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PubMed1999

Selection at the wobble position of codons read by the same tRNA in Saccharomyces cerevisiae.

The transfer RNA gene complement of Saccharomyces cerevisiae was utilized for a whole-genome analysis of the deviation from a neutral usage of pyrimidine-ending cognate codons, that is, codons read by a single tRNA species having either inosine or guanosine as the first anticodon base. Mutational pressure at the wobble position was estimated from the base composition of the noncoding portion of the yeast genome. The selective pressure for translational efficiency was inferred from the degree of codon adaptation to tRNA gene redundancy and from mRNA abundance data derived from yeast transcriptome analysis. Amino acid conservation in orthologous comparisons with wholly sequenced microbial genomes was used to estimate translational accuracy requirements. A close correspondence was observed between the usage of wobble position pyrimidines and the frequency predicted by mutational bias. However, in the case of four cognate pairs (Gly: ggu/ggc; Asn: aau/aac; Phe: uuu/uuc; Tyr: uau/ uac) all read by guanosine-starting anticodons, we found evidence for a strong selective pressure driven by translational efficiency. Only for the glycine pair, wobble pyrimidine choice also appears to fulfill a translational accuracy requirement. Wobble pyrimidine selection is strictly related to the number of hydrogen bonds formed by alternative cognate codons: whenever a different number of hydrogen bonds can be formed at the wobble position, there is selection against six- or nine-hydrogen-bonded codon-anticodon pairs. Our results indicate that an intrinsic codon preference, critically dependent on the stability of codon-anticodon interaction and mainly reflecting selection for the optimization of translational efficiency, is built into the translational apparatus.

Codon↗
PubMed1985

Codon usage and tRNA content in unicellular and multicellular organisms.

Choices of synonymous codons in unicellular organisms are here reviewed, and differences in synonymous codon usages between Escherichia coli and the yeast Saccharomyces cerevisiae are attributed to differences in the actual populations of isoaccepting tRNAs. There exists a strong positive correlation between codon usage and tRNA content in both organisms, and the extent of this correlation relates to the protein production levels of individual genes. Codon-choice patterns are believed to have been well conserved during the course of evolution. Examination of silent substitutions and tRNA populations in Enterobacteriaceae revealed that the evolutionary constraint imposed by tRNA content on codon usage decelerated rather than accelerated the silent-substitution rate, at least insofar as pairs of taxonomically related organisms were examined. Codon-choice patterns of multicellular organisms are briefly reviewed, and diversity in G+C percentage at the third position of codons in vertebrate genes--as well as a possible causative factor in the production of this diversity--is discussed.

Animals↗
PubMed1986

Natural selection versus primitive gene structure as determinant of codon usage.

Different codons are not utilized equally in known gene sequences. One of the important biases of codon usage is observed in the form of an enrichment of RNY codons, especially within RNN codon families. Such biases could represent the residue of a primitive repeating-RNY gene structure, or the outcome of natural selection, or both. Analyses based on the rates of silent substitutions, the frequencies of base doublets, and synonymous codon ratios for Escherichia coli, yeast, Drosophila and Xenopus proteins have been performed. The results rule out any significant support for a primitive repeating-RNY or repeating-RRY gene structure, and establish the important role of natural selection in determining the choice of codons. With strong intervention by natural selection, the relationship between primitive gene structure and codon usage necessarily becomes minimal.

Animals↗
PubMed1989

Bacillus subtilis mutant allele sup-3 causes lysine insertion at ochre codons: use of sup-3 in studies of translational attenuation.

The mutation sup-3 in Bacillus subtilis suppresses ochre (TAA) mutations at each of three codons in the 5' end of the cat-86 coding sequence. The suppressor is shown to insert lysine at ochre codons. The efficiency of suppression by sup-3 is about 15%, as determined by changing a cat-86 Lys codon (codon 12) to an ochre codon and measuring the level of CAT in the suppressor-containing strain. The results obtained are discussed in light of previous observations that ochre mutations at cat leader codons 2 and 3 can be phenotypically suppressed by sup-3, whereas ochre mutations at leader codons 4 and 5 cannot. Translation of the cat leader is essential to inducible expression of cat. Our data support the interpretation that the nature of amino acids 2 through 5 of the leader peptide contributes to determining whether chloramphenicol can stall a ribosome in the leader, which in turn leads to induction of cat expression.

Amino Acid Sequence↗
PubMed1989

Translation rates of individual codons are not correlated with tRNA abundances or with frequencies of utilization in Escherichia coli.

We analyzed 12 individual codons, which differed widely with respect to the frequency of use in Escherichia coli and the abundance of the corresponding tRNAs, for their influence on the coupling between transcription and translation. This was probed by determining the effects of codon substitutions in the leader peptide gene on transcription past the pyrE attenuator, as described previously by Bonekamp et al. (F. Bonekamp, H. D. Andersen, T. Christensen, and K. F. Jensen, Nucleic Acids Res. 13:4113-4123, 1985). In principle, the results revealed that either RNA polymerase or the (leading) ribosomes pass the different codon strings at different rates. However, under the assumption that the rate of transcription elongation is unaffected by the sequence changes, the results may be interpreted as indicating that different codons are translated at different rates and that these rates do not generally reflect the concentrations of the corresponding tRNAs or the frequencies with which the codons are used in E. coli. Moreover, it seems that codon synonyms that are served by the same isoaccepting tRNA species can deviate as much from each other in translational behavior as synonymous codons that are served by isoacceptors present in the cell in widely different amounts can.

Base Sequence↗
PubMed1990

tRNA(Trp) translation of leader peptide codon 12 and other factors that regulate expression of the tryptophanase operon.

Tryptophanase (tna) operon expression in Escherichia coli is induced by tryptophan. This response is mediated by features of a 319-base-pair leader region preceding the major structural genes of the operon. Translation of the coding region (tnaC) for a 24-amino-acid leader peptide is essential for induction. We have used site-directed mutagenesis to investigate the role of the single Trp codon, at position 12 in tnaC, in regulation of the operon. Codon 12 was changed to either a UAG or UGA stop codon or to a CGG arginine codon. Induction by tryptophan was eliminated by any of these changes. Studies with suppressor tRNAs indicated that tRNA(Trp) translation of codon 12 in tnaC is essential for induction of the operon. Reduction of tna expression by a miaA mutation supports a role for translation by tRNA(Trp) in regulation of the operon. Frameshift mutations and suppression that allows translation of tnaC to proceed beyond the normal stop codon result in constitutive tna operon expression. Deletion of a potential site for Rho factor utilization just beyond tnaC also results in partial constitutive expression. These studies suggest possible models for tryptophan induction of tna operon expression involving tRNA(Trp)-mediated frame shifting or readthrough at the tnaC stop codon.

Chromosome Deletion↗
PubMed1999

Translation initiation at the CUU codon is mediated by the internal ribosome entry site of an insect picorna-like virus in vitro.

AUG-unrelated translation initiation was found in an insect picorna-like virus, Plautia stali intestine virus (PSIV). The positive-strand RNA genome of the virus contains two nonoverlapping open reading frames (ORFs). The capsid protein gene is located in the 3'-proximal ORF and lacks an AUG initiation codon. We examined the translation mechanism and the initiation codon of the capsid protein gene by using various dicistronic and monocistronic RNAs in vitro. The capsid protein gene was translated cap independently in the presence of the upstream cistron, indicating that the gene is translated by internal ribosome entry. Deletion analysis showed that the internal ribosome entry site (IRES) consisted of approximately 250 bases and that its 3' boundary extended slightly into the capsid-coding region. The initiation codon for the IRES-mediated translation was identified as the CUU codon, which is located just upstream of the 5' terminus of the capsid-coding region by site-directed mutagenesis. In vitro translation assays of monocistronic RNAs lacking the 5' part of the IRES showed that this CUU codon was not recognized by scanning ribosomes. This suggests that the PSIV IRES can effectively direct translation initiation without stable codon-anticodon pairing between the initiation codon and the initiator methionyl-tRNA.

Amino Acid Sequence↗
PubMed2000

Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population.

Constitutively activating mutations of the human TSH receptor (hTSHR) gene have been implicated as a major cause of hyperfunctioning nonautoimmune thyroid disease. However, significant geographic differences in the prevalence of these mutations have been observed. Recently, a high frequency of a germline polymorphism at codon 727 of the cytoplasmic tail of the hTSHR has been demonstrated in patients with toxic multinodular goiter. In the present study we assessed whether the codon 727 polymorphism is associated with hyperfunctioning thyroid adenomas. PCR followed by restriction enzyme digestion were used to genotype a total of 128 European Caucasian patients with toxic nonautoimmune thyroid disease (83 with toxic adenoma, 31 with toxic multinodular goiter, and 14 with disseminated autonomy) and to compare their codon 727 polymorphism frequencies with those of 99 healthy controls and 108 patients with Graves' disease. All individuals were drawn from an identical ethnic background. Sequencing of PCR products was used to confirm the mutation analysis. We found no significant differences in codon 727 polymorphism frequencies between patients with autonomously functioning thyroid disorders (13.3%) and the healthy control group (16.2%; P = 0.57). Moreover, the subtypes of toxic nonautoimmune thyroid disease (toxic adenoma, 13.2%; multinodular goiter, 9.6%; disseminated autonomy, 21.4%) were not related to significant differences in codon 727 polymorphism frequencies compared with the healthy control group (P = 0.67, P = 0.40, and P = 0.70, respectively). Additionally, there were no significant differences between patients with Graves' disease (21.3%) and healthy controls (P = 0.38). In conclusion, our data do not support an association between the codon 727 polymorphism of the hTSHR and toxic thyroid adenomas or toxic multinodular goiter in our study population. Thus, the codon 727 polymorphism of the hTSHR does not appear to be involved in the evolution of autoimmune or nonautoimmune hyperthyroidism in the European Caucasian population.

Adenoma↗
PubMed1997

[Clinical significance of p21H-ras expression and H-ras codon 12 mutation in squamous intraepithelial lesion (SIL) and carcinoma of uterine cervix].

OBJECTIVE: To study the clinical significance of p21 H-ras expression and H-ras codon 12 mutation in SIL and cervical carcinoma. METHODS: p21 H-ras expression and H-ras codon 12 mutation was detected in the same paraffin embedded tissues of 171 cases of cervical carcinoma, 68 cases of SIL, and 29 cases of chronic cervicitis, by using immunohistochemical and PCR-RFLP techniques. RESULTS: (1)p21 H-ras was over-expressed in 25.0% of the cases with low-grade SIL but in most of them the immunohistochemical staining was not strong (score < 3). p21 H-ras over-expression was present in 64. 6% of the cases with high-grade SIL and in 35.4% of them, the staining was strong (score = 3). Even higher frequency of p21 H-ras over-expression was seen in cases with cervical carcinoma (66.1%) and in about one-half (49.7%) the staining was strong. (2) H-ras codon 12 mutation was only detected in stages II and III cervical carcinoma, with frequency rate of 27.0% and 52.5% respectively. The five-year survival rate of patients with H-ras codon 12 mutation (20.3%) was significantly lower than that without mutation (79.7%). Besides, there was a correlation between lymph node metastasis and H-ras codon 12 mutation. CONCLUSION: p21 H-ras expression is helpful for early detection of cervical carcinoma. Aggressive biological behavior of cervical carcinoma is significantly increased once the H-ras codon 12 mutation occurs. H-ras codon 12 mutation is helpful to judge prognosis of cervical carcinoma.

Aged↗
PubMed2001

Novel technique for scanning of codon 634 of the RET protooncogene with fluorescence resonance energy transfer and real-time PCR in patients with medullary thyroid carcinoma.

BACKGROUND: The multiple endocrine neoplasia 2 (MEN 2) syndromes [MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC)] are caused by germline mutations of the RET protooncogene. Because 85% of MEN 2A patients and 30% of FMTC patients have mutations at codon 634, the recommended molecular analyses begin at exon 11, where codon 634 is located. METHODS: We scanned codon 634 of the RET protooncogene with real-time PCR and fluorescence resonance energy transfer (FRET), using a unique pair of internal probes to detect mutations localized at codon 634. We compared results with sequencing results in 66 patients. RESULTS: The method detected all codon 634 mutations available in our laboratory (Cys634Tyr, Cys634Arg, Cys634Phe, Cys634Trp). Comparing this method with the direct sequencing of exon 11 in a cohort of 66 patients with MTC, the system identified all 14 MTC patients carrying germline mutations at codon 634. One apparent false-positive result occurred among 52 patients. CONCLUSIONS: The simultaneous scanning of multiple mutations is possible with the FRET system. The method allows rapid characterization of germline mutations at codon 634 in MTC patients.

Carcinoma, Medullary↗
PubMed1990

[Rare initiation codons are regulators of expression of the rpoC gene].

Translation of the rpoC genes in Escherichia coli and Salmonella typhimurium is known to start from the GUG codon. Now, using toeprint analysis we have shown UUG to be the initiation codon of the Pseudomonas putida rpoC gene. IF3 does not seem to proofread initiation at the UUG codon. The rpoC genes of P. putida, E. coli, and S. typhimurium, which use rare start codons, have strong SD-domains AGGAGG (P. p.) and GGGAG (E. c., S. t.), optimal seven-nucleotide spacing between SD and start codons, and good second codon AAA. We suggest that rpoC presents an infrequent case of the regulation of translation initiation by selecting the start codon.

Base Sequence↗
PubMedDate not supplied

[Analysis of the primary structure of mRNA from Escherichia coli: occurrence of nucleotides on the 3'-side of the codon].

The occurrence of nucleotides of the 3' side of codons has been determined in highly and weakly expressed genes from Escherichia coli. It was found that the usage of some amino acid codons in highly expressed genes was site specific, depending on the base 3' to the codon. The role of the 3' nucleotide as a modulator of codon translation effectiveness is discussed. The rules of synonymous codon usage in relation to the 3' flanking nucleotide have been established for highly expressed genes. For example, if a triplet next to the lysine codon starts with guanosine, lysine is preferably encoded by AAA and not by AAG (P less than 10(-8), while of cytidine is 3' to the lysine codon, AAG is preferred over AAA (P less than 0.001). These rules are observed in highly and absent in weakly expressed mRNAs and can be used in the chemical synthesis of genes designed for expression in E. coli.

Base Sequence↗
PubMed1989

Point mutations in both transforming and non-transforming codons of the N-ras proto-oncogene of Ph+ leukemias.

The distribution and frequency of point mutations in the first and second coding exons of the N-ras proto-oncogene was examined in 6 cases of Philadelphia positive (Ph+) hemopoietic malignancies. To increase the detection sensitivity of the mutations and to estimate more accurately the frequency of abnormal alleles in the hemopoietic cell population, a polymerase chain reaction (PCR)/shotgun cloning/double stranded DNA sequencing method was used. Mutations activating the ras oncogenes involving codon 61 were observed in 5 out of 6 cases; in one of these cases (CML3), mutation at codon 61 involved a two base transition. Mutations involving codon 59 were also observed in one case (CML1). In longitudinal studies of 3 cases of chronic myelogenous leukemia samples obtained at the time of initial diagnosis and 5 to 7 years later, a multiplicity of mutations were detected at the time of initial diagnosis prior to any therapy. In one case (CML3), a mutation in codon 61 detected at diagnosis was still present 5 years later, in a second case (CML1) a mutation in codon 61 appeared during the course of the disease and persisted for at least one year, and in the third case (CML2) a mutation in codon 61 was present at diagnosis but absent 5 years later. In one instance (CML1) a mutation in codon 59 was present at the time of initial diagnosis but was not detectable in later samples. Several other point mutations leading to aminoacid changes were scattered predominately through the second exon but were not consistently detected in longitudinal studies on cells from the same patient. The data suggest that there is considerable genetic instability in the 2nd exon of N-ras in the myeloid leukemias but in every case a small subset of cells contains the mutations and these cells do not have a proliferative advantage.

Adult↗
PubMed1988

12th codon mutation resulting in c-N-ras activation in acute myelogenous leukemia.

Activation of the cellular oncogene c-N-ras has been frequently observed in DNA from leukemic cells in acute myeloid leukemia (AML). Ras gene activation sufficient to mediate in vitro transformation and rodent tumorigenesis usually results from point mutations and amino acid substitutions in the 12th or 61st codons. In AML and the related myelodysplastic syndromes, amino acid substitution at the 13th codon has been observed. An activated c-N-ras gene from a 45-year-old patient with AML was isolated by transfection analysis and subjected to molecular cloning and sequence analysis. A point mutation of the 12th codon (GGT to GAT) resulting in aspartic acid substitution for glycine was observed. In other neoplasms such as colon cancer, specific ras mutations occur predominantly (e.g., K-ras, codon 12). This predominance has been of demonstrable value in analyzing large cohorts for ras activation with techniques that are rapid and economical, such as oligonucleotide hybridization. It had previously been thought that such a predominance for activation of c-N-ras at codon 13 existed in AML; however, this study in concert with others underscores the importance of 12th codon c-N-ras mutations, along with 13th and 61st codon mutations in the molecular pathogenesis of AML. Guanylate to adenylate transition mutations are commonly observed in AML and may provide insight into potential environmental leukemogens. Addressing all commonly prevalent ras activating mutations bears impact in the future design of molecular surveys of the role of ras activation in leukemogenesis.

Amino Acid Sequence↗
PubMedDate not supplied

[Sense codon in Escherichia coli are translated in context].

The nucleotide frequencies 5' and 3' to the sense codons in highly and weakly expressed genes have been investigated by the chi-squares method. A comparison between the experimental and computer-generated random nucleotide sequences (in which each codon is substituted by a random synonymous one) was made. It was shown that the choice of a particular codon among the synonymous ones in a given position of the gene depends on the three nucleotides 3' and 5' adjacent to the codon in highly expressed genes (the triplet 3' and a single nucleotide 5' to the codons in weakly expressed genes). Concrete patterns for the preferable choice of synonymous codons depending on their contexts are presented. It is suggested that these constraints are related to the efficiency of messenger translation. The constraints on the amino acid sequences of encoded proteins also lead to statistically significant bases in nucleotide frequencies around the sense codons. The biological role of these constraints is discussed.

Base Sequence↗
PubMed1983

Recognition of termination codon by release factor in the presence of a tRNA-occupied A site. Evidence for flexibility in accommodation of the release factor on the ribosome.

Recognition of the termination codon by release factor was studied with 70 S ribosomes containing initiator tRNA at the P site and an amino acid-specifying codon as well as the corresponding cognate tRNA at the A site. In vitro termination was not excluded when either the A site was occupied with an amino acid-specifying codon or the termination codon was displaced from the A site codon position by spacer nucleotides between UAA and the P site bound AUG. The release factor may have flexibility in its codon recognizing domain to be able to adjust to this enforced change in the position of the termination codon on the ribosome without loss of functional specificity. Deacylated tRNA bound at the A site of 70 S ribosomes did not interfere with stoichiometric UAA-directed release factor binding to these particles. In contrast, a ternary complex (aminoacyl-tRNA elongation factor-Tu . GTP) abolished the binding of the release factor while aminoacyl-tRNA inhibited it only weakly. This suggests that release factor and elongation factor-Tu have overlapping binding sites but the A site binding domains of the release factor and tRNA are exclusive.

Codon↗
PubMed1983

Unconventional reading of the glycine codons.

We have used a protein-synthesizing in vitro system programmed with the phage message MS2-RNA to investigate the ability of glycyl-tRNAs with different anticodons to read the glycine codons. Under conditions of no competition, when the glycyl-tRNA analyzed was the only source of glycine for protein synthesis, each of the isoacceptors tested, tRNA1Gly (anticodon CCC), tRNA2Gly (anticodon N/UCC), tRNA3Gly (anticodon GCC) from Escherichia coli, and tRNAGly (anticodon UCC) from Mycoplasma mycoides, could read all of the glycine codons in the MS2 coat protein cistron (GGU, GGC, GGA, and GGG). However, tRNA1Gly seemed to have difficulties reading through the whole cistron. Experiments in which two glycyl-tRNAs competed for the same codon showed that the mycoplasma tRNAGly (anticodon UCC) was almost as efficient in the unorthodox reading of the codons GGU and GGC as it was in conventional reading. It would seem to be the only tRNAGly present in Mycoplasma mycoides and our results are consistent with this finding since the mycoplasma tRNAGly appears to have been designed to read all four glycine codons with approximately equal efficiency. The competition experiments furthermore showed that E. coli tRNA1Gly (anticodon CCC) reads the codon GGA more efficiently than it reads GGU and GGC suggesting that the mispair C . A between the wobble position of the anticodon and the third codon position might have appreciable stability.

Amino Acid Sequence↗
PubMed1994

Oxy-radical induced mutagenesis of hotspot codons 248 and 249 of the human p53 gene.

Oxidants are suspected to represent important human carcinogens. They are mutagenic and may participate in the activation of proto-oncogenes and the inactivation of tumor suppressor genes. We have studied the capacity of hydrogen peroxide plus ferric chloride (FeCl3) to induce base pair changes in the hotspot codons 248 and 249 of the p53 tumor suppressor gene in human fibroblasts. In codon 248 (CGG) H2O2/FeCl3 only induced the transversion of G to C in the second position and the transition of G to A in the third position. No evidence was obtained for spontaneous or oxidant-induced deamination of 5-methylcytosine in the CpG dinucleotide of codon 248 since neither C to T transitions in the first position nor G to A transitions in the middle position were observed. H2O2/FeCl3 efficiently induced G to T transversions at both G-residues of codon 249 (AGG) and C to A transversions at the first position of codon 250 (CCC). It is evident that H2O2/FeCl3 possesses essentially the same mutagenic specificity for codons 249 and 250 of p53 as bulky carcinogens such as aflatoxin B1, benzo(a)pyrene or heterocyclic amines. In particular, it is not possible to eliminate oxidants from the list of candidate carcinogens which may be responsible for the high incidence of p53 codon 249 AGT mutations in hepatocellular carcinoma from certain areas of the world.

Cells, Cultured↗