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PubMed1990

The hepatitis B virus X-C fusion protein is unlikely to be produced by the mechanism of ribosomal frameshifting.

A novel hepatitis B viral (HBV) protein of 35-40 kDa, characterized by antibodies and proposed as an X-C fusion protein, was previously described in core particles isolated from HBV-, WHV-, and GSHV-infected livers. The X and C genes are two adjacent genes in all mammalian hepadnaviruses but are not contiguous in WHV and GSHV. After examination of the X and preC/C junction sequences of 10 HBV, 4 WHV, and 1 GSHV, we found that the ORF of preC can be extended 7 more sense codons upstream so that X overlaps with the preC/C gene in all sequences. The number of overlapping base pairs (bp) is varied: 46 bp in HBV, 19 bp in WHV, and 10 bp in GSHV. In this region a conserved A-track was found to be followed by a pair of inverted repeats, suggesting that a ribosomal frameshift may occur for X-C fusion protein production. To assess this possibility, we have used an in vitro transcription and translation coupling system to identify X-C protein production. Two recombinant SP6 plasmids were used. One contained a full length of the X and preC/C gene of wild-type HBV-DNA and the other fused the X-preC/C gene by inserting a 10-bp HindIII linker at the junction of the X-preC/C region. No X-C fusion protein was detected from the wild-type plasmid. In contrast a large amount of X-C fusion protein was produced from the linker-inserted clone. It appears, therefore, that the X-C fusion protein is unlikely to be produced via the mechanism of ribosomal frameshifting.

Amino Acid Sequence↗
PubMed1991

Expression and frameshifting but extremely inefficient proteolytic processing of the HIV-1 gag and pol gene products in stably transfected rodent cell lines.

Expression, ribosomal frameshifting, and proteolytic processing of HIV-1 GAG and POL proteins were investigated in heterologous mammalian cells in order to elucidate the influence of the cellular background on these events. DNA fragments encoded by the gag and pol region were expressed in two rodent cell lines, LTK- and BHK. Both stably transfected cell lines continuously produce recombinant proteins which react with HIV-specific antisera. The GAG precursor and a 39-kDa proteolytic fragment thereof were the major recombinant proteins detected. Expression of the gag-pol region leads to the production of the GAG-POL precursor. Ribosomal frameshifting at the HIV-1 shifty sequence to a typical extent could be positively demonstrated by an enzyme assay. Despite the presence of the viral protease within the GAG-POL precursors, proteolytic processing of the HIV-derived polyproteins was extremely inefficient. The efficiency could not be enhanced by overexpression of the HIV-1 protease encoding region.

Animals↗
PubMed1994

Antigenic diversity within a family of M proteins from group A streptococci: evidence for the role of frameshift and compensatory mutations.

The genes (emm) encoding M proteins, from isolates of group-A streptococci (GAS) serotyped as M52, M53, M80 and M nontypeable (MNT; serologically related to M53 and M80), were examined. Characterization of emm from these GAS revealed some discrepancies with serotyping, illustrating the difficulty in serotype determination when cross-reactions occur. DNA sequences corresponding to the N-terminal region of M proteins from the isolates showed considerable similarity both in the hypervariable region and the repeat regions. We propose that these serotypes form a family of closely related M types. Frameshift mutations in the hypervariable region followed by a corrective (compensatory) frameshift were observed. This may be an effective mechanism for generating antigenic diversity in the M protein.

Amino Acid Sequence↗
PubMed1992

Identification of five rare mutations including a novel frameshift mutation causing beta zero-thalassemia in Thai patients with beta zero-thalassemia/hemoglobin E disease.

6 out of 14 uncharacterized beta-thalassemia alleles from 187 Thai beta-thalassemia/HbE patients were identified by direct sequencing of DNA amplified by polymerase chain reaction. A novel mutation occurring from an insertion of adenosine in codon 95, which results in a shift of the reading frame with terminator at the new codon 101, was detected in one patient. In addition, two frameshift mutations not previously reported among the Thai population were also detected in 3 patients: one with a deletion of thymidine in codon 15 and two with an insertion of cytidine in codons 27/28. A frameshift mutation that occurred from a cytidine deletion in codon 41 was also found in one patient in this study. The remaining case was an amber mutation, GAG-TAG, in codon 43 in exon 2 of the beta-globin gene. These mutations bring the number of mutations known to be present in the Thai population to a total of 20, 15 of which were detected in beta-thalassemia/HbE patients.

Adult↗
PubMed1993

Frameshifting and antigenic variation in respiratory syncytial virus.

Recent studies have suggested that frameshift mutations in the attachment protein gene of respiratory syncytial (RS) virus may contribute to its variability. Many pathogens use several mechanisms for antigenic variation to elude their hosts' immune responses, and the frameshift mechanism is not unique to RS virus. Indeed, it may turn out to be a widespread genetic phenomenon among pathogens.

Antigens, Viral↗
PubMed2004

High frequency of frameshift mutation on p53 gene in Taiwanese with non small cell lung cancer.

Extensive researches have found that the mutation of p53 tumor suppressor gene is the most frequent event in many human cancers and associated with a poor clinical outcome in lung cancer patients. Because the p53 molecular mutation involved in tumorigenesis of patients with lung cancer in Taiwan remains poorly defined, the aim of this study was to assess the p53 mutation spectrum and possible etiological factors of Taiwan's patients with Non-Small Cell Lung Cancer (NSCLC). Cancer specimens were obtained surgically from 61 patients with pathologically proven NSCLC. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing were used to study p53 mutations in exon 4-8. We also performed immunohistochemistry (IHC) to detect p53 protein expression. Our results provided that 34 mutations of p53 gene were found in 27 cases with a mutation rate of 44% (27/61). There were six cases having more than two p53 mutations. Among the 34 mutations, 19 were point mutations (56%, 19/34) consisted of a majority of missense mutations including transversion (13/19, 68%) and transitions (6/19, 32%) with four cases (4/6, 67%) occurring in the CpG sequence. One of the most important finding in our study was the high frequency of frameshift (44%, 15/34) which included 11 insertions and 4 deletions of p53 in NSCLC in Taiwan. Surprisingly, our results disclosed distinct novel mutations at codon 181, 185, 208 (Exon 5-6) of p53. Especially, 4 cases with mutation at codon181 and codon 185 seemed to have more advanced clinical outcome with survival time less than 6 months. In addition, there were two recurring mutations at codon 168 and three at condon193. The different mutation spectrum in our series, including a high frequency of frameshift mutations and distinctly novel hot spots suggested the heterogenous entity of exogenous mutagens in NSCLC in Taiwan.

Aged↗
PubMed2006

Specificity of replicative and SOS-inducible DNA polymerases in frameshift mutagenesis: mutability of Salmonella typhimurium strains overexpressing SOS-inducible DNA polymerases to 30 chemical mutagens.

DNA replication is frequently hindered because of the presence of DNA lesions induced by endogenous and exogenous genotoxic agents. To circumvent the replication block, cells are endowed with multiple specialized DNA polymerases that can bypass a variety of DNA damage. To better understand the specificity of specialized DNA polymerases to bypass lesions, we have constructed a set of derivatives of Salmonella typhimurium TA1538 harboring plasmids carrying the polB, dinB or mucAB genes encoding Escherichia coli DNA polymerase II, DNA polymerase IV or DNA polymerase RI, respectively, and examined the mutability to 30 chemicals. The parent strain TA1538 possesses CGCGCGCG hotspot sequence for -2 frameshift. Interestingly, the chemicals could be classified into four groups based on the mutagenicity to the derivatives: group I whose mutagenicity was highest in strain YG5161 harboring plasmid carrying dinB; group II whose mutagenicity was almost equally high in strain YG5161 and strain TA98 harboring plasmid carrying mucAB; group III whose mutagenicity was highest in strain TA98; group IV whose mutagenicity was not affected by the introduction of any of the plasmids. Introduction of plasmid carrying polB did not enhance the mutagenicity except for benz[a]anthracene. We also introduced a plasmid carrying polA encoding E. coli DNA polymerase I to strain TA1538. Strikingly, the introduction of the plasmid reduced the mutagenicity of chemicals belonging to groups I, II and III, but not the chemicals of group IV, to the levels observed in the derivative whose SOS-inducible DNA polymerases were all deleted. These results suggest that (i) DNA polymerase IV and DNA polymerase RI possess distinct but partly overlapping specificity to bypass lesions leading to -2 frameshift, (ii) the replicative DNA polymerase, i.e., DNA polymerase III, participates in the mutagenesis and (iii) the enhanced expression of E. coli polA may suppress the access of Y-family DNA polymerases to the replication complex.

Benzo(a)pyrene↗
PubMed2006

A novel frameshift mutation in the 5alpha-reductase type 2 gene in Korean sisters with male pseudohermaphroditism.

OBJECTIVE: To describe two cases of 5alpha-reductase deficiency and the identification of a novel frameshift mutation in this sibling pair. DESIGN: Case report. SETTING: An adolescent clinic at a university hospital. PATIENT(S): A 14-year-old girl and her younger sister, who presented with primary amenorrhea, deepening of the voice, and clitoromegaly. INTERVENTION(S): Deoxyribonucleic acid was extracted from peripheral blood, and 8 exons of the androgen receptor gene and 5 exons of the steroid 5alpha-reductase type 2 gene (encoded by SRD5A2 gene) were amplified by polymerase chain reaction and subjected to sequence analyses. MAIN OUTCOME MEASURE(S): Genetic diagnosis of 5alpha-reductase deficiency. RESULT(S): There was no evidence of a genetic abnormality in the 8 screened exons of the androgen receptor gene, but exon 4 of the SRD5A2 gene showed a novel homozygous deletion of the thymine at nucleotide position c.655 (c.655delT), leading to a frameshift mutation predicted to result in an abnormally long protein with an extended termination signal. CONCLUSION(S): The molecular characterization of the mutation can be a relevant tool for a correct diagnosis of 5alpha-reductase deficiency.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2005

Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac Myosin-binding protein C gene among Japanese.

OBJECTIVES: We studied the longitudinal evolution of hypertrophic cardiomyopathy (HCM) caused by a founder frameshift mutation in the cardiac myosin-binding protein C (MyBPC) gene. BACKGROUND: Mutations in the MyBPC gene have been associated with delayed expression of HCM and a good prognosis. Few studies, however, demonstrated the phenotype-genotype correlations in the longitudinal study. METHODS: We studied long-term evolution of clinical features of 15 unrelated families who were found to have an identical frameshift mutation in the MyBPC gene: a one-base deletion of a thymidine at nucleotide 11645 (V592fs/8). RESULTS: Thirty-nine individuals in 15 families were genotype-positive. Thirty of the 39 individuals with the mutation were phenotype-positive. The disease penetrance was 100% in subjects > or =50 years and 65% in those <50 years. "End-stage" HCM (ejection fraction <50%) was observed in 7 (18%) of the 39 genotype-positive individuals (7 [23%] of the 30 phenotype-positive patients); 6 of them were 60 years or older. Seven patients were hospitalized for treatment of repeated congestive heart failure, and four patients died or had implantable cardioverter-defibrillator discharge (13%; incidence, 1.4%/year) during a mean follow-up period of 9.2 +/- 5.5 years. CONCLUSIONS: Elderly patients with a V592fs/8 mutation in the MyBPC gene may evolve into the "end-stage" HCM, characterized by left ventricular systolic dysfunction, cavity dilation, and irreversible heart failure. The clinical course in patients with this mutation is not benign in the long run, with progressive left ventricular remodeling with advancing age.

Adolescent↗
PubMed2004

Long-chain adducts of trans-4-hydroxy-2-nonenal to DNA bases cause recombination, base substitutions and frameshift mutations in M13 phage.

Oxidative stress enhances lipid peroxidation (LPO) implicated in the promotion and progression of carcinogenesis. One of the major LPO products is trans-4-hydroxy-2-nonenal (HNE), which was shown to react with guanosine and under peroxidizing conditions also with adenosine. We show here that all four DNA bases are targets for HNE, although displaying different reactivity: dG > dC > dA approximately equal to dT. HPLC and mass spectrometry analyses of HNE reactions with deoxynucleosides showed in each case the formation of several products, with mass peaks corresponding to HNE-dN adducts at a 1:1 and also 2:1 and 3:1 ratios. In the dA, dC and dG reactions, mass peaks corresponding to heptyl-substituted etheno-adducts were also detected, indicating HNE oxidation to its epoxide by air oxygen. In DNA pretreated with HNE, DNA synthesis by T7 DNA polymerase was stopped in a sequence-dependent manner at G > or = C > A and T sites. HNE increased the mutation rates in the lac Z gene of M13 phage transfected into wild type Escherichia coli. The most frequent event was the recombination between lacZ gene sequences in M13 and the E. coli F' factor DNA. Base substitutions and frameshifts were also observed in approximately similar numbers. Over 50% of base substitutions were the C-->T transitions, followed by the G-->C and A-->C transversions. In the E. coli recA strain recombination was not observed, although one mutational G-->T hot-spot appeared within the DNA fragment undergoing recombination in the wild type E. coli. We conclude that long chain HNE adducts to DNA bases arrest DNA synthesis and cause recombination, base substitutions and frameshift mutations in ssDNA.

Aldehydes↗
PubMed2005

Frameshift mutations induced by the acridine mustard ICR-191 in embryos and in the adult gill and hepatopancreas of rpsL transgenic zebrafish.

To determine whether frameshift mutations can be detected in rpsL transgenic zebrafish (Brachydanio rerio), embryos, and adult fish were treated with 6-chloro-9-[3-(2-chloroethylamino)-propylamino]-2-methoxyacridine (ICR-191). Embryos exposed to 0, 10, or 20 microM ICR-191 in a water bath for 18 h exhibited induced mutant frequencies (MFs) of 14 x 10(-5), 16 x 10(-5), and 25 x 10(-5), respectively. Only embryos exposed to 20 microM ICR-191 showed a significant increase in MF. The mutational spectra differed between the control and ICR-191-treated groups and single G:C pair insertions, which are a marked characteristic of ICR-191 mutagenesis, were observed in both 10 and 20 microM-treated embryos. In adult fish treated with 1 microM ICR-191 in a water bath for 18 h, a significant increase in MFs was observed in both gill (12 x 10(-5) and 44 x 10(-5) in control and treated fish, respectively), and hepatopancreas (5 x 10(-5) and 29 x 10(-5), respectively) 2 weeks after exposure. Sequence analysis showed that 58% of mutations in gill and 94% of mutations in hepatopancreas were single G:C pair insertions, which is typical of mutations induced by ICR-191. Additionally, these mutations occurred predominantly at a single site (CC sequence at bps 140-141) in the rpsL gene. Three weeks after exposure, however, the increased MFs and prominent mutational spectra of ICR-treated fish were undetectable. These findings suggest that using our protocols the rpsL transgenic zebrafish mutation assay is more effective for adult fish than for embryos, but that frameshift mutations can be detected in both embryos and adults at appropriate sampling times after treatment with ICR-191.

Aminacrine↗
PubMed2005

Epistatic participation of REV1 and REV3 in the formation of UV-induced frameshift mutations in cell cycle-arrested yeast cells.

Mutations arising in times of cell cycle arrest may provide a selective advantage for unicellular organisms adapting to environmental changes. For multicellular organisms, however, they may pose a serious threat, in that such mutations in somatic cells contribute to carcinogenesis and ageing. The budding yeast Saccharomyces cerevisiae presents a convenient model system for studying the incidence and the mechanisms of stationary-phase mutation in a eukaryotic organism. Having studied the emergence of frameshift mutants after several days of starvation-induced cell cycle arrest, we previously reported that all (potentially error-prone) translesion synthesis (TLS) enzymes identified in S. cerevisiae did not contribute to the basal level of spontaneous stationary-phase mutations. However, we observed that an increased frequency of stationary-phase frameshift mutations, brought about by a defective nucleotide excision repair (NER) pathway or by UV irradiation, was dependent on Rev3p, the catalytic subunit of the TLS polymerase zeta (Pol zeta). Employing the same two conditions, we now examined the effect of deletions of the genes coding for polymerase eta (Pol eta) (RAD30) and Rev1p (REV1). In a NER-deficient strain background, the increased incidence of stationary-phase mutations was only moderately influenced by a lack of Pol eta but completely reduced to wild type level by a knockout of the REV1 gene. UV-induced stationary-phase mutations were abundant in wild type and rad30Delta strains, but substantially reduced in a rev1Delta as well as a rev3Delta strain. The similarity of the rev1Delta and the rev3Delta phenotype and an epistatic relationship evident from experiments with a double-deficient strain suggests a participation of Rev1p and Rev3p in the same mutagenic pathway. Based on these results, we propose that the response of cell cycle-arrested cells to an excess of exo- or endogenously induced DNA damage includes a novel replication-independent cooperative function of Rev1p and Pol zeta, which has the potential to generate mutations.

Cell Cycle↗
PubMed2005

A family with a novel frameshift mutation in the PMP22 gene (c.433_434insC) causing a phenotype of hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies is usually due to PMP22 deletion. Point mutations of PMP22 causing an hereditary neuropathy with liability to pressure palsies phenotype are rare. We describe a clinical and electrodiagnostic phenotype of hereditary neuropathy with liability to pressure palsies in a 21-year-old woman, which led to our detecting a novel frameshift mutation of PMP22. This mutation was also found in her mother and brother and corresponded to an insertion of one cytidine between nucleotides 433 and 434 in the last coding exon (c.433_434insC). The mutated PMP22 protein lacks the last 15 amino acids and has a modified C terminus lengthened to 221 residues instead of 160 (Leu145fsX222). The mother and the proband had a clinical and electrophysiological hereditary neuropathy with liability to pressure palsies phenotype. The brother was asymptomatic, but the results of electrodiagnostic tests were suggestive of hereditary neuropathy with liability to pressure palsies. This observation of a new mutation mostly leading to a PMP22 haploinsufficiency provides further evidence of the diversity of phenotypes associated with frameshift PMP22 mutations.

Adult↗
PubMed2005

Functional divergence of proteins through frameshift mutations.

Frameshift mutations are generally considered to be deleterious and of little importance for the evolution of novel gene functions. However, by screening an exhaustive set of vertebrate gene families, we found that, when a second transcript encoding the original gene product compensates for this mutation, frameshift mutations can be retained for millions of years and enable new gene functions to be acquired.

Amino Acid Sequence↗
PubMed1999

Binding of oligopyrimidines to the RNA hairpin responsible for the ribosome gag-pol frameshift in HIV-1.

The 12 bp stem of the RNA hairpin responsible for the gag-pol frameshifting of the ribosomes during translation of the polycistronic HIV-1 mRNA has a pyrimidine-rich 5' strand and, consequently, a purine-rich 3' strand. Electrophoretic mobility shift assays have shown that DNA oligopyrimidines, 12 and 20 nucleotides long (but not oligopurines or G,T-containing oligomers), designed to form triplexes actually bind to the double-stranded RNA target. RNase V1 footprinting studies have confirmed the interaction between the hairpin stem and the RNA and 2'-O-methyl oligoribonucleotide analogues of the 12-mer oligodeoxypyrimidine as well as 5 propynyl,cytosine, containing the 12-mer oligodeoxypyrimidine, bind more strongly to the RNA target than the unmodified parent DNA oligomer. The complexes formed by the RNA hairpin and either the 12-mer oligodeoxypyrimidine or the 20-mer oligopyrimidine are stable at a neutral pH and in the absence of Mg2+ but blocked neither the reverse transcription nor cell-free translation of a RNA template in which the gag-pol frameshifting hairpin was inserted at the 5' end of the luciferase open reading frame.

Biological Assay↗
PubMed1999

Transfer RNA modification: influence on translational frameshifting and metabolism.

Transfer RNA modification improves the rate of aa-tRNA selection at the A-site and the fitness in the P-site and thereby prevents frameshifting according to a new model how frameshifting occurs [Qian et al. (1998) Mol. Cell 1, 471-482]. Evidence that the presence of various modified nucleosides in tRNA also influences central metabolism, thiamine metabolism, and bacterial virulence is reviewed.

Frameshifting, Ribosomal↗
PubMed2002

Solution structure of a luteoviral P1-P2 frameshifting mRNA pseudoknot.

A hairpin-type messenger RNA pseudoknot from pea enation mosaic virus RNA1 (PEMV-1) regulates the efficiency of programmed -1 ribosomal frameshifting. The solution structure and 15N relaxation rates reveal that the PEMV-1 pseudoknot is a compact-folded structure composed almost entirely of RNA triple helix. A three nucleotide reverse turn in loop 1 positions a protonated cytidine, C(10), in the correct orientation to form an A((n-1)).C(+).G-C(n) major groove base quadruple, like that found in the beet western yellows virus pseudoknot and the hepatitis delta virus ribozyme, despite distinct structural contexts. A novel loop 2-loop 1 A.U Hoogsteen base-pair stacks on the C(10)(+).G(28) base-pair of the A(12).C(10)(+).G(28)-C(13) quadruple and forms a wedge between the pseudoknot stems stabilizing a bent and over-rotated global conformation. Substitution of key nucleotides that stabilize the unique conformation of the PEMV-1 pseudoknot greatly reduces ribosomal frameshifting efficacy.

Base Pairing↗