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PubMed2001

Two overlapping reading frames in a single exon encode interacting proteins--a novel way of gene usage.

The >1 kb XL-exon of the rat XLalphas/Galphas gene encodes the 37 kDa XL-domain, the N-terminal half of the 78 kDa neuroendocrine-specific G-protein alpha-subunit XLalphas. Here, we describe a novel feature of the XL-exon, the presence of an alternative >1 kb open reading frame (ORF) that completely overlaps with the ORF encoding the XL-domain. The alternative ORF starts 32 nucleotides downstream of the start codon for the XL-domain and is terminated by a stop codon exactly at the end of the XL-exon. The alternative ORF encodes ALEX, a very basic (pI 11.8), proline-rich protein of 356 amino acids. Both XLalphas and ALEX are translated from the same mRNA. Like XLalphas, ALEX is expressed in neuroendocrine cells and tightly associated with the cytoplasmic leaflet of the plasma membrane. Remarkably, ALEX binds to the XL-domain of XLalphas. Our results reveal a mechanism of gene usage that is without precedent in mammalian genomes.

Amino Acid Sequence↗
PubMed1982

In vitro suppression of a nonsense mutant of Drosophila melanogaster.

When RNA isolated from the Drosophila melanogaster alcohol dehydrogenase (ADH) negative mutant CyOnB was translated "in vitro" in the presence of yeast opal suppressor tRNA, a wild type size ADH protein was obtained in addition to the mutant gene product. This identifies the CyOnB mutant as an opal (UGA) nonsense mutant. From the molecular weight of the mutant protein, and from the known sequence of the ADH gene (Benyajati et al., Proc.Natl.Acad.Sci. USA 78, 2717-2721, 1981), we conclude that the tryptophan codon UGG in position 234 has been changed into a UGA nonsense codon in the CyOnB mutant. Furthermore, we show that the UAA stop codon of the wild type ADH gene is resistant to suppression by a yeast ochre suppressor tRNA. This is in contrast to the high efficiency of suppression of the CyOnB UGA nonsense codon, despite an almost identical codon context.

Alcohol Dehydrogenase↗
PubMed1986

The ILV5 gene of Saccharomyces cerevisiae is highly expressed.

The nucleotide sequence of the yeast ILV5 gene, which codes for the branched-chain amino acid biosynthesis enzyme acetohydroxyacid reductoisomerase, has been determined. The ILV5 coding region is 1,185 nucleotides, corresponding to a polypeptide with a molecular weight of 44,280. Transcription of the ILV5 mRNA initiates at position -81 upstream from the ATG translation start codon and terminates between 218 and 222 bases downstream from the stop codon. Consensus sequences have been identified for initiation and termination of transcription, and for general control of amino acid biosynthesis, as well as repression by leucine. The ILV5 gene is regulated slightly by general amino acid control. Codon usage of the ILV5 gene has the strong bias observed in yeast genes that are highly expressed. In agreement with this, the reductoisomerase monomer, with an apparent molecular weight of 40,000, has been identified in an SDS polyacrylamide gel pattern of total soluble yeast proteins as a gene dosage dependent band.

2-Acetolactate Mutase↗
PubMed1990

A 40 kilodalton rat liver nuclear protein binds specifically to apolipoprotein B mRNA around the RNA editing site.

Apolipoprotein (apo) B-48 mRNA is the product of RNA editing which consists of a C----U conversion changing a CAA codon encoding Gln-2153 in apoB-100 mRNA to a UAA stop codon in apoB-48 mRNA. In the adult rat, RNA editing occurs both in the small intestine and the liver. We have studied the ability of rat liver nuclear extracts to bind to synthetic apoB mRNA segments spanning the editing site. Using an RNA gel mobility shift assay, we found the sequence-specific binding of a protein(s) to a 65-nucleotide apoB-100 mRNA. UV crosslinking followed by T1 ribonuclease digestion and SDS-polyacrylamide gel electrophoresis demonstrated the formation of a 40 kDa protein-RNA complex when 32P-labeled apoB-100 mRNA was incubated with a rat liver nuclear extract but not with HeLa nuclear extract. Binding was specific for the sense strand of apoB mRNA, and was not demonstrated with single-stranded apoB DNA, or antisense apoB RNA. The complex also failed to form if SDS was present during the UV light exposure. Binding experiments using synthetic apoB mRNAs indicate that the 40 kDa protein would also bind to apoB-48 mRNA but not apoA-I, apoA-IV, apoC-II or apoE mRNA. Experiments using deletion mutants of apoB-100 mRNA indicate efficient binding of wildtype 65-nucleotide (W65), 40-nucleotide (W40) and 26-nucleotide (W26) apoB-100 mRNA segments, but not 10-nucleotide (or smaller) segments of apoB-100 mRNA to the 40 kDa protein. In contrast, two other regions of apoB-100 mRNA, B-5' (bases 1128-3003) and B-3' (bases 11310-11390), failed to bind to the protein. The 40 kDa sequence-specific binding protein in rat liver nuclear extract may play a role in apoB-100 mRNA editing.

Animals↗
PubMed2001

The Crithidia fasciculata RNH1 gene encodes both nuclear and mitochondrial isoforms of RNase H.

The Crithidia fasciculata RNH1 gene encodes an RNase H, an enzyme that specifically degrades the RNA strand of RNA-DNA hybrids. The RNH1 gene is contained within an open reading frame (ORF) predicted to encode a protein of 53.7 kDa. Previous work has shown that RNH1 expresses two proteins: a 38 kDa protein and a 45 kDa protein which is enriched in kinetoplast extracts. Epitope tagging of the C-terminus of the RNH1 gene results in localization of the protein to both the kinetoplast and the nucleus. Translation of the ORF beginning at the second in-frame methionine codon predicts a protein of 38 kDa. Insertion of two tandem stop codons between the first ATG codon and the second in-frame ATG codon of the ORF results in expression of only the 38 kDa protein and the protein localizes specifically to the nucleus. Mutation of the second methionine codon to a valine codon prevents expression of the 38 kDa protein and results in exclusive production of the 45 kDa protein and localization of the protein only in the kinetoplast. These results suggest that the kinetoplast enzyme results from processing of the full-length 53.7 kDa protein. The nuclear enzyme appears to result from translation initiation at the second in-frame ATG codon. This is the first example in trypanosomatids of the production of nuclear and mitochondrial isoforms of a protein from a single gene and is the only eukaryotic gene in the RNase HI gene family shown to encode a mitochondrial RNase H.

Alternative Splicing↗
PubMedDate not supplied

Natural instability of Agrobacterium vitis Ti plasmid due to unusual duplication of a 2.3-kb DNA fragment.

The octopine/cucumopine (o/c) Ti plasmids of Agrobacterium vitis carry two T regions, TA and TB. The TA region resembles the octopine TL region. The TB region contains the auxin synthesis genes TB-iaaM and TB-iaaH and the cucumopine synthesis gene cus. Within the group of o/c isolates, strains 2608 and 2641 are closely related. However, 2641 lacks the TB region. The restriction maps of pTi2608 and pTi2641 were established and showed that the TB deletion resulted from intramolecular recombination between two directly repeated sequences separated by 66 kb in pTi2608. The 2,294-bp repeated sequence lacks inverted repeats and does not duplicate its target site, indicating that it is not a classical bacterial insertion sequence (IS element). It was therefore called an RSAv element (repeated sequence of A. vitis). The RSAv element carries two open reading frames: ORF234 is homologous to the traR gene of the A. tumefaciens nopaline Ti plasmid pTiC58; ORF488 is homologous to the sucrose phosphorylase gene of Leuconostoc mesenteroides and the glucosyl transferase A gene of Streptococcus mutans. The RSAv repeat starts precisely at the start codon of ORF488 and ends two base pairs 3' of the stop codon of ORF234. The structural organization of the RSAv element suggests that the amplification event did not result from a random amplification process. A study of the distribution of the two RSAv copies (RSAv-1 and RSAv-2) in pTi2608 and other o/c isolates indicates that the ancestor o/c Ti plasmid contained only RSAv-1 and that this sequence was duplicated at one point during the divergent evolution of the o/c Ti plasmids.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2000

Invasiveness in chickens, stress resistance and RpoS status of wild-type Salmonella enterica subsp. enterica serovar typhimurium definitive type 104 and serovar enteritidis phage type 4 strains.

The heat and acid resistance and the ability to survive airdrying on commonly used kitchen surfaces were assessed for clinical and environmental strains of Salmonella enterica subsp. enterica serovar Typhimurium, definitive type (DT) 104. Three out of thirty-eight strains of DT 104 were found to be more sensitive in stationary phase to the stresses examined than the other strains. This compares to a previous study by the authors which showed that seven out of forty serovar Enteritidis phage type (PT) 4 strains were more sensitive. RpoS activity was examined indirectly in selected strains of DT 104 and PT 4. In those with normal stress resistance a 100-fold induction of an RpoS-dependent spvR/A:'::luxCDABE fusion was observed upon entry into stationary phase. The sensitive strains examined showed either no induction or a reduced level of spvR/A:'::luxCDABE expression. The rpoS gene was sequenced from these strains and three were found to harbour mutations including one deletion, one base-pair substitution resulting in a nonsense codon, and one insertion causing a frameshift resulting in an early stop codon. Strains with negligible or reduced spvR/A:'::luxCDABE expression had low stress resistance. All strains of DT 104 could be recovered from liver and spleen tissues of infected hens 14 d post-infection, but one with no induction of spvR/A:'::luxCDABE expression was significantly less likely to be recovered from chicken reproductive tissues, liver or spleen than the majority of other strains, including one with reduced spvR/A:'::luxCDABE expression. This work has demonstrated that clinical and environmental strains of DT 104 and PT 4 not infrequently harbour mutations in the rpoS allele. It is possible that the rpoS mutations may have occurred during the initial isolation of the strains. The ability of a strain to cause infection, however, also depends on factors such as host susceptibility and dose.

Animals↗
PubMed1995

Genome structure and nucleotide sequence of a lipolytic enzyme gene of Aspergillus oryzae.

Aspergillus oryzae, which is widely used for Japanese traditional fermentation, produced at least two lipolytic enzymes (L1 and L2). Southern hybridization analysis of restriction enzyme-digested genomic DNA fragments of Aspergillus oryzae with 23-mer oligonucleotides synthesized according to the amino acid sequence of the enzyme L1 as probes suggested that there is single copy of the L1 gene in the genome. DNA fragments containing the L1 gene were cloned in Escherichia coli. Nucleotide sequencing of the DNA fragments revealed an open reading frame consisting of 213 amino acid residues. It had three putative introns whose sizes were 52 bp, 48 bp and 53 bp, respectively. Putative CAAT and TATA boxes were found at positions -147 and -100 from A (+1) of the translational initiation codon, and a polyadenylation site at 158 bp downstream of the stop codon. The deduced amino acid sequence of the L1 gene was highly similar to those of cutinases from phytopathogenic fungi. Thus, it is interesting to note that the non-phytopathogenic fungus, A. oryzae, produces cutinase, which seems to play an important role in flavor formation.

Amino Acid Sequence↗
PubMed2006

Internal promoter characterization and expression of the Deinococcus radiodurans pprI-folP gene cluster.

PprI is a general gene switch responsible for the extraordinary radioresistance of Deinococcus radiodurans. From NCBI DNA sequence analysis, it was predicted that the translation start codon of the downstream folP (DR0168) gene overlaps the pprI (DR0167) stop codon, suggesting that these genes may form an operon. In this study, we show that a mutant containing an inserted sequence in folP does not grow unless folate is added to the medium, but is not affected in extreme radioresistance, whereas a pprI disruptant strain could grow in the absence of folate. It was found that expression of a pprI-lacZ fusion is constitutive and unaltered following ionizing radiation as is the production of the PprI protein. PprI protein is not expressed if its promoter is deleted and the transcription from the entire pprI promoter is essential for radioresistance of D. radiodurans. However, the deletion of pprI promoter has no effect on the expression of the folP-lacZ fusion. Primer extension analysis of the folP promoter region shows that folP is transcribed from its own promoter located within the pprI structural gene. All these results do support neither the existence of a pprI-folP operon nor a regulatory role of FolP in pprI expression.

Bacterial Proteins↗
PubMed1997

In vivo effects of leptin-related synthetic peptides on body weight and food intake in female ob/ob mice: localization of leptin activity to domains between amino acid residues 106-140.

In C57BL/6J ob/ob mice, a single base mutation of the ob gene in codon 105 results in the replacement of arginine by a premature stop codon and production of a truncated inactive form of leptin. These observations suggest that leptin activity may be localized, at least in part, to domains distal to amino acid residue 104. To investigate this possibility, we synthesized six overlapping peptide amides corresponding to residues 106-167 of leptin, and examined their effects on body weight and food intake in female C57BL/6J ob/ob mice. When compared with vehicle-injected control mice, weight gain by mice receiving 28 daily 1-mg i.p. injections of LEP-(106-120), LEP-(116-130), or LEP-(126-140) was significantly (P < 0.01) reduced with no apparent toxicity. Weight gain by mice receiving LEP-(136-150), LEP-(146-160), or LEP-(156-167) was not significantly different from that of vehicle-injected control mice. The effects of LEP-(106-120), LEP-(116-130), or LEP-(126-140) were most pronounced during the first week of peptide treatment. Within 7 days, mice receiving these peptides lost 12.3%, 13.8%, and 9.8%, respectively, of their initial body weights. After 28 days, mice given vehicle alone, LEP-(136-150), LEP-(146-160), or LEP-(156-167) were 14.7%, 20.3%, 25.0%, and 24.8% heavier, respectively, than they were at the beginning of the study. Mice given LEP-(106-120) or LEP-(126-140) were only 1.8% and 4.2% heavier, respectively, whereas mice given LEP-(116-130) were 3.4% lighter. Food intake by mice receiving LEP-(106-120), LEP-(116-130), or LEP-(126-140), but not by mice receiving LEP-(136-150), LEP-(146-160), or LEP-(156-167), was reduced by 15%. The results of this study indicate 1) that leptin activity is localized, at least in part, in domains between residues 106-140; 2) that leptin-related peptides have in vivo effects similar to those of native leptin; and 3) offer hope for development of peptide analogs of leptin having potential application in human or veterinary medicine.

Amino Acid Sequence↗
PubMed1995

A family with hereditary serum cholinesterase deficiency.

A family with serum cholinesterase (SChE) deficiency is reported. A 64-year-old woman was admitted for the excision of colon adenoma; her laboratory data revealed a markedly decreased level of SChE. SChE genes of the patient and her family members were amplified by the polymerase chain reaction (PCR) and analyzed by direct sequencing. The patient's SChE gene had a homozygous frame shift mutation, in which an extra adenine was inserted in codon 315 (ACC-->AACC), resulting in the appearance of a new stop codon in codon 322. The family study disclosed that her brother and sister had the same frame shift mutations in homozygote and heterozygote, respectively.

Base Sequence↗
PubMed2006

Pedigree and genetic analysis of a novel mutation carrier patient suffering from hereditary nonpolyposis colorectal cancer.

AIM: To screen a suspected Hungarian HNPCC family to find specific mutations and to evaluate their effect on the presentation of the disease. METHODS: The family was identified by applying the Amsterdam and Bethesda Criteria. Immunohistochemistry was performed, and DNA samples isolated from tumor tissue were evaluated for microsatellite instability. The identification of possible mutations was carried out by sequencing the hMLH1 and hMSH2 genes. RESULTS: Two different mutations were observed in the index patient and in his family members. The first mutation was located in exon 7, codon 422 of hMSH2, and caused a change from Glu to STOP codon. No other report of such a mutation has been published, as far as we could find in the international databases. The second mutation was found in exon 3 codon 127 of the hMSH2 gene, resulting in Asp-->Ser substitution. The second mutation was already published, as a non-pathogenic allelic variation. CONCLUSION: The pedigree analysis suggested that the newly detected nonsense mutation in exon 7 of the hMSH2 gene might be responsible for the development of colon cancers. In family members where the exon 7 mutation is not coupled with this missense mutation, colon cancer appears after the age of 40. The association of these two mutations seems to decrease the age of manifestation of the disease into the early thirties.

Adaptor Proteins, Signal Transducing↗
PubMed2002

[A novel rhodopsin E341ter mutation in patients with retinitis pigmentosa and corresponding clinical phenotype].

OBJECTIVE: To detect rhodopsin (RHO) mutation in Chinese families with autosomal dominant retinitis pigmentosa (ADRP) and study on the association of RHO gene mutations with clinical phenotype. METHODS: Twenty-seven members from 13 Chinese families with ADRP and 30 normal subjects were recruited. The complete coding regions of the rhodopsin gene were amplified with polymerase chain reaction (PCR) and then DNA single-strand conformation polymorphism (SSCP) technique was used to screen RHO gene mutations. When a variant band was observed after the SSCP electrophoresis, the variant band was analyzed by sequencing PCR-amplified DNA. All subjects were examined clinically by slit-lamp, direct funduscopy, Goldmann kinetic perimetry, Humphrey threshold perimetry and electroretinogram. RESULTS: Nine affected subjects and 2 boys (11 and 9 years old respectively) in one pedigree among 13 families were found to have three DNA single strand bands by SSCP analysis. Results of assaying sequence showed the 11 members were heterozygous for rhodopsin E341ter mutation. The codon 341 is changed from GAG to TAG, resulting in a stop codon mutation. Thirty normal controls and unaffected subjects in this family were the wild type of RHO gene. Affected individuals reported night blindness in the second decade, showed optic atrophy, vessel attenuation and a few bone spicule-like pigments in the peripheral retina. The impairment of visual acuity was relatively severe, loss of peripheral visual field was greatly considerable after 30 years of age, rod and cone ERG were not detectable in the second decade, and only slight cone response was left. CONCLUSIONS: The natural history of RP in this family begins with a loss of rod function, progresses to involve the cone system, and leads eventually to a severe loss of visual function. A novel rhodopsin gene mutation E341ter is responsible for a Chinese family with ADRP.

Adult↗
PubMed2006

[Fructose 1,6-bisphosphatase deficiency as a cause of recessive serious hypoglycaemia].

Fructose 1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive disorder of gluconeogenesis. Here we describe a family from Morocco with parental consanguinity with three affected children. All were homozygous for a novel mutation in exon 5: 685 C-->T of the gene coding for the liver isoform of fructose 1,6-bisphosphatase (FBP1). The mutation changed the amino acid codon (Q229X) from a glutamine (CAG) in position 229 to a stop codon (TAG), which caused a shortening of the protein from the normal 338 amino acids to 228. The shortened protein lacks a major part of the active site and is therefore probably without enzymatic activity.

Consanguinity↗
PubMed1989

[Evolutionary changes in the structural and regulatory regions of aminoglycoside-3'-phosphotransferase type I gene of E. coli].

To investigate the evolutionary relationships between the aph(3') genes from different plasmids, the nucleotide sequence of the aph(3') gene from the E. coli R plasmid was determined and compared with the known aph(3') genes of Tn903 and Tn4352. Three point mutations in the structural part of the cloned aph(3') gene caused amino acid changes in the enzyme molecule at positions 19, 27 and 48 beginning from the start codon. The structural part of the gene was followed by two stop codons and a long DNA region containing no nucleotide sequences homologous to the sequences of Tn903 or Tn4352. Both the cloned aph(3') gene and Tn4352 were limited on the left by the spacer sequence and the insertion sequence IS176. Twenty one base pairs deletion abolished the -35 sequence of the promoter suggested for the aph(3') gene of Tn4352 and resulted in formation of a fusion promoter utilizing the -35 box of IS176 and the -10 box of the aph(3') gene. The distance between the -35 and -10 sequences changed from 18 to 17 bp. Changes in the cloned aph(3') gene and the flanking DNA regions resulted in formation of a new promoter and loss of the right IS176 element.

Base Sequence↗
PubMed1989

Sequence requirements for apolipoprotein B RNA editing in transfected rat hepatoma cells.

Apolipoprotein (apo) B mRNA undergoes a novel tissue-specific editing reaction, which replaces a genomically templated cytidine with uridine. This substitution converts codon 2153 from glutamine (CAA) in apo B100 mRNA to a stop codon (UAA) in apoB48 mRNA (Powell, L. M., Wallis, S. C., Pease, R. J., Edwards, Y. H., Knott, T. J., and Scott, J. (1987) Cell 50, 831-840). To examine sequences in the human apoB mRNA required for the editing reaction, a series of deletion mutants around the cytidine conversion site was prepared and transfected into a rat hepatoma cell line (McArdle 7777). This cell makes both apoB100 and apoB48. Editing was detected by a primer extension assay on cDNA that had been amplified by the polymerase chain reaction. RNAs of between 2385 and 26 nucleotides spanning the conversion site underwent similar levels of conversion. Editing was confirmed by cloning and sequencing of cDNA corresponding to the transfected RNAs. Conversion did not occur in transfected human hepatoblastoma (HepG2) or epithelial carcinoma (HeLa) cell lines, which do not make apoB48. These results verify that apoB48 is generated by a genuine tissue-specific RNA editing reaction and show that 26 nucleotides of apoB mRNA are sufficient for editing.

Animals↗
PubMed1999

Indirect regulation of translational termination efficiency at highly expressed genes and recoding sites by the factor recycling function of Escherichia coli release factor RF3.

Prokaryotic release factor RF3 is a stimulatory protein that increases the rate of translational termination by the decoding release factors RF1 and RF2. The favoured model for RF3 function is the recycling of RF1 and RF2 after polypeptide release by displacing the factors from the ribosome. In this study, we have demonstrated that RF3 also plays an indirect role in the decoding of stop signals of highly expressed genes and recoding sites by accentuating the influence of the base following the stop codon (+4 base) on termination signal strength. The efficiency of decoding strong stop signals (e.g. UAAU and UAAG) in vivo is markedly improved with increased RF3 activity, while weak signals (UGAC and UAGC) are only modestly affected. However, RF3 is not responsible for the +4 base influence on termination signal strength, since prfC- strains lacking the protein still exhibit the same qualitative effect. The differential effect of RF3 at stop signals can be mimicked by modest overexpression of decoding RF. These findings can be interpreted according to current views of RF3 as a recycling factor, which functions to maintain the concentration of free decoding RF at stop signals, some of which are highly responsive to changes in RF levels.

Base Sequence↗
PubMed1990

Codon context.

The analysis of coding sequences reveals nonrandomness in the context of both sense and stop codons. Part of this is related to nucleotide doublet preference, seen also in non-coding sequences and thought to arise from the dependence of mutational events on surrounding sequence. Another nonrandom context element, relating the wobble nucleotides of successive codons, is observed even when doublet preference, codon usage and bias in amino acid doublets are all allowed for. Several phenomena related to protein synthesis have been shown in vivo to be affected by the nucleotide sequence around codons. Thus, nonsense and missense suppression, elongation rate, precision of tRNA selection and polypeptide chain termination are all affected by codon context. At present, it remains unclear how these phenomena may influence the evolution of nonrandomness in the context of codons in natural sequences.

Codon↗