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Mistranslation in bacteriophage-infected anucleate minicells of Escherichia coli: a test for error propagation.

The theory of error propagation proposes that errors occurring during expression of the genetic code lead to increased levels of error occurrence in successive generations. A model system for testing error propagation in bacteriophage T7 infected anucleate minicells of Escherichia coli is described. Errors in translation were were stimulated by addition of gentamicin to phage infected minicells, and the error frequency based on the illegitimate incorporation of L-[35S] cysteine into the T7 0.3 gene protein calculated to be on the order of 1 error per 10 000 codons translated. Errors in the synthesis of T7 early gene products have also been detected as suppression of a UAG nonsense codon in gene 1 of the T7 DNA-dependent RNA polymerase, and as increased charge heterogeneity in the gene 1.3 product (DNA ligase). The question of error propagation has been addressed by infecting minicells with a mutant of T7 containing nonsense mutations in the early gene 1 and late gene 16. Results demonstrate that a T7 DNA-dependent RNA polymerase containing misincorporated amino acids is unable, by mistranscription, to suppress a UAG nonsense codon located in the late T7 gene 16.

Cysteine↗

The suppression of defective translation by ppGpp and its role in the stringent response.

Amino acid starvation is shown to decrease the fidelity of translation in E. coli. When proteins are analyzed by two-dimensional gel electrophoresis, missense errors are detected as an unusual heterogeneity in their isoelectric points, while premature termination of protein synthesis can be recognized by a decreased relative rate of synthesis of higher molecular weight proteins and by the the accumulation of a complex group of new small polypeptides. The types of translational errors observed are amino acid-specific. For example, starvation of a rel- strain for histidine produces severe isoelectric point heterogeneity with little evidence of premature termination, while starvation for leucine has little effect on the isoelectric points, but produces a drastic decrease in the average molecular weight of the newly synthesized protein. These differences suggest codon-specific errors in reading the genetic code. In these rel- cells, the effect of amino acid starvation on the rates of synthesis of complete individual proteins is both protein- and amino acid-specific. For example, ribosomal protein L7/12, which lacks histidine, is made at a higher level during histidine starvation than during isoleucine or leucine starvation. This suggests that in rel- cells, the modulation of gene expression caused by the lack of a particular amino acid is, at least in part, a function of the abundance of that amino acid in particular proteins-that is, the response of rel- cells to starvation is consistent with the theory that the inhibition of protein synthesis and the accompanying increase in error frequency both result from low levels of the correct substrate. In marked contrast, virtually no starvation-induced translational errors are detected in a rel+ strain, and the response is not amino acid-specific. Varoius data strongly imply that in this rel+ strain, essentially all the changes caused by starvation are due to the accumulation of ppGpp, which independently reduces protein synthesis, thereby suppressing all the direct effects of amino acid limitation seen in rel- strains (where ppGpp does not accumulate upon starvation). A model is presented which describes how ppGpp might suppress the direct effects of starvation and avoid the loss of translational fidelity. In addition, the direct and specific effects of ppGpp on gene expression are examined independently of amino acid starvation.

Amino Acids↗

Development of CCK-B antagonists.

Our approach to design small molecule non-peptide analogues of the neuropeptide cholecystokinin (CCK) has led to the discovery of the CCK-B antagonist 'dipeptoids'. A representative member of this series of compounds, PD134308 [R-(R*,R*)]-4-[[2-[[3-(1H-Indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]propyl] amino]-1-phenylethyl]amino]-4-oxobutanoic acid has high affinity (Ki = 1.7 nM) and selectivity for the CCK-B receptor (CCK-A/B ratio is 2500:1), is well absorbed and shows robust anxiolytic properties in several anxiogenic models in a dose related manner by both s.c. and oral routes of administration over the dose range 0.1-30 mg/Kg. The rational design of these dipeptoids from CCK 26-33 has involved the identification of the non-contiguous dipeptide fragment of CCK, Boc-Trp-Phe-NH2 with low micromolar affinity in binding assays. This dipeptide has been systematically chemically modified at the N- and C-terminal to increase CCK-B binding affinity 10,000-fold. These modifications include replacement of the L-tryptophan moiety by the non-genetically coded D-alpha-methyltryptophan residue. The modifications also enhance the stability of the molecule towards enzymatic and acid degradation and increase overall lipophilicity compared with the peptide in order to facilitate penetration of the blood-brain barrier.

Amino Acid Sequence↗

Genetic effects of acridine compounds.

Acridines and a very large number of acridine derivatives are used in enormous quantities both in medicine and industry. The mutagenic action of these compounds has been demonstrated in a wide variety of organisms and is known to occur both in the dark as well as in the presence of light (photodynamic action). At the molecular level, acridines have been shown to cause frameshift mutations of both the addition and deletion types, a characteristic which has been of tremendous help in elucidating the nature of the genetic code. These and various other biological effects of acridines, such as inhibition of DNA repair, curing of plasmids and cell-growth inhibition, are examined in this review.

Acridines↗

Proflavin: an unusual mutagen.

In the Salmonella typhimurium mutagenicity assay, proflavin (PF), in the dark, was shown to possess some direct-acting frameshift mutagenic activity for strains TA1537 and TA98. In the presence of microsomal enzymes from mouse, hamster and rat livers, frameshift mutagenic activity for strain TA1538 and enhanced mutagenicity for strain TA1537 was observed. Exposure of bacteria to PF in the presence of visible light resulted in base substitution (strain TA1535) as well as frameshift (TA1537, TA1538, TA98) genetic activities. The findings are taken to indicate that PF possesses direct-acting frameshift activity (TA1537 and TA98) by virtue of its ability to intercalate between DNA base-pairs. The frameshift activity (TA1538, TA98 and enhanced TA1537) seen following metabolic or photo-activation may be due to the formation of chemical adducts between the cellular DNA and oxidation products of PF (a base-displacement effect). The light-induced base-substitution activity probably results from the generation of singlet oxygen which reacts with the guanine moiety of DNA. The mutagenic photoproduct of PF appears to be stable.

Acridines↗

New insights into mRNA decoding--implications for heterologous protein synthesis.

The primary structure of a polypeptide can be predicted by translating its mRNA sequence according to the 'universal' genetic code. Yet, recent evidence has shown that a number of nonstandard translational events may occur in cells, generating microheterogeneity in the translation product at the amino acid level. Such events can be programmed by sequences within the mRNA, or may just represent nonprogrammed errors that occur during translation as a result of depletion of specific aminoacyl-tRNAs. The potential occurrence of such errors must be considered and steps taken both to identify and eliminate them when expression strategies are being developed for producing recombinant proteins for human therapeutic use.

Codon↗

Yeast retrotransposons and tRNAs.

The role of tRNAs in protein synthesis seems routine when compared with the novel ways in which the Ty retrotransposons of Saccharomyces cerevisiae use these interpreters of the genetic code. tRNAs and tRNA genes control essential steps in the retrotransposon life cycle by regulating protein expression, priming DNA synthesis and specifying integration target sites.

Base Sequence↗

Studies toward the biosynthesis of vasoactive intestinal peptide (VIP).

In view of the potential biological importance of VIP, we have begun to examine the regulation of its biosynthesis. For this purpose we have, as a first step, searched for an enriched source of VIP biosynthesis. By a combination of chromatographic procedures and radioimmunoassays we discovered an as yet unknown source for VIP production, namely a human buccal tumor, containing 0.67 +/- 0.05 ng VIP/micrograms protein which is greater than the richest source in brain (the cerebral cortex). Thus, we decided to use the tumor tissue for VIP-mRNA purification and characterization. To identify VIP-mRNA we are using as hybridization probes, synthetic oligodeoxynucleotides with relatively unambiguous nucleotide sequence complementary to the predicted VIP-mRNA sequence. These probes are synthesized, using the deoxynucleoside phosphoramidite approach, to a length of 17 bases each, and contain all the possible DNA sequences according to the genetic code. These specific probes are then radioactively labelled using the reaction catalyzed by the enzyme polynucleotide kinase and afterwards hybridized to mRNA, which had been resolved on denaturing agarose gels. Employing this approach, we identified a single putative VIP-mRNA band which was then partially purified by sucrose gradient centrifugation. Upon in vitro translation in a rabbit reticulocyte lysate cell free system, this mRNA was found to code for VIP immunoreactive proteins. In conclusion, our studies suggest the existence of high molecular weight precursors to VIP cross-reactive with anti-VIP antibodies, that are coded for by a partially purified mRNA containing VIP sequences.

Base Sequence↗

Molecular analysis of HLA class I and class II antigen loss mutants reveals a homozygous deletion of the DR, DQ, and part of the DP region: implications for class II gene order.

The mutant human B-lymphoblastoid cell lines, 721.174 and 721.180, previously reported to exhibit greatly reduced expression of human HLA class I and II antigens (DeMars et al., Hum Immunol 11:77, 1984), were analyzed by Southern blotting using class II cDNA and genomic clones as hybridization probes. All genomic sequences complementary to DR alpha, DR beta, DQ alpha, and DQ beta probes were absent from these mutants. DZ alpha genomic sequences were deleted as were the DP alpha 1 and DP beta 1 loci but the DP beta 2 and most, if not all, of the DP alpha 2 locus were retained. However, no RNA transcripts for either DP alpha 2 or DP beta 2 could be detected. The mapping of the deletion breakpoint within the DP cluster allows the orientation of the loci in the DP region with respect to the centromere as follows: centromere, DP beta 2, DP beta 1, DP alpha 1, (DQ, DR). In addition, the analysis of a set of DR-, DQ-, DP+ homozygous deletion mutants (721.82, 721.84, and 721.101) reveals a deletion breakpoint between the DQ alpha 1/DQ beta 1 loci and the DQ alpha 2/DQ beta 2 loci. These mutants retain DZ alpha genomic sequences, tentatively mapping the DZ alpha locus between the DQ and the DP region. The residual ability of the DR-, DQ-, DP- mutants (174 and 180)* to stimulate allogeneic and autologous lymphoproliferative responses must be attributed to expression of as yet unidentified class II antigens, or to non-class II antigens.

Cell Line↗

Structural aspects and evolutionary implications of the recognition between tRNAs and aminoacyl-tRNA synthetases.

Recent structural discoveries in the fields of tRNAs and aminoacyl-tRNA synthetases (aaRS), such as the existence of two classes of aminoacyl tRNA synthetases, the modular character of aaRS with domains homologous to other existing proteins, and the absence of direct interactions between the catalytic site containing the aminoacid binding pocket and the anticodon point the way to an understanding of the origin of the genetic code.

Amino Acyl-tRNA Synthetases↗

Evolution of the mitochondrial protein synthetic machinery.

Comparative analysis of the components of the mitochondrial translational apparatus reveals a remarkable variability. For example the mitochondrial ribosomal rRNAs, display a three-fold difference in size in different organisms as a result of insertions or deletions, which affect specific areas of the rRNA molecule. This suggests that such areas are either not essential for mitoribosome function or that they can be replaced by proteins. Also mitochondrial tRNAs and mitoribosomal proteins are much less conserved than their cytoplasmic counterparts. Not only do the mitochondrial translational molecules vary in properties, also the location of the genes from which they are derived is not the same in all cases: mitochondrial tRNA genes which usually are found in the mtDNA, may have a nuclear location in protozoa and, conversely, only in fungi one finds a mitoribosomal protein gene in the organellar genome. The high rate of change of the components of the mitochondrial protein synthesizing machinery is accompanied by a number of unique features of the translation process: (i) the mitochondrial genetic code differs substantially from the standard code in a species-specific manner; (ii) special codon-anticodon recognition rules are followed; (iii) unusual mechanisms of translational initiation may exist. These observations suggest that the evolutionary pressures that have shaped the present day mitochondrial translational apparatus have been different in different organisms and also distinct from those acting on the cytoplasmic machinery. In spite of the interspecies variability, however, many features of the mitochondrial and bacterial protein synthetic apparatus show a clear resemblance, providing support for the hypothesis of a prokaryotic endosymbiont ancestry of mitochondria.

Animals↗

Production and characterization of recombinant turkey prolactin.

1. Recombinant turkey prolactin (rctPRL) was produced as a fusion protein in E. coli, purified by affinity chromatography followed by cleavage with thrombin. The final yield of the released rctPRL (> 90% purity) was 1-2 mg/l of bacterial culture. 2. Recombinant tPRL co-migrated with the main immunoreactive band (25 kDa) in turkey pituitary extracts and was identical to natural tPRL except for the addition of three amino acids (Gly-Ser-Ser) resulting from the cloning strategy at the amino terminal end. 3. The bioactivity of the rctPRL was equipotent to ovine PRL in a rabbit mammary explant system and in the Nb2 lymphoma mitogenic assay.

Amino Acid Sequence↗