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PubMed2002

Cloning and complete sequence of a novel HLA-A null allele, A*0253 N, with a termination codon generated by a C to G mutation in exon 2.

A novel HLA-A null allele, A*0253 N, has been identified in two generations of a Chinese family using combined serological and molecular cloning approaches. Full-length genomic DNA sequencing indicated that this new allele differs from HLA-A*02011 by a single C to G substitution at nucleotide position 324 in exon 2. This mutation results in an amino acid change from a tyrosine codon to a stop codon at position 108. A PCR-SSP based method was developed to distinguish A*0253 N from A*02 alleles. No further individuals of A*0253 N were found in 718 Chinese blood donors who carry the HLA-A*02 allele1.

Alleles↗
PubMed2002

The beta-globin C-->G mutation at 6 bp 3' to the termination codon causes beta-thalassaemia by decreasing the mRNA level.

We have studied the expression of the silent beta-thalassaemia term+6 (C-->G) mutation, at nucleotide 6 after the stop codon within the human beta-globin 3' untranslated regions (3'UTR), by stable transfection in murine erythroleukaemia (MEL) cells. Steady state mRNA levels from transfected MEL cells containing the term+6 mutant allele were reduced by 52-60%, compared with those obtained from the normal beta-globin gene, in both total and cytoplasmic RNA fractions, showing that the mutation itself is responsible for the similar data obtained from patients. Upon analysis of nuclear RNA, the term+6 mutation was found to also lower the ratio of cleaved/uncleaved transcripts by 22-30%, thus revealing that it interferes with correct 3'-end formation of beta-globin mRNA. The term+6 mutation lies within a polypyrimidine track, similar to that in the beta-intervening sequence II (beta-IVSII), which is known to be an important contributor to the promotion of premRNA 3'-end formation. We propose that the two polypyrimidine tracks flanking the translated region of exon III of the human beta-globin gene may co-operate during beta-globin mRNA biogenesis.

Child↗
PubMed2000

Premature termination codons destabilize ferredoxin-1 mRNA when ferredoxin-1 is translated.

Ferredoxin-1 (Fed-1) mRNA is poorly translated in dark-treated tobacco (Nicotiana tabacum) leaves, resulting in destabilization of Fed-1 mRNA and a differential light/dark accumulation of the mRNA. Insertion of nonsense codons within the Fed-1 coding sequence disrupts the light regulation of Fed-1 mRNA abundance. Here we show that the nonsense codon effect results primarily from lowering the Fed-1 mRNA stability in light-treated leaf tissue and in rapidly growing tobacco cell cultures, but not in dark-treated leaf tissue. These results suggest that nonsense codons trigger a decay pathway distinct from that seen for Fed-1 mRNA in the dark. We propose that nonsense-mediated decay of nonsense-containing Fed-1 mRNA occurs in light-treated leaves and in non-photosynthetic tobacco culture cells where Fed-1 mRNA is being actively translated.

Cells, Cultured↗
PubMed1995

Identification and characterization of genes that are required for the accelerated degradation of mRNAs containing a premature translational termination codon.

In both prokaryotes and eukaryotes nonsense mutations in a gene can enhance the decay rate of the mRNA transcribed from the gene, a phenomenon described as nonsense-mediated mRNA decay. In yeast, the products of the UPF1 and UPF3 genes are required for this decay pathway, and in this report we focus on the identification and characterization of additional factors required for rapid decay of nonsense-containing mRNAs. We present evidence that the product of the UPF2 gene is a new factor involved in this decay pathway. Mutation of the UPF2 gene or deletion of it from the chromosome resulted in stabilization of nonsense-containing mRNAs, whereas the decay of wild-type transcripts was not affected. The UPF2 gene was isolated, and its transcript was characterized. Our results demonstrate that the UPF2 gene encodes a putative 126.7-kD protein with an acidic region at its carboxyl terminus (-D-E)n found in many nucleolar and transcriptional activator proteins. The UPF2 transcript is 3600 nucleotides in length and contains an intron near its 5' end. The UPF2 gene is dispensable for vegetative growth, but upf2 delta strains were found to be more sensitive to the translational elongation inhibitor cycloheximide than UPF2+. A genetic analysis of other alleles proposed to be involved in nonsense-mediated mRNA decay revealed that the UPF2 gene is allelic to the previously identified sua1 allele, a suppressor of an out-of-frame ATG insertion shown previously to reduce translational initiation from the normal ATG of the CYC1 gene. In addition, we demonstrate that another suppressor of this cyc1 mutation, sua6, is allelic to upf3, a previously identified lesion involved in nonsense-mediated mRNA decay.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Transition C2718T in the AR gene, resulting in generation of a termination codon and truncated form of the androgen receptor, causes complete androgen insensitivity syndrome.

The action of testosterone and 5 alpha-dihydrotestosterone are essential to the development of the male phenotype. Patients with karyotype 46,XY, resistant to these hormones, exhibit a wide spectrum of phenotypes: from phenotypic female, through a range of incomplete masculinization, to under-virilized, infertile man. These disturbances are caused by mutations in the androgen receptor gene (AR). We studied a 46,XY fenotypic female with typical symptoms of Complete Androgen Insensitivity Syndrome (CAIS). Multiple temperature single-stranded conformation polymorphism (MSSCP) and sequence analysis of exon 6 of the AR gene in a patient revealed a C2718T transition causing R786X mutation in the loop between helices VII and VIII of the LBD of the androgen receptor. The R786X mutation has been described in a patient with CAIS only once and no such mutations have been described in Eastern Europe.

Androgens↗
PubMedDate not supplied

[Arrangement of the sense and terminating codons of the template in the A-segment of human ribosomes from photocrosslinking data withe oligonucleotide derivatives].

Oligoribonucleotide derivatives containing Phe codon UUC along with a 3'-flanking sense codon or stop codon carrying a perfluoroarylazido group at G or U were used to study the position of each nucleotide of the latter codon relative to the 18S rRNA in the A site of the 80S ribosome. To place the modified sense or stop codon in the A site, UCC-recognizing tRNA(Phe) was bound in the P site. Regardless of the position in the sense or stop codon, the modified nucleotide crosslinked with invariant dinucleotide A1823/A1824 or nucleotide A1825 in helix 44 close to the 3' end of the 18S rRNA. Located in the second or third position of either codon, the modified G bound with invariant nucleotide G626, which is in the evolutionarily conserved 530 stem-loop segment. The results were collated with the X-ray structure of the bacterial ribosome, and the template codon was assumed to be similarly arranged relative to the small-subunit rRNA in various organisms.

Base Sequence↗
PubMed2005

Translational readthrough of a termination codon in the yeast mitochondrial mRNA VAR1 as a result of mutation in the release factor mRF1.

Yeast mitochondrial DNA codes for eight major polypeptides. Translation of he mitochondrially encoded polypeptides in strains with mutated mitochondrial release factor, mRF1, was found to result in the synthesis of a novel protein, V2. Different mrf1 alleles were associated with different efficiency of V2p synthesis. Translation of V2p was enhanced by paromomycin. Comparative analysis of peptides resulting from protease digestion indicated that V2p is a derivative of Var1p. According to our hypothesis, V2p represents a readthrough product of the natural stop codon in VAR1 mRNA.

Codon, Terminator↗
PubMed2004

Efficient downregulation of immunoglobulin mu mRNA with premature translation-termination codons requires the 5'-half of the VDJ exon.

Premature translation-termination codons (PTCs) elicit rapid degradation of the mRNA by a process called nonsense-mediated mRNA decay (NMD). NMD appears to be significantly more efficient for mRNAs of genes belonging to the immunoglobulin superfamily, which frequently acquire PTCs during VDJ rearrangment, than for mRNAs of other genes. To identify determinants for efficient NMD, we developed a minigene system derived from a mouse immunoglobulin micro gene (Ig-micro) and measured the effect of PTCs at different positions on the mRNA level. This revealed that PTCs located downstream of the V-D junction in the VDJ exon of Ig-micro minigenes and of endogenous Ig-micro genes elicit very strong mRNA downregulation, whereas NMD efficiency decreases gradually further upstream in the V segment where a PTC was inserted. Interestingly, two PTCs are in positions where they usually do not trigger NMD (<50 nt from the 3'-most 5' splice site) still resulted in reduced mRNA levels. Using a set of hybrid constructs comprised of Ig-micro and an inefficient substrate for NMD, we identified a 177 nt long element in the V segment that is necessary for efficient downregulation of PTC-containing hybrid transcripts. Moreover, deletion of this NMD-promoting element from the Ig-micro minigene results in loss of strong NMD.

Animals↗
PubMed1990

Initiation of protein synthesis from a termination codon.

We show that the amber termination codon UAG can initiate protein synthesis in Escherichia coli. We mutated the initiation codon AUG of the chloramphenicol acetyltransferase (CAT) gene to UAG (CATam1) and translated mRNA derived from the mutant CAT gene in E. coli S-30 extracts. A full-length CAT polypeptide was synthesized in the presence of tRNA(fMetCUA), a mutant E. coli initiator tRNA which has a change in the anticodon sequence from CAU to CUA. Addition of purified E. coli glutaminyl-tRNA synthetase substantially stimulated synthesis of the CAT polypeptide. Thus, initiation of protein synthesis with UAG and tRNA(fMetCUA) most likely occurs with glutamine and not methionine. The UAG codon also initiates protein synthesis in vivo. To eliminate a weak secondary site of initiation from AUC, the fifth codon, we further mutagenized the CATam1 gene at codons 2 (GAG----GAC) and 5 (AUC----ACC). Transformation of E. coli with the resultant CATam1.2.5 gene yielded transformants that synthesized CAT polypeptide and were resistant to chloramphenicol only when they were also transformed with the mutant tRNA(fMetCUA) gene. Immunoblot analyses and assays for CAT enzyme activity in extracts from transformed cells indicate that initiation from UAG is efficient, 60-70% of that obtained from AUG. Initiation of protein synthesis from UAG using a mutant initiator tRNA allows tightly regulated expression of specific genes. This may be generally useful for overproduction in E. coli and other eubacteria of proteins which are toxic to these cells.

Anti-Bacterial Agents↗
PubMed2005

Translation of aberrant mRNAs lacking a termination codon or with a shortened 3'-UTR is repressed after initiation in yeast.

A novel mRNA surveillance for mRNA lacking a termination codon (nonstop mRNA) has been proposed in which Ski7p is thought to recognize stalled ribosomes at the 3' end of mRNA. Here we report our analysis of translation and decay of nonstop mRNAs in Saccharomyces cerevisiae. Although the reduction of nonstop mRNAs was only 4.5-fold, a level that is sufficient for residual protein synthesis, translation products of nonstop mRNAs were hardly detectable. We show that nonstop mRNAs were associated with polysomes, but not with Pab1p. We also show that ribosomes translating nonstop mRNA formed stable and heavy polysome complexes with mRNA. These data suggest that ribosome stalling at the 3' end of nonstop mRNA may block further rounds of translation, hence repressing protein synthesis. Furthermore, it was found that the 5' --> 3' decay pathway was accelerated for nonstop mRNA decay in the absence of Ski7p. We also found that translation of aberrant mRNAs with a shortened 3'-UTR was repressed, suggesting that an improper spatial distance between the termination codon and the 3' end of mRNA results in translation repression.

3' Untranslated Regions↗
PubMed1998

Direct evidence of autosomal recessive inheritance of Arg24 to termination codon in purine nucleoside phosphorylase gene in a family with a severe combined immunodeficiency patient.

Purine nucleoside phosphorylase (PNP) deficiency is a rare immunodeficiency disease involving a T-lymphocyte-dysfunction that is fatal unless bone marrow transplantation is successful. In this study we undertook genetic analysis of a patient with PNP deficiency. Sequencing of the PNP gene, which is located on chromosome 14ql3, of the patient led to the identification of three point mutations in exon 2 at amino acid positions 20 (His, silent mutation), 24 (Arg-->termination codon) and 51 (Ser-->Gly). Intrafamilial sequence analysis of exon 2 revealed that both parents were heterozygous for the Arg24 and termination codon 24 alleles. Two of their three children had inherited different homozygous alleles, termination codon 24 for the patient, and Arg24 for his healthy sibling. Transcriptional termination was suggested as the mechanism giving rise to the disorder in this case. A lack of PNP protein was also confirmed by immunoblot analysis of the patient's hemolysate. This could be the first report providing evidence of autosomal recessive inheritance in PNP deficiency by sequence-based analysis.

Amino Acid Sequence↗