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PubMed2005

Are stop codons recognized by base triplets in the large ribosomal RNA subunit?

The precise mechanism of stop codon recognition in translation termination is still unclear. A previously published study by Ivanov and colleagues proposed a new model for stop codon recognition in which 3-nucleotide Ter-anticodons within the loops of hairpin helices 69 (domain IV) and 89 (domain V) in large ribosomal subunit (LSU) rRNA recognize stop codons to terminate protein translation in eubacteria and certain organelles. We evaluated this model by extensive bioinformatic analysis of stop codons and their putative corresponding Ter-anticodons across a much wider range of species, and found many cases for which it cannot explain the stop codon usage without requiring the involvement of one or more of the eight possible noncomplementary base pairs. Involvement of such base pairs may not be structurally or thermodynamically damaging to the model. However, if, according to the model, Ter-anticodon interaction with stop codons occurs within the ribosomal A-site, the structural stringency which that site imposes on sense codon.tRNA anticodon interaction should also extend to stop codon.Ter-anticodon interactions. Moreover, with Ter-tRNA in place of an aminoacyl-tRNA, for each of the various Ter-anticodons there is a sense codon that can interact with it preferentially by complementary and wobble base-pairing. Both these considerations considerably weaken the arguments put forth previously.

Base Pairing↗

PubMed2003

In vitro selection for sense codon suppression.

The universal genetic code links the 20 naturally occurring amino acids to the 61 sense codons. Previously, the UAG amber stop codon (a nonsense codon) has been used as a blank in the code to insert natural and unnatural amino acids via nonsense suppression. We have developed a selection methodology to investigate whether the unnatural amino acid biocytin could be incorporated into an mRNA display library at sense codons. In these experiments we probed a single randomized NNN codon with a library of 16 orthogonal, biocytin-acylated tRNAs. In vitro selection for efficient incorporation of the unnatural amino acid resulted in templates containing the GUA codon at the randomized position. This sense suppression occurs via Watson-Crick pairing with similar efficiency to UAG-mediated nonsense suppression. These experiments suggest that sense codon suppression is a viable means to expand the chemical and functional diversity of the genetic code.

Amino Acid Sequence↗

PubMed2004

The modified wobble nucleoside uridine-5-oxyacetic acid in tRNAPro(cmo5UGG) promotes reading of all four proline codons in vivo.

In Salmonella enterica serovar Typhimurium five of the eight family codon boxes are decoded by a tRNA having the modified nucleoside uridine-5-oxyacetic acid (cmo5U) as a wobble nucleoside present in position 34 of the tRNA. In the proline family codon box, one (tRNAProcmo5UGG) of the three tRNAs that reads the four proline codons has cmo5U34. According to theoretical predictions and several results obtained in vitro, cmo5U34 should base pair with A, G, and U in the third position of the codon but not with C. To analyze the function of cmo5U34 in tRNAProcmo5UGG in vivo, we first identified two genes (cmoA and cmoB) involved in the synthesis of cmo5U34. The null mutation cmoB2 results in tRNA having 5-hydroxyuridine (ho5U34) instead of cmo5U34, whereas the null mutation cmoA1 results in the accumulation of 5-methoxyuridine (mo5U34) and ho5U34 in tRNA. The results suggest that the synthesis of cmo5U34 occurs as follows: U34 -->(?) ho5U -->(CmoB) mo5U -->(CmoA?) cmo5U. We introduced the cmoA1 or the cmoB2 null mutations into a strain that only had tRNAProcmo5UGG and thus lacked the other two proline-specific tRNAs normally present in the cell. From analysis of growth rates of various strains and of the frequency of +1 frameshifting at a CCC-U site we conclude: (1) unexpectedly, tRNAProcmo5UGG is able to read all four proline codons; (2) the presence of ho5U34 instead of cmo5U34 in this tRNA reduces the efficiency with which it reads all four codons; and (3) the fully modified nucleoside is especially important for reading proline codons ending with U or C.

Amino Acid Sequence↗

PubMed2003

Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis.

OBJECTIVES: The aim of this study was first to investigate whether early total thyroidectomy (ETT; 1-5 years of age) can prevent medullary thyroid carcinoma with persistent or recurrent disease (PRD) in pediatric patients with multiple endocrine neoplasia type 2A (MEN-2A) and second, to evaluate the strength of codon analysis in children with MEN-2A as prognostic parameter. METHODS: Case reports and review of the literature for pediatric patients with MEN-2A were conducted. Inclusion criteria were age (0-20 years) and histologic degree of C-cell disease (normal = N, C-cell hyperplasia = CCH, medullary thyroid carcinoma = MTC, metastatic MTC = MMTC). To evaluate therapeutic results of ETT (1-5 years) versus late total thyroidectomy (LTT; 6-20 years), age-dependent histologic stages of C-cell disease and postoperative occurrence of PRD were compared. Prognostic value of specific codons, age-dependent histologic distribution, and long-term outcome were analyzed. RESULTS: In a total of 260 cases, 42 (16%) underwent ETT, and 218 (84%) underwent LTT. Histologic analysis showed significant difference between ETT versus LTT (57% vs 76%) regarding malignant stage of C-cell disease (of combined rate of MTC and MMTC). Long-term outcome was documented in 74 patients (28%). During a median follow-up period of 2 years (range: 0-15 years), 21 of 65 of the LTT group versus 0 of 9 of the ETT group suffered PRD. Information about codon analysis was available in 150 patients (58%). Mutated codons were c634 (63%), c618 (19%), c620 (9%), and c804 (6%). Codon-related histologic analysis resulted in prognostic differences: 81% of patients with c634-mutation had MCT or MMTC in contrast to c804 (44%), c618 (34%), and c620 (7%). Fifteen of 17 MMTC and 7 of 9 PRD occurred in patients with c634-mutation. CONCLUSIONS: 1) ETT until 5 years of age in MEN-2A gene carriers results in significant reduction of MTC and MMTC in favor of CCH and improved disease-free long-term outcome. 2) Codon analysis is an important prognostic factor. Timing of TT could be individualized based on codon-specific prognosis. Until more detailed knowledge is available, consequent genetic and biochemical screening is mandatory for appropriate individual timing of ETT before age of 5 years.

Adolescent↗

PubMedDate not supplied

Detection of codon 61 point mutations of the K-ras gene in lung and colorectal cancers by enriched PCR.

Mutation of the Kirsten ras (K-ras) gene is one of most common alterations in solid tumors including lung and colorectal cancers. We developed new enriched PCR-RFLP assay to detect mutations of K-ras codon 61 at the 1st and 2nd letters and non-enriched PCR-RFLP assay to detect the 3rd letter mutation. One mutant allele among 10(3) wild-type alleles was detected by enriched PCR-RFLP assay, while one mutant in 10 wild-type alleles was detected by non-enriched PCR-RFLP assay for codon 61 3rd letter. We then examined K-ras codon 12, 13 and 61 mutations in lung and colorectal cancers using these assays. K-ras codon 12 mutation was detected in 10 of 109 (9%) lung cancer and 19 of 83 (23%) colorectal cancer cases. K-ras codon 13 mutation was detected in 2 of 83 (2%) colorectal and 0 of 109 NSCLC cases, respectively. There was no K-ras codon 61 mutation in either type of cancer. Our results demonstrate that enriched PCR-RFLP is a sensitive assay to detect K-ras codon 61 mutation, however, it was extremely rare in lung and colorectal cancers, suggesting organ-specific pathways in mutagenesis of the ras gene family.

Aged↗

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↗

PubMed2002

5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites.

We evaluated polymorphisms in methylenetetrahydrofolate reductase (MTHFR), folate intake and alcohol consumption in relation to risk of colon cancer in a population-based case-control study in North Carolina. The study included 555 cases (244 African Americans and 311 whites) and 875 controls (331 African Americans and 544 whites). Total folate intake of <400 versus > or =400 microg/day showed a weak positive association with colon cancer among both African Americans [adjusted odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.0-2.0] and whites (OR = 1.6, 95% CI = 1.2-2.2). No association was observed with use of alcohol. Compared with wild-type genotypes, there was no association between the low activity MTHFR codon 677 TT genotype and colon cancer, but the low activity codon 1298 CC genotype was inversely associated with colon cancer in whites (OR = 0.5, 95% CI = 0.3-0.9). Unlike previous studies, we did not observe a strong protective effect of the codon 677 TT low-activity genotype when folate intake was high. Instead, we observed an increased risk of colon cancer when folate intake was low for participants with wild- type genotypes. Adjusted ORs for the combined effects of codon 677 CC and codon 1298 AA genotypes and folate intake <400 microg/day were 1.9 (95% CI = 1.1-3.4) in African Americans and 2.5 (95% CI = 1.2-5.2) in whites. Our results suggest that variation at MTHFR codon 1298 (within the COOH-terminal region) may be more important for colon cancer than variation at codon 677 (NH(2)-terminal region), and in populations where folate intake is low, wild-type MTHFR activity may increase risk for colon cancer.

Adult↗

PubMed2003

Genotyping of p53 codon 175 in colorectal cancer.

BACKGROUND: The gene encoding the tumor suppressor protein p53 is one of the most frequently mutated in human cancer. Over 8000 mutations of this gene have been identified. The spectrum of p53 mutations varies among tumor types. More than half of these mutations appear in three hotspot codons: 175, 248 and 273. The purpose of the present study was to evaluate the GgA transition in codon 175 of the p53 gene as a potential marker of colon cancer progression. MATERIAL/METHODS: The prognostic significance of alterations in codon 175 exon 5 of p53 gene was studied in 32 patients with colorectal cancer. The ASA-PCR method was used to assess GgA (ArggHis) transition in codon 175. RESULTS: The analyzed point mutation was identified in 56% of the tested cases of colorectal cancer. The frequency of codon 175 p53 gene mutation was found to increase with cancer aggressiveness. Screening for the studied point mutation in codon 175 showed no alteration in analyzed samples classified as Dukes' A stage, while variations were observed in 43%, 50% and 75% of the cases classified as Dukes' B, C, and D, respectively. In three cases the studied mutation was also found in some mucosal cells obtained from resectional borders. CONCLUSIONS: The GgA transition in codon 175 of the p53 gene may be useful as a potential marker of colorectal cancer progression and as a means of evaluating the margins of surgical resection.

Adult↗

PubMed2004

[Analysis of codon usage in potato and its application in the modification of t-PA gene].

Bioperl-1.0 was used under Hongqi LINUX system to program the codon analysis software. According to the analysis of 98 codon DNA sequences with this software, the codon usage in potato was calculated and 4 codons have been inferred to the optimal codons. The codons of tissue plasminogen activator (t-PA) gene sequence have been reconstructed according to the results. The t-PA gene sequence containing the optimal codons of potato will be used for t-PA production by potato bioreactor.

Amino Acid Sequence↗

PubMed2003

[Codon optimization and expression in Pichia pastoris of E2 gene of classical swine fever virus].

Codon bias was one of the important parameter which influence heterogenous gene expression, optimizing codon sequence could improve expression level of heterogenous gene. In the preview study, wildtype E2 gene was expressed poorly in Pichia pastoris, in order to improve the expression level of E2 gene in Pichia pastoris, the low usage codons of E2 gene were mutated into high usage codons in Pichia pastoris by directed-mutagenesis based on PCR. The result showed that, compared with the results reported in preview study, the expression level of E2 gene in Pichia pastoris was improved observably by substituting 24 low usage codons of E2 gene for the high usage synonymous codons. It suggested the stragety to improve the expression of E2 gene in Pichia pastoris by codon optimization was successful.

Base Sequence↗

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↗