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At least 19 recordsLinked to original sources
PubMed1991

Transient mutators: a semiquantitative analysis of the influence of translation and transcription errors on mutation rates.

A population of bacteria growing in a nonlimiting medium includes mutator bacteria and transient mutators defined as wild-type bacteria which, due to occasional transcription or translation errors, display a mutator phenotype. A semiquantitative theoretical analysis of the steady-state composition of an Escherichia coli population suggests that true strong genotypic mutators produce about 3 x 10(-3) of the single mutations arising in the population, while transient mutators produce at least 10% of the single mutations and more than 95% of the simultaneous double mutations. Numbers of mismatch repair proteins inherited by the offspring, proportions of lethal mutations and mortality rates are among the main parameters that influence the steady-state composition of the population. These results have implications for the experimental manipulation of mutation rates and the evolutionary fixation of frequent but nearly neutral mutations (e.g., synonymous codon substitutions).

Bacteria↗
PubMed2025

A transient mutational burst occurs during yeast colony development.

Characterizing the contribution of mutators to mutation accumulation is essential for understanding cellular adaptation and diseases like cancer. By measuring single and double mutation rates, including point mutations, segmental duplications, and reciprocal translocations, we found that wild-type yeast colonies exhibit double mutation rates up to 17 times higher than expected from experimentally determined single mutation rates. These double mutants retained wild-type mutation rates, indicating they originated from genetically normal cells that transiently expressed a mutator phenotype. Numerical simulations suggest that transient mutator subpopulations likely consist of less than a few thousand cells, and experience high-intensity mutational bursts for less than five generations. Most double mutations accumulated sequentially across cell cycles, with simultaneous acquisition being rare and likely linked to systemic genomic instability. Additionally, we explored the genetic control of transient hypermutation and found that the excess of double mutants can be modulated by replication stress and the DNA damage tolerance pathway. Our findings suggest that transient mutators play a significant role in genomic instability and contribute to the mutational load accumulating in growing isogenic populations.

Saccharomyces cerevisiae↗
PubMed1973

Somatic mutational transients. 3. Response by two genes in a clone of Nicotiana to 24 roentgens of gamma radiation applied at various intensities.

Somatic effects of radiation intensity on the mutable V and stable R genes were detected in plants of a heterozygous clone (v(S3)/v(s), R/r) subjected to the same dose at four rates. The effects were compared by counting speckled and purple sectors in flowers from irradiated and control plants. Response curves were estimated from the mutant sector averages, observed over a period of transient response for successive mature flowers. A structure for integrating the mutational contributions from different flowers was provided by models. The average control mutation rates are 8,110 per 10(7) cells for the V gene, and 49.45 for R. At a constant intensity of 4320 roentgens/hour, average induced mutation rates per 10(7) cells per roentgen for V increase from 194 (at 24 r total dose) to 1,116 (at 3 r dose); the corresponding rates for R increase from 7.24 to 27.65. With these responses as standards, both genes at corresponding total doses yield lower rates at lower intensities. For the series of intensities 1.2, 0.6, 0.3 and 0.15 roentgens/hour, the decreases in mutation rate for the V gene are, respectively, 66, 148, 315, and 617 per 10(7) cells per roentgen. The corresponding decrements for R are 4.86, 8.70, 14.61, and 23.51. These effects are non-linear functions of intensity for both genes, but V is at least 13 times as sensitive as R. Radiation operating to extinguish a buffering system against final mutation can account for the dose and dose-rate effects observed.

Cell Division↗
PubMed1991

Tottering and leaner mutations perturb transient developmental expression of tyrosine hydroxylase in embryologically distinct Purkinje cells.

The mouse mutants tottering and leaner exhibit neurologic disorders associated, in part, with global noradrenergic hyperinnervation. Therefore, the expression of tyrosine hydroxylase (TH) mRNA and protein was examined in mutant and control mice. TH expression was normal in the major catecholaminergic nuclei. However, TH was expressed in vermal Purkinje cells of adult mutant but not control mice. TH expression in the Purkinje cells of both mutants was first observed on P21 and persisted throughout adulthood; in contrast, Purkinje cells of normal mice expressed TH transiently during development from P21 to P35. Thus, tottering and leaner mice are deficient in suppressing the normal transient expression of TH in developing Purkinje cells, suggesting that the protein encoded by the tg locus may play a crucial role in neuronal development.

Animals↗
PubMed1992

The 3'-flanking sequence of the bovine growth hormone gene contains novel elements required for efficient and accurate polyadenylation.

In addition to the conserved AAUAAA hexanucleotide, GU- and U-rich sequences in the 3'-flanking region are thought to be critical for efficient polyadenylation. The 3'-flanking sequence requirements for efficient and accurate polyadenylation of the bovine growth hormone (bGH) gene were determined by quantitative S1 nuclease analysis of transcripts derived from various bGH 3' deletions and block mutations transiently transfected into COS-1 cells. Though the bGH 3'-flanking sequence contains a portion of the putative GU efficiency element, we find that mutation of this element leads to a marginal decrease in efficiency similar to that from mutation of other sequences that do not contain recognizable GU- or U-rich motifs. The data are consistent with a diffuse efficiency element in the bGH polyadenylation signal rather than a discrete element as is thought to exist in other mammalian signals. We have also determined that a region from 18 to 27 nucleotides downstream of the cleavage site contains sequences required for correctly positioning the cleavage site.

Animals↗
PubMed1985

Molecular basis of an inherited retinal defect in Drosophila.

Fruitflies carrying the autosomal recessive mutation transient receptor potential (trp) are blind in bright light because the receptor potential of such a mutant decays almost completely during an intense stimulus. The trp gene has been localized and a set of partially overlapping genomic clones that include the trp gene has been isolated. The stretch of DNA represented by these genomic clones is found to contain genes that encode for four RNA species. Two of these RNA species are missing in the mutant. This observation is consistent with the notion that the mutation alters the DNA sequence in a region containing signals necessary for the expression of the gene. Accordingly, the molecular basis of the mutant phenotype may be due to the lack of a protein(s) that is/are important for normal visual transduction.

Animals↗
PubMed1990

A combination of closely associated positive and negative cis-acting promoter elements regulates transcription of the skeletal alpha-actin gene.

The chicken skeletal alpha-actin gene promoter region provides at least a 75-fold-greater transcriptional activity in muscle cells than in fibroblasts. The cis-acting sequences required for cell type-restricted expression within this 200-base-pair (bp) region were elucidated by chloramphenicol acetyltransferase assays of site-directed Bg/II linker-scanning mutations transiently transfected into primary cultures. Four positive cis-acting elements were identified and are required for efficient transcriptional activity in myogenic cells. These elements, conserved across vertebrate evolution, include the ATAAAA box (-24 bp), paired CCAAT-box-associated repeats (CBARs; at -83 bp and -127 bp), and the upstream T+A-rich regulatory sequence (at -176 bp). Basal transcriptional activity in fibroblasts was not as dependent on the upstream CBAR or regions of the upstream T+A-rich regulatory sequence. Transfection experiments provided evidence that positive regulatory factors required for alpha-actin expression in fibroblasts are limiting. In addition, negative cis-acting elements were detected and found closely associated with the G+C-rich sequences that surround the paired CBARs. Negative elements may have a role in restricting developmentally timed expression in myoblasts and appear to inhibit promoter activity in nonmyogenic cells. Cell type-specific expression of the skeletal alpha-actin gene promoter is regulated by combinatorial and possibly competitive interactions between multiple positive and negative cis-acting elements.

Actins↗
PubMed1992

Transient expression and mutational analysis of the rotavirus intracellular receptor: the C-terminal methionine residue is essential for ligand binding.

Maturation of rotavirus involves an intracellular membrane budding event in which the single-shelled icosahedral particle interacts with a virus-encoded receptor glycoprotein, NS28, that is located in the rough endoplasmic reticulum membrane. The receptor is a tetramer and is oriented with the C-terminal 131 amino acids on the cytoplasmic side of the membrane (A.R. Bellamy and G.W. Both, Adv. Virus Res. 38:1-48, 1990). We have used the T7-vaccinia virus transient expression system to deliver mutant variants of the NS28 gene to CV1 cells in order to assess the effects of site-specific modifications on receptor function. Three types of mutant proteins have been constructed by altering the extreme C-terminal methionine, cysteine residues within the third hydrophobic domain, and internal residues located within the cytoplasmic portion of the receptor, respectively. Deletion or conservative substitution of the C-terminal methionine completely abolishes receptor activity. Substitution of cysteine residues has no effect on receptor activity or on the ability of the receptor to adopt its native oligomeric state. Internal deletions result only in a reduction in the level of binding. An N-terminally truncated form of the receptor, containing only the cytoplasmic domain, retains full receptor activity and can form membrane-associated tetramers.

Animals↗
PubMed2026

Decreased TXNRD1 is associated with resistance to tagraxofusp in blastic plasmacytoid dendritic cell neoplasms, as seen in phase II.

Tagraxofusp is a CD123-targeted therapy comprised of a recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin payload. It is the first approved treatment specifically for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). To identify biomarkers of response, bone marrow samples from 12 BPDCN patients who were treated with tagraxofusp in the pivotal phase II trial (NCT02113982) were profiled longitudinally using a gene panel and single-cell RNA sequencing. Residual tumor cells following tagraxofusp expressed lower levels of TXNRD1 that would reduce the efficacy of tagraxofusp. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp. Responders had either wild-type or missense TET2 mutations, while transient and non-responders had at least one truncating TET2 mutation. Examples of these mutations within the catalytic domain of TET2 were constructed and transduced into cells. Missense and truncating mutants displayed reduced sensitivities to hypomethylating agents and prolonged S-phase stasis. These results suggest that the levels of TXNRD1 interact with intrinsic TET2 truncating mutations within the bone marrow to modulate patient response to tagraxofusp.

Female↗
PubMed1992

Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects.

The order of appearance in the reverse transcriptase gene of four mutations implicated in the development of resistance to zidovudine was investigated by selective polymerase chain reaction. Serial human immunodeficiency virus isolates were studied from 18 initially asymptomatic individuals who had been treated with zidovudine for 2 years. Most subjects had similar patterns. The first mutation occurred transiently at codon 70; its disappearance was paralleled by the appearance of a mutation at codon 215. Subsequently, in some individuals, the mutation at codon 70 reappeared. During the 2 years of treatment, no mutations developed at codon 219 and only one at codon 67, suggesting that most individuals developed only partly resistant virus. This was confirmed by plaque-reduction assay. Six subjects progressed to AIDS within the 2-year study period, confirming that the development of highly resistant isolates is not required for progression in treated individuals. No clear temporal relationship was found between the development of partial resistance and progression.

Acquired Immunodeficiency Syndrome↗
PubMed1976

[Genetic control of the RecF recombination pathway. II. Effect of recL- and uvrE- mutations].

It was found earlier that the effect of the uvrE- mutation on the yield of recombinants formed via RecF pathway of recombination was mainly due to the decreased viability of the recB-C-sbcB-uvrE- recipient. The results of the present paper show the uvrE- and recL- mutations reduce the recipient ability of the recB-C- sbcB- strains to the same extent. We were unable to find any evidence for complementation between the recL- and uvrE- mutations in transient as well as in stable uvrE-/recL- merozygotes. The recL152 as well as the uvrE502 mutation is lethal for the strains deficient in DNA polymerase I. Both recL- and uvrE- mutations reduce in the recB-C- sbcB- strains the probability of inheritance of the proximal non-selective donor markers as well as selective markers located close to the leading end of the donor chromosome. The former effect however could not be completely due to the latter.

Alleles↗
PubMed1971

Effect of point mutations in the lac promoter on transient and severe catabolite repression of the lac operon of Escherichia coli.

1. Experiments were devised to show whether the point mutations L8 and L29 in the lac promoter alleviate transient repression. 2. Several recombinants were picked from matings between a single F(-)p(+) strain and Hfr strains carrying mutations L8 and L29. All of the 19 p(-) recombinants tested proved to suffer no transient repression, whereas all of the eight p(+) recombinants tested suffered prolonged transient repression. 3. A diploid strain was constructed in which more than 90% of the thiogalactoside transacetylase is synthesized from the episome with a wild-type lac promoter, whereas 100% of the beta-galactosidase is synthesized from the chromosome with a promoter carrying mutation L8. In this diploid the synthesis of thiogalactoside transacetylase suffered transient repression but the synthesis of beta-galactosidase did not. 4. Exactly similar results were obtained with a diploid strain in which the chromosomal promoter carried mutation L29. 5. The same diploid strains were used in experiments to show whether mutations L8 and L29 alleviate the severe catabolite repression caused by growth in glucose plus gluconate. In both strains glucose+gluconate repressed the synthesis of beta-galactosidase much less than the synthesis of thiogalactoside transacetylase. 6. These and previously reported results can be explained by assuming (a) that both mutations L8 and L29 render the lac promoter partially, but not completely, insensitive to catabolite repression, and (b) that transient repression is an exceptionally severe form of catabolite repression.

Acyltransferases↗
PubMed1989

Thyroid hormones regulate rat thyrotropin beta gene promoter activity expressed in GH3 cells.

Thyroid hormones suppress the synthesis of TSH in part by decreasing the rate of alpha and TSH beta gene transcription. Cis-acting DNA sequences present in the rat TSH beta subunit gene that are induced in transcriptional regulation by thyroid hormone have been identified by deletion-mutation and transient expression studies. Plasmid expression vectors were constructed including 2900, 900, 204, 77, 17 base pairs (bp) of 5'-flanking sequence and exon (5'-untranslated sequence, transcriptional start sites) fused to the coding region of the bacterial chloramphenicol acetyltransferase (CAT) gene. The transfected chimaeric plasmids demonstrated expression (with TSH beta DNA sequences in the 5'- to -3'-but not 3'- to -5'-orientation) in both a clonal pituitary cell line, GH3, and primary pituitary cell cultures, both of which are responsive to thyroid hormones. T3 (10(-11) M to 10(-7) M) treatment of transfected cells produced a dose-dependent decrease in CAT expression with a maximal 70% decrease at 10(-8) M. While a decrease in the basal level of expression was noted with progressive removal of both 5'-flanking and intronic sequences adjacent to exon 1, the fold-decrease in response to T3 was equivalent even in the 57 bp construct. In contrast, T3 had no effect on CAT expression directed by the promoter of the herpes simplex virus thymidine kinase gene. Thus, the rat TSH beta gene 5'-flanking region can direct heterologous gene expression in GH3 cells and contains sequences which have properties of a putative cis-active T3 responsive regulatory element(s).2+he

Animals↗
PubMed1989

Kinetics of complementary RNA-RNA interaction involved in plasmid ColE1 copy number control.

Binding of a small antisense RNA (RNA I) to the primer transcript (RNA II) of plasmid ColE1 inhibits formation of primer for DNA polymerase I-mediated plasmid replication. It is thought that RNA I and RNA II transiently interact via their single-stranded loop regions to form an unstable complex that subsequently converts into a more stable complex by hybridization. Rom (or Rop) protein enhances the inhibitory effect of RNA I on replication by enhancing the binding of the two RNAs. In this paper, we develop a model for the kinetics of the RNA I-RNA II binding reaction, estimate the rate constants, and provide a quantitative description of the effects of Rom protein. We show that the reaction kinetics are consistent with a stepwise binding model in which Rom protein binds to RNA I and RNA II, while the RNAs are held together in a transient complex. Mutations that replace C.G pairs by T.A pairs in the RNA loop regions and thus display weaker hydrogen bonding between the loop regions should be associated with an increased rate of dissociation for the unstable complex. Our model predicts that such destabilization of the loop interactions leads to a greater enhancement in the binding rate by Rom protein. The available data support this prediction.

Bacterial Proteins↗
PubMed1992

An enhancer element responsive to ras and fms signaling pathways is composed of two distinct nuclear factor binding sites.

In order to precisely define the sequences that constitute the ras-responsive enhancers element present in the murine retrotransposon NVL3, point mutations were introduced into the previously defined minimal transcriptional enhancer DNA. Analyses of the effects of these point mutations in transient transfection experiments, in gel retention assays, and by methylation interference footprinting indicated that the enhancer element was composed of two binding sites for distinct nuclear factors. Both binding sites were required for activation of the enhancer by either ras or v-fms oncogenes, and the distinct nuclear factors were found in extracts from cells that contained either oncogene. UV cross-linking analysis revealed that the AP1-related binding site, TGACTCT, was recognized by a nuclear factor of apparent molecular size of 50 kilodaltons, that is probably c-jun. The other binding site, CAGGATAT, is very similar to sites recognized by the ets-family of transcription factors, and was recognized by the 120-kilodalton ras-responsive factor-1. Activation of the NVL3 element was reconstituted in an in vitro transcription assay. The ets-related binding site was necessary for this in vitro reconstitution of activity. Thus, the NVL3 enhancer is related to the previously described oncogene-responsive enhancer element present in polyoma virus and is also related to elements identified in several cellular genes known to be ras-responsive, including the transforming growth factor-beta 1 gene.

Base Sequence↗
PubMed1992

The dissonance mutation at the no-on-transient-A locus of D. melanogaster: genetic control of courtship song and visual behaviors by a protein with putative RNA-binding motifs.

Genetic and molecular results are here presented revealing that the dissonance (diss) courtship song mutation is an allele of the no-on-transient-A (nonA) locus of Drosophila melanogaster. diss (now called nonAdiss) was originally isolated as a mutant with aberrant pulse song, although it was then noted to exhibit defects in responses to visual stimuli as well. The lack of transient spikes in the electroretinogram (ERG) and optomotor blindness associated with nonAdiss are shown to be similar to the visual abnormalities caused by the original nonA mutations. nonAdiss failed to complement either the ERG or optomotor defects associated with four other nonA mutations. However, all four of these nonA mutants--which were isolated on visual criteria alone--sang a normal courtship song. nonAdiss complemented at least three of the nonA mutations with regard to the singing phenotype, as assessed by a new method for temporal analysis of the male's pulse song. Both visual and song abnormalities caused by nonAdiss were rescued by P-element-mediated transformation with overlapping 11 and 16 kilobase (kb) fragments of genomic DNA (originally cloned from the nonA locus by Jones and Rubin, 1990). Analysis of behavioral phenotypes in transformed flies carrying mutagenized versions of the 11 kb genomic fragment (in a nonAdiss genomic background) localized the rescuing DNA to a region containing an open reading frame that encodes a polypeptide (NONA) with similarity to a family of RNA-binding proteins. Immunohistochemical determination of NONA's spatial and temporal expression revealed that it is localized to the nuclei of cells in many neural and non-neural tissues, at all stages of the life cycle after very early in development. Genetic connections between the control of two quite different behaviors--reproductive and visual--are discussed, along with precedences for generally expressed gene products playing roles in specific behaviors.

Alleles↗