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At least 865 records · Page 48Linked to original sources
PubMed1997

Mutations at codon 249 of p53 gene in human hepatocellular carcinomas from Tongan, China.

Codon 249 (exon 7) of the putative tumor suppressor gene p53 is a mutational hot-spot for hepatocellular carcinoma (HCC) but not other tumors. DNA samples from primary HCC patients from Tongan, an area of high HCC incidence in China (> 40 per 100,000 population), were analyzed for specific mutations in codon 249 of the p53 gene using polymerase chain reaction (PCR)/restriction-digest methods and direct DNA sequencing. Seven of the 21 samples screened were found to have a point mutation at the third base position of codon 249 (AGG to AGT). The result is consistent with previous reports that the G-->T transversion is positively associated with the level of dietary aflatoxin B1 (AFB1) contamination, which has been implicated as one of the risk factors in Tongan area. Of the 7 HCC patients that contained the codon 249 point mutation, one was hepatitis B virus (HBV)-negative. This is only the second documentation of an HCC patient harboring the p53 codon 249 mutation, who was HBV-negative.

Adult↗
PubMed1999

Genetic polymorphism near HIV-1 reverse transcriptase resistance-associated codons is a major obstacle for the line probe assay as an alternative method to sequence analysis.

The performance of the line probe assay (LIPA) for the detection of mutations conferring resistance to nucleoside inhibitors of HIV-1 reverse transcriptase was evaluated in comparison with sequence analysis. The tests were undertaken on plasma samples from 63 patients (61 receiving combination therapy and 2 without treatment at the time of inclusion). In 27 cases (43%) which included codons 41, 69, 70, 74, 184 and 215, the sequence of the RT gene was distinct from the hybridization probes used in LIPA. Correspondingly, LIPA gave uninterpretable results in 15, 30 and 41% of cases for codons 184, 215 and 41, respectively. Overall, the concordance between LIPA and sequence analysis varied from 52% (codons 41 and 215) to 85% (codon 70). These data show that the polymorphism of the nucleotide sequence near resistance-associated codons is a major shortcoming of LIPA.

Codon↗
PubMed2003

Glutamine is incorporated at the nonsense codons UAG and UAA in a suppressor-free Escherichia coli strain.

Readthrough of the nonsense codons UAG, UAA, and UGA is seen in Escherichia coli strains lacking tRNA suppressors. Earlier results indicate that UGA is miscoded by tRNA(Trp). It has also been shown that tRNA(Tyr) and tRNA(Gln) are involved in UAG and UAA decoding in several eukaryotic viruses as well as in yeast. Here we have investigated which amino acid(s) is inserted in response to the nonsense codons UAG and UAA in E. coli. To do this, the stop codon in question was introduced into the staphylococcal protein A gene. Protein A binds to IgG, which facilitates purification of the readthrough product. We have shown that the stop codons UAG and UAA direct insertion of glutamine, indicating that tRNA(Gln) can read the two codons. We have also confirmed that tryptophan is inserted in response to UGA, suggesting that it is read by tRNA(Trp).

Codon, Nonsense↗
PubMed2001

A reassessment of the translation initiation codon in vertebrates.

More than two decades ago Marilyn Kozak proposed the scanning model of translation initiation, whereby translation is initiated at the first AUG codon that is in a particular context. In this article, we re-examine the context of initiator codons using a large dataset of curated human transcripts. We find that more than 40% of transcripts contain AUG codons upstream of the actual start codon and that most authentic AUGs contain three or more mismatches from the consensus sequence, CCACCaugG. Also, in a large fraction of transcripts, the sequences surrounding the initiator codon deviate more from the consensus than those surrounding upstream AUGs, indicating that translation initiation from downstream AUGs is more common than generally believed.

5' Untranslated Regions↗
PubMed1996

Codon reassignment in Candida species: an evolutionary conundrum.

A number of Candida species translate the standard leucine CUG codon as serine rather than as leucine. Such codon reassignment in nuclear-encoded mRNAs is unusual and raises a number of important questions about the origin of the genetic code and its continuing evolution. In particular we must establish how a codon can come to be reassigned without extinction of the species and what, if any, selective pressure drives such potentially catastrophic changes. Recent studies on the structure and identity of the novel CUG-decoding tRNA(Ser) from several different Candida species have begun to shed light on possible evolutionary mechanisms which could have facilitated such changes to the genetic code. These findings are reviewed here and a possible molecular mechanism proposed for how the standard leucine CUG codon could have become reassigned as a serine codon.

Base Sequence↗
PubMed2001

Correlation between sequence conservation of the 5' untranslated region and codon usage bias in Mus musculus genes.

The codon adaptation index (CAI) values of all protein-coding sequences of the full-length cDNA libraries of Mus musculus were computed based on the RIKEN mouse full-length cDNA library. We have also computed the extent of consensus in flanking sequences of the initiator ATG codon based on the 'relative entropy' values of respective nucleotide positions (from -20 to +12 bp relative to the initiator ATG codon) for each group of genes classified by CAI values. With regard to the two nucleotides positions (-3 and +4) known to be highly conserved in Kozak's consensus sequence, a clear correlation between CAI values and relative entropy values was observed at position -3 but this was not significant at position +4, although a significant correlation was found at position -1 of the consensus sequence. Further, although no correlation was observed at any additional positions, relative entropy values were very high at positions -4, -6, and -8 in genes with high CAI values. These findings suggest that the extent of conservation in the flanking sequence of the initiator ATG codon including Kozak's consensus sequence was an important factor in modulation of the translation efficiency as well as synonymous codon usage bias particularly in highly expressed genes.

5' Untranslated Regions↗
PubMed1997

The majority of long non-stop reading frames on the antisense strand can be explained by biased codon usage.

In recent studies it has been suggested that long reading frames on the antisense strand of open reading frames (ORFs) are more frequent than expected. The vertebrate DNA database was searched for long (greater than 900 bp) antisense non-stop reading frames (aNRFs) that overlap known coding regions. The sequences obtained were predominantly positioned in DNA with a high usage of G or C in the third codon position of the sense ORF. The major class of sequences revealed by the search was that of the heat-shock protein 70 kDa (Hsp70) family. A long Hsp70 aNRF was found in many Hsp70 sequences and occurred in species as diverse as fish, flies, fungi and bacteria. The role of codon usage bias was analysed both in the specific case of the Hsp70 genes and in a general species-wide context. The data obtained showed that even the very long aNRFs present in the Hsp70 family could be explained by codon usage bias on the sense strand. Codon usage bias is determined by GC content at the third codon position of the sense ORF and, in some species, by a high expression level of the gene in question. Such an explanation for the occurrence of long aNRFs cannot exclude that some aNRFs are transcribed and translated.

Animals↗
PubMedDate not supplied

p21 gene codon 31 polymorphism is associated with bladder cancer.

The function of p21 is related to cell apoptosis, progression and malignancies. It is thought that p21 is related to cancer formation but is not related to tumor grade. We aimed to investigative the polymorphism of p21 codon 31 as a candidate for the genetic marker of bladder cancer and its progression. The distribution was analyzed in 53 bladder cancer patients, 119 healthy controls in Taiwanese patients. Polymerase chain reaction based restriction analysis was used for the study of the association of p21 codon 31 polymorphism with bladder cancer. There was a significant difference in p21 codon 31 polymorphism between the control and the cancer patients (p < 0.01). The arginine form was prominent in the cancer patient (per copy of the A allele, odds ratio = 2.03, 95% confidence interval = 1.23-3.37). Furthermore, the distribution of this polymorphism was significantly different from non-invasive to invasive bladder cancer (p < 0.05). Serine heterozygote was more prominent in the invasive group with 25 to 1% respectively when compared with the non-invasive group. The polymorphism of p21 codon 31 is associated with bladder cancer. An individual possessing one allele of arginine form in p21 codon 31 has a higher risk of developing bladder cancer than the serine form. Although the mechanism is unclear, our results show p21 gene is associated with tumor grade.

Aged↗
PubMed2001

Incorporation of nonnatural amino acids into proteins by using various four-base codons in an Escherichia coli in vitro translation system.

Incorporation of nonnatural amino acids into proteins is a powerful technique in protein research. Amber suppression has been used to this end, but this strategy does not allow multiple incorporation of nonnatural amino acids into single proteins. In this article, we developed an alternative strategy for nonnatural mutagenesis by using four-base codons. The four-base codons AGGU, CGGU, CCCU, CUCU, CUAU, and GGGU were successfully decoded by the nitrophenylalanyl-tRNA containing the complementary four-base anticodons in an Escherichia coli in vitro translation system. The most efficient four-base decoding was observed for the GGGU codon, which yielded 86% of the full-length protein containing nitrophenylalanine relative to the wild-type protein. Moreover, highly efficient incorporation of two different nonnatural amino acids was achieved by using a set of two four-base codons, CGGG and GGGU. This work shows that the four-base codon strategy is more advantageous than the amber suppression strategy in efficiency and versatility.

Amino Acids↗
PubMed2007

Energetics of codon-anticodon recognition on the small ribosomal subunit.

Recent crystal structures of the small ribosomal subunit have made it possible to examine the detailed energetics of codon recognition on the ribosome by computational methods. The binding of cognate and near-cognate anticodon stem loops to the ribosome decoding center, with mRNA containing the Phe UUU and UUC codons, are analyzed here using explicit solvent molecular dynamics simulations together with the linear interaction energy (LIE) method. The calculated binding free energies are in excellent agreement with experimental binding constants and reproduce the relative effects of mismatches in the first and second codon position versus a mismatch at the wobble position. The simulations further predict that the Leu2 anticodon stem loop is about 10 times more stable than the Ser stem loop in complex with the Phe UUU codon. It is also found that the ribosome significantly enhances the intrinsic stability differences of codon-anticodon complexes in aqueous solution. Structural analysis of the simulations confirms the previously suggested importance of the universally conserved nucleotides A1492, A1493, and G530 in the decoding process.

Anticodon↗
PubMed1998

Rabbit beta-globin is extended beyond its UGA stop codon by multiple suppressions and translational reading gaps.

Translational reading gaps occur when genetic information encoded in mRNA is not translated during the normal course of protein synthesis. This phenomenon has been observed thus far only in prokaryotes and is a mechanism for extending the reading frame by circumventing the normal stop codon. Reading frames of proteins may also be extended by suppression of the stop codon mediated by a suppressor tRNA. The rabbit beta-globin read-through protein, the only known, naturally occurring read-through protein in eukaryotes, was sequenced by ion trap mass spectrometry to determine how the reading frame is extended. Seven different proteolytic peptide fragments decoded by the same sequence that spans the UGA stop codon of rabbit beta-globin mRNA were detected. Three of these peptides contain translational reading gaps of one to three amino acids that correspond to the UGA stop codon site and/or one or two of the immediate downstream codons. To our knowledge, this is the first reported example of the occurrence of reading gaps in protein synthesis in eukaryotes. This event is unique in that it is associated with bypasses involving staggered lengths of untranslated information. Four of the seven peptides contain serine, tryptophan, cysteine, and arginine decoded by UGA and thus arise by suppression. Serine is donated by selenocysteine tRNA, and it, like the other tRNAs, has previously been shown to suppress UGA in vitro in mammals, but not in vivo.

Amino Acid Sequence↗
PubMedDate not supplied

Positional effects on the structure and stability of abbreviated H-ras DNA sequences containing O6-methylguanine residues at codon 12.

Activation of the H-ras protooncogene in rats by methylating carcinogens results from a G-to-A transition mutation at the second position of codon 12 (GGA), presumably due to formation of an O6-methylguanine (m6G) at this position. A similar transition at the first position of codon 12 appears not to occur in vivo. To study the possible structural basis for this bias in mutation, we synthesized a series of 11-base H-ras sequences [e.g., 5'-d(CGCTG*G*AGGCG)-3' and two complementary strands] containing an m6G at the first, second, or both positions of codon 12 (i.e., G* = m6G). The results of solution chemical studies indicated that the individual strands formed stable hairpin structures among which that containing m6G at the second position of codon 12 was most stable. Further, the DNA duplex with m6G at the second position was significantly more stable than that with m6G at the first position, and under certain conditions, it was more stable than the unmodified duplex as well. It is possible that such a difference in stability might lead to more ready recognition of an m6G at the first position by repair proteins, and this could contribute to the apparent site specificity of mutation by methylating carcinogens at codon 12 of the H-ras gene.

Animals↗
PubMed1997

Rare codons are not sufficient to destabilize a reporter gene transcript in tobacco.

In plants, as in other eukaryotes, most synonymous codons of the genetic-code are not used with equal frequency, but instead some codons are preferred, whereas others are rare. Circumstantial evidence led to the suggestion that rare codons have a negative influence on mRNA stability. To address this question experimentally, rare codons encoded by a Bacillus thuringiensis (B.t.) toxin gene (cryIA(c)) or a synthetic sequence were introduced into a phytohemagglutinin (PHA) reporter gene. In neither case was the mRNA stability appreciably diminished in stably transformed tobacco cell cultures nor was the accumulation of mRNA in transgenic plants affected. Thus rare codons do not appear to be sufficient to cause rapid degradation of the PHA mRNA and potentially other mRNAs in plants.

Cell Line↗
PubMed2003

Optimization of codon usage is required for effective genetic immunization against Art v 1, the major allergen of mugwort pollen.

BACKGROUND: As the major allergen of mugwort pollen, Art v 1 is an important target for specific immunotherapy. However, both recombinant protein as well as a gene vaccine for Art v 1 failed to be immunogenic in mice. In order to improve immunogenicity we focused on genetic immunization because interspecific differences of codon usage have been shown as an obstacle for effective induction of immune responses with gene vaccines encoding infectious pathogens. OBJECTIVE: In order to find out, whether codon usage might also be used to improve genetic immunization with allergen genes, the response against a gene vaccine expressing the wild-type gene of Art v 1 (pCMV-wtArt) was compared with a synthetic codon-optimized vector with human codon usage (pCMV-humArt). METHODS: Balb/c mice were injected intradermally with pCMV-wtArt or pCMV-humArt. In vitro expression levels of both constructs were compared in transfection experiments. Total immunoglobulin G (IgG), IgG1, IgG2a and IgE antibodies were analyzed by enzyme-linked immunosorbent assay and the anaphylactic activity of the sera was determined by allergen-specific degranulation of rat basophil leukemia-2H3 cells. RESULTS: No immune response was detectable with the gene vaccine expressing the wildtype Art v 1, but immunization with pCMV-humArt revealed a strong and allergen-specific induction of antibody responses. The antibodies recognized both the recombinant as well as the purified natural (glycosylated) Art v 1 molecule. The response type was Th1-biased, as indicated by high levels of IgG2a antibodies. Expression analysis with B16 mouse melanoma cells transfected with pCMV-humArt or pCMV-wtArt revealed an impaired expression of the wild-type vector but normal translation after recoding. CONCLUSION: The results demonstrate that optimization of codon usage offers a simple way to improve immunogenicity and therefore should be routinely considered in the development of gene vaccines for the treatment of allergy.

Allergens↗
PubMed2003

Strong associations between gene function and codon usage.

The association between codon usage and gene function was analyzed in the complete genomes of Eschericia coli, Bacillus subtilis, Lactococcus lactis and Campylobacter jejuni, using the functional annotation provided by NCBI. Two distinctly different ways of quantifying codon usage were used in the analysis. By using contingency tables it was found that for most amino acids a highly significant association with gene function exists for all species, indicating that codon usage at the level of individual amino acids is generally closely coordinated with gene function. By computing the effective number of codons in the annotated genes and comparing the median values in groups of different gene functions it was shown for all species that codon bias gene by gene also differs.

Amino Acids↗
PubMed2003

Association of the phi nucleotide with codon bias, amino acid usage and expressivity: differences between Bacillus subtilis and Escherichia coli.

By measuring the non-randomness in Shine-Dalgarno regions it was recently shown that the compositional non-randomness peaks approximately 10 nucleotides upstream of the start codons. This position, termed the phi position, was furthermore shown to be associated with certain characteristics of the gene/protein and start codon usage. This raises the question whether codon usage in general is associated with the phi position. In this study, the connection between the phi nucleotide and general codon usage, both gene-wide and at the level of individual amino acids, was studied in Eschericia coli and Bacillus subtilis. E. coli but not B. subtilis shows a strong general association between the phi position and codon usage bias. In both species, the genes with higher expressivity show stronger conservation in the Shine-Dalgarno region compared to the genes with lower expressivity.

Amino Acids↗
PubMed2001

Clinical and hematological features of codon 17, A-T mutation of beta-thalassemia in Thai patients.

Forty-one patients with codon 17, A-T mutation of beta-thalassemia, which is commonly found in Thailand, were studied to determine whether it is possible to predict phenotypic severity from genetic factors. The clinical phenotype of homozygotes for codon 17, A-T and compound heterozygotes for codon 17, A-T and beta+-thalassemia may be used to predict a severe phenotype with TM. However, the clinical phenotype of compound heterozygotes for codon 17, A-T and beta+-thalassemia or Hb E were variable and could not be accurately predicted. The association of alpha-thalassemia2 and milder disease was and was not evident in patients with codon 17, A-T and Hb E. The association between Hb CS gene or the presence of XmnI-Ggamma polymorphism and a mild clinical phenotype is not apparent, indicating the involvement of other ameliorating determinants or genetic modifications.

Age of Onset↗
PubMedDate not supplied

Initiation of translation at internal AUG codons in mammalian cells.

Initiation of translation of eukaryotic mRNAs typically occurs at the first AUG triplet from the 5' end of the message, although several notable exceptions have been described. Using vectors which efficiently express the gene encoding the surface antigen of hepatitis B virus in monkey cells, we have studied the consequences of inserting ATG triplets in all three reading frames upstream of the usual translational initiation codon of this gene. In agreement with the scanning model for eukaryotic translation initiation, these additional codons can severely depress the initiation of translation at the 'authentic' start codon, although the extent of inhibition depends on sequences flanking the upstream AUG. Such inhibition can, however, be at least partially suppressed by the presence of a translation termination codon in-frame with the upstream AUG. These results raise the possibility that mammalian ribosomes can reinitiate translation at an AUG codon after previously initiating, and terminating, at an upstream site.

Animals↗