae↗

PubMed1977

Biochemical genetics of Chinese hamster cell mutants with deviant purine metabolism. VI. Enzymatic studies of two mutants unable to convert inosinic acid to adenylic acid.

Ade-H and ade-I are two auxotrophic mutants of Chinese hamster ovary (CHO-K1) cells which specifically require adenine as the purine source to grow. The enzymatic defects of these mutants were examined in cell-free extracts. It was found that ade-H did not have any detectable adenylosuccinate synthetase activity and ade-I was defective in the adenylosuccinate lyase enzyme. The relevance of adenine-requiring mutants to the study of the regulation of purine metabolism in mammalian cells is discussed.

Adenine↗