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PubMed1982

The yeast frameshift suppressor gene SUF16-1 encodes an altered glycine tRNA containing the four-base anticodon 3'-CCCG-5'.

The SUF16 frameshift suppressor locus encodes a glycine tRNA. The SUF16-1 suppressor tRNA is inferred by DNA sequence analysis to contain the four-base anticodon sequence 3'-CCCG-5' in place of the wild-type anticodon 3'-CCG-5'. SUF16-1 mediates translation of the four-base messenger RNA (mRNA) sequence 5'-GGGU-3' but apparently fails to act at the sequence 5'-GGGG-3'. A molecular model is presented that accounts for the observed specificity of tRNA-mediated frameshift suppression in Saccharomyces cerevisiae.

Anticodon↗
PubMed1990

The where, what and how of ribosomal frameshifting in retroviral protein synthesis.

The gag and pol genes of most retroviruses occur in different reading frames and their translation as a single polypeptide is carried out by ribosomal frameshifting in the -1 direction. The alignment of the different reading frames occurs by overlapping reading in response to at least two signals within the RNA: one is a heptanucleotide stretch at the frameshift site and the other is a stem-loop structure which occurs just downstream of the first signal.

Protein Biosynthesis↗
PubMed2005

Structural and dynamic effects of single 7-hydro-8-oxoguanine bases located in a frameshift target DNA sequence.

DNA 7-hydro-8-oxoguanine (8-oxoG) is implicated in frameshift formation in an G(6) sequence of the HPRT gene in mismatch repair (MMR) defective cells. Using oligonucleotides based on this frameshift hotspot, we investigated how a single 8-oxoG modified the structural and dynamic properties of the G(6) tract. A 30 ns molecular dynamics (MD) simulation indicated compression of the minor groove in the immediate vicinity of the lesion. Fluorescence polarization anisotropy (FPA) and MD demonstrated that 8-oxoG increases DNA torsional rigidity and also constrains the movement of the single-stranded region at the single/double stranded DNA junction of model DNA replication template/primer. These constraints influenced the efficiency of primer extension by Klenow (exo(-)) DNA polymerase.

Base Pair Mismatch↗
PubMed2026

Establishment of a human induced pluripotent stem cell line, KMUGMCi011-A, from a patient bearing a frameshift mutation in the KMT2D gene leading Kabuki syndrome 1.

Kabuki syndrome 1 is a rare genetic disorder typically characterized by facial abnormalities, cognitive impairment, developmental delay and organ dysfunction. It is caused by a loss-of-function mutation in the KMT2D gene. The peripheral blood mononuclear cells from a patient carrying frameshift mutation in the KMT2D gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. This frameshift mutation results in a truncated protein. This established human induced pluripotent cell line will allow proper in vitro disease modelling of Kabuki syndrome 1.

Journal Article↗
PubMed1986

Frameshift mutagenesis in Salmonella typhimurium by reversible DNA intercalators: effect of a UVR B mutation.

The simple reversible intercalating agents isopropyl-oxazolopyridocarbazole and 9-aminoacridine have been found to induce frameshift -1 mutations at a much lower level in Salmonella typhimurium delta uvrB TA 1537 than in the uvr+ wild type TA 1977 strain. This phenomenon can neither be explained by differential cytotoxicity of the drug nor by selective permeation and accessibility to intercalating sites to bacterial DNA. These finding indicate that the lower mutagenicity of intercalating agents in the delta uvrB strains does not result from nonspecific phenotypic modifications of parameters which control the mutagenesis. That leads to the hypothesis that in agreement with the Streisinger's model, the excision repair system could be directly involved in the appearance of frameshift mutations.

Aminacrine↗
PubMedDate not supplied

Construction of frameshift mutation hot spots within the tetracycline resistance gene of pBR322.

The chemical carcinogen, N-2-acetylaminofluorene (AAF) when bound covalently to DNA induces a majority (greater than 90%) of frameshift mutations. The mutations occur with high frequencies at defined sequences (i.e. mutation hot spots). Two classes of mutation hot spots were found: at repetitive sequences and at specific non-repetitive sequences. Mutations at the repetitive sequences depend upon a functional umuC gene whereas mutations at specific non-repetitive sequences are umuC-independent. The first discovered sequence of this class is the NarI restriction enzyme recognition sequence (5'GGCGCC3'). In an attempt to define a family of such sequences we constructed a related sequence 5'GCGCGC3' within the tetracycline resistance gene of pBR322. This sequence was also found to be an--AAF induced--2 frameshift mutation hot spot in both wild type and umuC strains.

2-Acetylaminofluorene↗
PubMed1980

Leaky +1 and -1 frameshift mutations at the same site in a yeast mitochondrial gene.

Two mutations in a mitochondrial structural gene, which cause leaky premature polypeptide chain termination and leaky growth, are +1 and -1 frameshifts in the same run of five T residues. The partial restoration of reading frame is probably due to ribosomal frameshifting at this site, and may be promoted by the unique structure of the yeast mitochondrial t RNAPhe.

DNA, Mitochondrial↗
PubMedDate not supplied

Expression of peptide chain release factor 2 requires high-efficiency frameshift.

Peptide chain release factors are soluble proteins that participate in the stop codon-dependent termination of polypeptide biosynthesis. In Escherichia coli, two release factors are necessary for peptide chain termination: release factor 1 (RF1) specifies UAG- and UAA-dependent termination whereas release factor 2 (RF2) specifies UGA- and UAA-dependent termination. Release factors are found in low concentrations relative to other translation factors, suggesting that their expression is tightly regulated and, accordingly, making the study of their structure-function relationship difficult. RF1 and RF2 exhibit significant sequence homology, probably reflecting their similar functions and perhaps a common evolutionary origin. DNA and peptide sequencing have suggested the existence of a unique mechanism for the autogenous regulation of RF2 in which an in-frame UGA stop codon requires an obligatory +1 frameshift within the coding region of the RF2 gene. In this report we present in vitro experimental results consistent with the autogenous regulation of RF2. Additionally, we used RF2-lacZ gene fusions to demonstrate that autogenous regulation occurs, at least in part, by premature termination at the in-frame stop codon, since deletion of this stop codon leads to overproduction of the RF2-LacZ fusion protein. Frameshifting at this premature termination codon occurs at the remarkably high rate of 50%.

Codon↗
PubMed1989

Biosynthesis of the reverse transcriptase of hepatitis B viruses involves de novo translational initiation not ribosomal frameshifting.

Retroviruses and many other types of genetic elements replicate by reverse transcription of RNA. Although structurally and biologically very diverse, such elements carry conserved polymerase genes (pol) that encode proteins required for reverse transcription. In most cases, the pol gene is preceded by an overlapping gene encoding one or more nucleocapsid proteins, in a different reading frame. Because both coding regions are represented in a single mRNA, the question arises of how the reverse transcriptase in the alternative reading frame is expressed. In retroviruses and retrotransposons it is expressed as a nucleocapsid-polymerase fusion protein by ribosomal frameshifting during translation of the overlapping region. We have examined the mechanism of polymerase biosynthesis in another family of animal viruses that use reverse transcription, the hepatitis B viruses. Genetic and biochemical studies reveal that these viruses do not use ribosomal frameshifting to generate this enzyme, but instead direct translation initiation at an internal initiation (AUG) codon in the polymerase gene.

Animals↗
PubMed1972

Low activity of -galactosidase in frameshift mutants of Escherichia coli.

16 lac frameshift mutants induced by an acridine derivative, ICR-191D, in E. coli are leaky for beta-galactosidase activity. Activities of all mutants differ from each other and from the wild type in their stability to thermal denaturation. The leakiness is under ribosomal control, since it is strongly reduced by strA restrictive mutations and is restored by ram mutations that reverse restriction. Addition of streptomycin during growth has an effect similar to the presence of the ram mutation. These ribosomal alterations do not modify the thermal stability of the enzyme.It is suggested that the leakiness is due to an infrequent 2- or 4-base reading close to the frameshift mutation site. The possibility that not only the ribosome, but also the reading context in the messenger, plays a role in securing code fidelity is discussed.

Acridines↗
PubMed1976

Hemoglobin Wayne: a frameshift mutation detected in human hemoglobin alpha chains.

Hemoglobin Wayne is an alpha chain variant which manifests itself as two minor hemoglobin (Hb) components that migrate more rapidly than Hb A on electrophoresis at pH 8.6. It has been found in a child with Fanconi's anemia and in three generations of the child's family. Each of the minor components yields an alpha chain in which the carboxyl-terminal tripeptide sequence, Lys-Tyr-Arg, has been replaced by the octapeptide sequence Asx-Thr-Val-Lys-Leu-Glu-Pro-Arg. In alpha Wayne I, the slower of the pair, Asx is asparagine, whereas in alpha Wayne II it is aspartic acid. Comparison of the alpha Wayne sequences with the amino-acid sequences of alpha A and alpha Constant Spring leads to the conclusion that Hb Wayne I is the result of a -1 frameshift mutation in the alpha chain and that Hb Wayne II is formed secondarily by spontaneous deamidation of the new asparagine residue. A frameshift is consistent with a single mRNA base sequence for the last eight codons involved and supports the view of Clegg, Weatherall, and Milner [Nature (1971) 234, 337-341] that Hb Constant Spring is the result of a terminator mutation leading to translation of 31 codons not normally translated.

Amino Acid Sequence↗
PubMed1979

Disparity of gene conversion in frameshift mutants located in locus b2 of Ascobolus immersus.

The frequency of conversion and the disparity in the direction of conversion were studied for six frameshift mutants lying in locus b2 of Ascobolus immersus and giving more 2 wild type:6 mutant (2+6m) than 6 wild type:2 mutant (6+2m) aberrant asci (type B). The frequency of conversion decreased from left to right in the locus. The disparity steadily increased from left to right and then reached a plateau. Twenty-two frameshift mutants giving more 6+2m than 2+6m aberrant asci (type A) and closely linked to three type B mutants were also studied; they showed the same frequency of conversion and the same disparity (but in the opposite direction) as the type B mutant to which they are linked. The polar variation of both the frequency of conversion and the disparity as a function of position were expected on the basis of a previous study of 15 mutants giving postmeiotic segregations and located in locus b2. This variation is assumed to reflect the existence of a preferential region for the initiation of hybrid DNA (HDNA) during recombination and a duality in the distribution of this HDNA, with preponderant asymmetrical HDNA near the starting point and preponderant symmetrical HDNA farther from it.

Journal Article↗
PubMed1982

Nucleotide sequence of the SUF2 frameshift suppressor gene of Saccharomyces cerevisiae.

To elucidate the molecular mechanism of frameshift suppression by the SUF2 gene of yeast, the sequences of DNA fragments carrying the SUF2-1 and suf2+ alleles of the gene and surrounding regions have been determined. Comparison of the suppressor and wild-type sequences indicates that the SUF2 gene product is a proline tRNA. Disregarding possible base modifications, we find that the wild-type suf2+ anticodon of the tRNA inferred from the DNA sequence is 3'-GGA-5'. The SUF2-1 mutation represents the insertion of a G-C base pair at a position in the gene that corresponds to the anticodon loop of the tRNA. Replacement of the wild-type suf2+ anticodon by a 3'-GGGA-5' fourbase anticodon enables the SUF2-1 tRNA to suppress the 5'-CCCU-3' four-base codons generated as the result of the his4-712 and his4-713 frameshift mutations. This nontriplet codon-anticodon interaction restores the correct reading frame and allows synthesis of a functional his4 protein.

Base Sequence↗
PubMed1983

A frameshift mutation affecting the carboxyl terminus of the simian virus 40 large tumor antigen results in a replication- and transformation-defective virus.

We have constructed a frameshift mutation in the simian virus 40 early region using a novel method of oligonucleotide-directed mutagenesis. The mutated DNA specifies an 84,000-dalton large tumor antigen that consists of approximately equal to 75,000 daltons encoded by the wild-type reading frame and 9,000 daltons, by the alternative reading frame (wild-type large tumor antigen is approximately equal to 82,000 daltons). The frameshifted carboxyl terminus of the protein bears a strong similarity to the same region of polyoma virus middle-sized tumor antigen. We have found that the mutant DNA is unable to replicate when introduced into permissive monkey cells and incapable of transforming nonpermissive mouse cells.

Amino Acid Sequence↗
PubMed1984

Molecular model of ribosome frameshifting.

Normal tRNAs can cause two- and four-base translocation errors by mistranslating certain noncognate codons. Several cases have been reported that reveal the identities of the frameshift-provoking tRNAs--i.e., the shifty tRNAs--and the mRNA sequence encompassing the site of frameshifting--i.e., the shifty codons. Here, a striking uniformity between the anticodon loops of the shifty tRNAs and their shifty codons is described. Stable "offset" anti-codon X codon pairs are postulated for each of the shifty tRNA-shifty codon combinations. This offset anticodon X codon pair leads to two- and four-base translocations when viewed in terms of the reciprocating ratchet mechanism of translocation.

Codon↗
PubMed1984

Suppressor sufJ: a novel type of tRNA mutant that induces translational frameshifting.

We describe the DNA sequence change responsible for the creation of a frameshift-suppressor gene in Salmonella typhimurium. The suppressor, sufJ, results from a base-pair insertion in the gene coding for a threonine transfer RNA (tRNA3Thr). Unlike previously studied frameshift suppressor mutations, the sufJ insertion does not fall within the sequence corresponding to the tRNA anticodon. The insertion (a G.C base pair) occurs within a run of three G.C base pairs in that region of the gene coding for one strand of the anticodon stem. In the secondary structure of the mature tRNA, the net result is that an extra, unpaired cytidine residue is pushed into the anticodon loop, thus increasing the size of the loop to eight nucleotides. These findings are discussed in connection with the peculiar "three-out-of-four" method of reading by the sufJ suppressor. A unifying model is presented accounting for the contrasting decoding behaviors of tRNAs with eight-nucleotide-long anticodon loops.

Alleles↗
PubMed1987

Mutation to male fertility and toxin insensitivity in Texas (T)-cytoplasm maize is associated with a frameshift in a mitochondrial open reading frame.

Tissue culture-derived mutants of male-sterile and disease toxin-sensitive Texas (T)-cytoplasm maize that exhibit male fertility and toxin insensitivity carry numerous alterations in mitochondrial DNA. In these mutants, a 6.7-kilobase Xho I fragment characteristic of parental T cytoplasm has been rearranged. In the mutant T-4, the parental 6.7-kilobase Xho I fragment contains a guanine to adenine transition adjacent to a 5-base-pair insertion not found in T cytoplasm. The insertion, internal to a 345-base-pair open reading frame (T ORF13), generates a frameshift, resulting in a premature stop codon that terminates the open reading frame at base pair 222. In other mutants, the 345-base-pair ORF is part of a 3-kilobase deletion, which extends into a 5-kilobase repeat characteristic of mtDNA from T but not N male-fertile cytoplasm. Clones specific to T ORF13 hybridize to eight transcripts in T and T-4, yet only hybridize to three transcripts in T-7, a deletion mutant. Transcription of the T ORF13 region appears not to be altered in T-4, but the frameshift mutation in the T ORF13 reading frame indicates that a biologically inactive gene product could be associated with the mutational events. The results suggest that cytoplasmic male sterility and disease toxin sensitivity may be associated with presence of T ORF13 in T-cytoplasm maize.

Journal Article↗
PubMed1989

Glycine tRNA mutants with normal anticodon loop size cause -1 frameshifting.

Mutations in the acceptor stem, the 5-methyluridine-pseudouridine-cytidine (TFC) arm, and the anticodon of Salmonella tRNA2Gly can cause -1 frameshifting. The potential for standard base pairing between acceptor stem positions 1 and 72 is disrupted in the mutant sufS627. This disruption may interfere with the interaction of the tRNA with elongation factor-Tu.GTP or an as-yet-unspecified domain of the ribosome. The potential for standard base pairing in part of the TFC stem is disrupted in mutant sufS625. The nearly universal C-61 base of the TFC stem is altered in mutant sufS617, and the TFC loop is extended in mutant sufS605. These changes are expected to interfere with the stability of the TFC loop and its interaction with the D arm. The mutation in mutant sufS605, and possibly other mutants, alters nucleoside modification in the D arm. Three mutants, sufS601, sufS607, and sufS609, have a cytidine substituted for the modified uridine at position 34, the first anticodon position. None of the alterations grossly disrupts in-frame triplet decoding by the mutant tRNAs. The results show that -1 frameshifting in vivo can be caused by tRNAs with normal anticodon loop size and suggest that alternative conformational states of the mutant tRNAs may allow them to read a codon in frame or to shift reading frame.

Anticodon↗