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At least 19 recordsLinked to original sources
PubMed1975

Requirement for ribosome-releasing factor for the release of ribosomes at the termination codon.

With the use of 3H-labeled R 17 amB2 phage RNA having an UAG codon at the seventh triplet of the coat cistron, release of the RNA from ribosomes at the termination codon was studied. The ribosome-releasing factor previously described was shown to stimulate the process of mRNA release at the termination factor (RF-1). GTP was required for this process and guanosine 5'-(beta,gamma-methylene)triphosphate could not replace GTP. No apparent change of size of R 17 RNA was observed during the release of the R 17 RNA from the ribosomes. The ribosome-releasing factor is distinct from the known termination codon-specific factor such as RF-1.

Amino Acids↗
PubMed1975

Ribosome run through of the termination codon in the absence of the ribosome releasing factor.

The ribosome releasing factor (RR factor) which releases ribosomes from mRNA at the termination codon has been examined for its effects on the amino acid incorporation programmed by wild type R17 Phage RNA and amB2 R17 RNA. When RR factor was added at the beginning of the incorporation, there was no effect on the initial rate of incorporation but it reduced the final level of incorporation. The reduction of the final level of incorporation was more pronounced for histidine incorporation than for valine incorporation suggesting that the translation of the RNA polymerase cistron was more influenced by RR factor. These experiments were carried out under conditions where no reinitiation of protein synthesis occurred. In the presence of RR factor, suppressor tRNA functioned better for the incorporation of amino acids into proteins with amB2 R17 RNA than did wild type tRNA. No such differential effect of suppressor tRNA was observed in the absence of RR factor. This suggests that the ribosome has to be released from mRNA by RR factor in order for the amber mutation to be effective.

Codon↗
PubMed1975

The synthetase gene of the RNA phages R17, MS2 and f2 has a single UAG terminator codon.

Translation of the RNA from the wild-type bacteriophages R17, MS2, and f2 in bacterial cell-free extracts containing an amber suppressor yields 30-40% of the synthetase with an approximate molecular weight of 63 500, slightly larger than the major synthetase product (63 000 daltons). The occurrence of the 63 500 dalton in vitro product is dependent on the presence of an amber suppressor, and we predict that it is due to read-through of a UAG termination codon at the end of the synthetase gene. Previous results of Capecchi and Klein (Nature, 226, 1029-1033, 1070) showed that antibodies to both release factors RF1 and RF2 are required to block release of synthetase, suggesting that synthetase is released at a UAA codon. If the interpretations of both experiments are correct, the termination and release may not be synonomous and may be spatially separated. In addition there is the unexplained fact that 7% of the synthetase made in vitro in both su+ and su- extracts with either R17, MS2 or f2 as template has an apparent molecular weight of 66 000.

Autoradiography↗
PubMed1978

Organization and expression of early genes of simian virus 40.

The early region of simian virus 40 codes for at least two immunologically related polypeptides: large-T and small-t, with apparent molecular weights of 90,000-100,000 and 15,000-20,000, respectively. Because small-t shares methionine-containing tryptic peptides with large-T, the two polypeptides are probably coded, in part, by a common nucleotide sequence. To locate the coding sequences for large-T and small-t in the DNA, the production of these proteins was examined after infection of CV-1 cells with wild-type and deletion mutants of simian virus 40. We found that a deletion at the distal portion of the early region alters the structure of large-T but not of small-t; but deletions within the region between map coordinates 0.59 and 0.55 result in an alteration or absence of small-t and a normal large-T. These findings have been rationalized by a model that proposes the existence of two early mRNAs, one coding for large-T and the other for small-t. Both mRNAs span virtually the entire early region; but the mRNA coding for large-T lacks the nucleotide sequence between map coordinates 0.59 and 0.54. We suggest that small-t is translated from the larger of the two mRNAs, beginning at or near its 5' end and terminating at a termination codon at about map coordinate 0.54. Larger-T, on the other hand, is translated from the shorter mRNA, beginning at the same initiator codon, and, because of the deletion of the terminator codon at 0.54, translation proceeds to the terminator codon at or near map position 0.18.

Antigens, Viral↗
PubMed1975

Effects of dihydrostreptomycin on ribosome function in vivo: lack of correlation between changes in ribosome patterns and growth.

In vivo treatment of susceptible Escherichia coli cultures with low concentrations of dihydrostreptomycin leads to a decline in polysomes and a corresponding increase in 70S particles which behave as run-off ribosomes, as well as free 30S and 50S subunits. We have examined the timing and extent of these effects on ribosomes and compared them to the effects of this antibiotic on growth and protein synthesis. We have shown that no changes in ribosome distribution are observed until growth inhibition by dihydrostreptomycin is almost complete. Thus, intracellular dihydrostreptomycin can inhibit growth and net protein synthesis without apparently affecting the ribosome cycle. Since it is known that the antibiotic combines with free 30S subunits, the question is how such combination can bring about the observed inhibition of protein synthesis and growth. We suggest that specific interaction of intracellular antibiotic with proteins of the 30S subunits allows repeated use of the ribosome cycle by such affected particles, but with selective misreading of certain amino acid codons as terminator codons, so that they produce incomplete polypeptide chains. The cumulative effect of such a mechanism would lead to eventual cessation of protein synthesis and growth.

Dihydrostreptomycin Sulfate↗
PubMed1977

Human beta-globin messenger RNA. I. Nucleotide sequences derived from complementary RNA.

Sequence analysis studies were carried out on human beta-globin mRNA (beta-mRNA) prepared from alpha-thalassemic, sickle cell, and Hb A reticulocytes. Highly purified beta-mRNA served as substrate for the preparation of cDNA by RNA-dependent DNA polymerase. The cDNA was transcribed by Escherichia coli RNA polymerase and the resulting cRNA was analyzed. Over 300 nucleotides were assigned to the beta-mRNA coding region and 37 nucleotides were assigned to the 3'-terminal noncoding region. The normal termination codon is UAA which is separated by 28 nucleotides from an out of phase UAA triplet. The origin of each of the abnormally long beta-globin variants Tak and Cranston is consistent with reduplication of dinucleotides prior to the normal termination codon, and both globin variants can terminate at the out of phase UAA.

Anemia, Sickle Cell↗
PubMed1978

Nucleotide sequence of gene VII and of a hypothetical gene (IX) in bacteriophage M13.

A DNA fragment containing gene VII of bacteriophage M13 has been transcribed and the nucleotide sequence of this 169-nucleotides long transcript was determined by RNA sequencing methods. Additionally, the nucleotide sequence of this gene and parts of its neighbouring genes V and VIII has been determined by the dimethylsulphate-hydrazine technique. The reading frame of gene VII has been established by determining the nucleotide changes occurring in the transcripts of two amber mutants of this gene. From these combined data it is apparent that gene VII is only 99 nucleotides long and is immediately followed by the termination codon UGA. Its initiation codon AUG is separated from gene V by only a single nucleotide. It was noted that between the UGA termination codon of gene VII and the initiation codon of the next gene (gene VIII) there is space for another, hitherto unknown gene. This gene (IX) most probably codes for the small polypeptide ("C-protein") present in mature M13 phage particles.

Base Sequence↗
PubMed1975

Nucleotide sequences of the 3'-terminal untranslated region of messenger RNA for human beta globin chain.

In normal messenger RNA for the human beta-globin chain, nucleotide sequences have been identified which can be matched to the amino-acid sequence of the abnormally long segment of the beta-chain of hemoglobin Cranston. The finding of these sequences strengthens the hypothesis that the betaCranston chain arose by a frameshift mutation allowing the "readthrough" of the normal termination codon and translation of usually untranslated portions of the messenger RNA for the beta-globin chain. The oligonucleotides which match the amino-acid sequence of hemoglobin Cranston provide a sequence of 36 nucleotides which follows the normal beta-chain termination codon UAA.

Base Sequence↗
PubMed1979

A different genetic code in human mitochondria.

Comparison of the human mitochrondial DNA sequence of the cytochrome oxidase subunit II gene and the sequence of the corresponding beef heart protein shows that UGA is used as a tryptophan codon and not as a termination codon and suggests that AUA may be a methionine and not an isoleucine codon. The cytochrome oxidase II gene is contiguous at its 5' end with a tRNAAsp gene and there are only 25 bases at its 3' end before a tRNALys gene. These tRNA'S are different from all other known tRNA sequences.

Aspartic Acid↗
PubMed1979

Suppression of the nonsense mutation in homozygous beta 0 thalassaemia.

The common form of beta thalassaemia associated with elevated haemoglobin A2 levels can be broadly classified as beta + or beta 0 type according to the presence or absence of beta-globin chain synthesis in the homozygous state. The molecular pathology of each type is heterogeneous. Apart from a subgroup of Indo-Pakistani patients, the beta-globin structural gene is intact in the majority of patients with beta 0 thalassaemia. The amount of beta-globin mRNA present in the reticulocytes of these patients varies: in some it is absent or barely detectable; in others, a substantial amount is present, but it is nonfunctional. We recently demonstrated that the molecular lesion in a Chinese patient with nonfunctional beta-globin mRNA was due to the mutation of the normal lysine codon AAG at amino acid 17 to the amber terminator codon UAG, which prematurely terminates the beta-globin chain. In the present study we demonstrate the first example of a nonsense mutation in humans which can be suppressed in vitro by the suppressor tRNA, as has been found in other eukaryotic cells and viruses.

Codon↗
PubMed1977

Hemoglobin and the genetic code. Evolution of protection against somatic mutation.

One-half of the twenty amino acids of the genetic code are just one mutational step away from the chain-terminator codons UAA, UAG, and UGA. It is postulated that somatic mutation to terminator is a hazard to which the organism has and to respond by adjusting certain proteins in the direction of fewer mutable residues. This view is supported by calculations based on the primary structure of five of the human hemoglobin chains. Each chain is scored for mutability to terminator in accord with the numbers and kinds of amino acids present. Among the adult chains, the most essential one, the alpha, has lowest mutability. The beta and delta follow, and in order of the presumed harm to the organism of a shortage of chain copies. Ante-natal chains tend to have higher mutabilities, supporting the view that cumulative mutational change in DNA can do little if the gene ceases to transcribe early in life. Two other predicitons based on the supposition of effective selection against mutability to terminator are also met: chain length of polypeptides is negatively correlated with their scores for mutability to terminator, and examination of the recently determined sequence of beta messenger RNA shows preferential use of codons that are not readily mutable to terminator.

Amino Acid Sequence↗
PubMed1978

Nucleotide sequence of DNA template for the 3' ends of SV40 mRNA. II. The sequence of the DNA fragment EcorII-F and a part of EcorII-H.

The nucleotide sequence for two-thirds of restriction endonuclease fragment EcoRII-F and part of RII-H of SV40 DNA is presented. This segment of SV40 DNA is complementary to the sequence near the 3' end of early mRNA. This sequence could be translated in one reading frame to form a large protein. However, in a second translational frame there are four AUG codons followed by 91 sense triplets, followed by a termination codon. These results provide the sequence for the entire 3' untranslated ends of SV40 early and late mRNAs and for the DNA beyond the 3' ends of the mRNAs. The ends of early and late mRNA are transcribed from the opposite strands of the same segment of DNA. At or beyond the 3' ends of both early and late mRNA are sequences whose transcripts would include uridylic acid-rich products.

Base Sequence↗
PubMed1975

Yeast super-suppressors are altered tRNAs capable of translating a nonsense codon in vitro.

tRNA isolated from two different yeast super-suppressor strains translates a known nonsense mutation in vitro, whereas tRNA from a closely related nonsuppressing strain does not. Suppression was assayed by translation of RNA isolated from an amber coat mutant of bacteriophage Qbeta (GB11) in a protein-synthesizing system derived from mouse tissue culture cells (L cells). Suppressed forms of Qbeta coat protein synthesized in vitro were quantitatively detected by a specific immunoprecipitation assay. The L-cell protein-synthesizing system also responds to E. coli suppressor tRNA. This indicates that the biochemical mechanism for nonsense suppression is very similar in yeast and E. coli. These findings also provide additional evidence that the amber codon (UAG) functions as one of the mammalian chain-terminating codons. Since the suppression assay utilizes protein-synthesizing components isolated from mammalian cells, it should prove useful in the search for mammalian nonsense suppressors.

Codon↗
PubMed1975

Sequence of the promoter-operator proximal region of the major leftward RNA of bacteriophage lambda.

The sequence of the first 149 nucleotides of the major leftward RNA of bacteriophage lambda has been determined. Preliminary sequence information was also obtained for a portion of the untranscribed area immediately upstream of the point on the template when RNA synthesis normally starts. Several restriction endonuclease sites, deletion endpoints, and single base changes have been localized within the sequence. The first potential translation initiation codon which is not followed by an in-phase termination codon is a GUG located 90 nucleotides from the transcription startpoint.

Base Sequence↗
PubMed2026

RNA sequencing resolves a novel noncanonical splice-region variant in PHKA2 causing glycogen storage disease type IX α2: a case report.

BACKGROUND: Glycogen storage disease type IX α2 (GSD IX α2) is an X-linked hepatic glycogenosis caused by pathogenic variants in PHKA2. Noncanonical splice-region variants located outside the invariant GT/AG dinucleotides pose significant interpretive challenges, as in silico predictions alone are often insufficient for definitive classification. CASE DESCRIPTION: We report a 2.9-year-old boy presenting with short stature, hepatomegaly, markedly elevated aminotransferases, fasting hypoglycemia with ketonuria, hypercholesterolemia, coagulation parameter abnormalities (decreased fibrinogen and prolonged thrombin time), and histological evidence of early hepatic fibrosis as demonstrated by Masson's trichrome staining (portal fibrosis and perisinusoidal fibrosis). Whole-exome sequencing (WES) identified a hemizygous, previously unreported PHKA2 variant [NM_000292.3:c.2517+5G>T, genomic location (GRCh38): NC_000023.11: g.18907895G>T], initially classified as a variant of uncertain significance (VUS) under American College of Medical Genetics and Genomics (ACMG) criteria. RNA sequencing of peripheral blood leukocytes demonstrated predominant exon 22 skipping in 94.2% of informative junction reads, predicting a frameshift and premature termination codon [p.(Gly788Profs*74)] with predicted loss of the C-terminal CBL 2 subdomain. Incorporating this transcript-level evidence, the variant was reclassified as pathogenic (PVS1 + PM2_Supporting + PP4). Following dietary management with uncooked cornstarch supplementation, the patient showed progressive biochemical improvement over a 2.2-year follow-up. CONCLUSIONS: This case expands the mutational spectrum of PHKA2 and demonstrates that RNA sequencing of accessible tissues is a practical and diagnostically informative strategy for resolving noncanonical splice-region variants in pediatric hepatic GSD. Early hepatic fibrosis detected by histological examination before age 3 years underscores the importance of longitudinal hepatic surveillance in GSD IX α2.

Glycogen storage disease type IX α2 (GSD IX ↗