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At least 145 records · Page 8Linked to original sources
PubMed1997

Insertion of tandem direct repeats consisting of avian leukosis virus LTR sequences into the inverted repeat region of Marek's disease virus type 1 DNA.

The BC-1 strain DNA of Marek's disease virus type 1 (MDV1) at high-passage in culture was found to contain tandem direct repeats of the complete long terminal repeat (LTR) sequence of avian leukosis virus RAV0 strain as the repeat unit within the short inverted repeats of the MDV1 DNA. Since the attenuated BC-1 strain grows well in cultured cells, the insertion site for retroviral DNA sequence within the short inverted repeat of MDV1 DNA is not essential for viral growth in culture.

Animals↗
PubMed1987

Unusual structure of geranium chloroplast DNA: A triple-sized inverted repeat, extensive gene duplications, multiple inversions, and two repeat families.

Physical and gene mapping studies reveal that chloroplast DNA from geranium (Pelargonium hortorum) has sustained a number of extensive duplications and inversions, resulting in a genome arrangement radically unlike that of other plants. At 217 kilobases in size, the circular chromosome is about 50% larger than the typical land plant chloroplast genome and is by far the largest described to date, to our knowledge. Most of this extra size can be accounted for by a 76-kilobase inverted duplication, three times larger than the normal chloroplast DNA inverted repeat. This tripling has occurred primarily by spreading of the inverted repeat into regions that are single copy in all other chloroplast genomes. Consequently, 10 protein genes that are present only once in all other land plants are duplicated in geranium. At least six inversions, occurring in both the inverted repeat and large single-copy region, must be postulated to account for all of the gene order differences that distinguish the geranium genome from other chloroplast genomes. We report the existence in geranium of two families of short dispersed repeats and hypothesize that recombination between repeats may be the major cause of inversions in geranium chloroplast DNA.

Journal Article↗
PubMed1993

A polymorphic X-linked tetranucleotide repeat locus displaying a high rate of new mutation: implications for mechanisms of mutation at short tandem repeat loci.

We report a high rate of new mutation at a short tandem repeat sequence polymorphism (STR, microsatellite) at locus DXS981 on the proximal long arm of the human X chromosome. Among individuals of the CEPH pedigrees, new allele lengths are detected at this tetranucleotide repeat with a frequency of approximately 1.5%. In cases where the origin of the new allele was traceable, new mutant alleles at DXS981 varied by exactly one repeat length (4 bp) relative to that on the originating parental chromosome. Complete linkage disequilibrium between two additional insertion/deletion polymorphisms which closely flank the variation at the tetranucleotide repeat suggests that, to the extent that these new mutants are germline in origin, they are not generated by unequal exchange between homologues. Considered in light of the types of new mutations detected and the substantial linkage disequilibrium at this locus, these data have implications for the mechanism of variation at other loci containing short tandemly repeated sequences.

Alleles↗
PubMed1995

Heterogeneity of DM kinase repeat expansion in different fetal tissues and further expansion during cell proliferation in vitro: evidence for a casual involvement of methyl-directed DNA mismatch repair in triplet repeat stability.

We have analysed the mitotic behaviour of expanded CTG repeats in somatic tissues and cultured somatic cells from myotonic dystrophy (DM) fetuses using indirect and direct methods. Heterogeneity of expansions between fetal tissues was demonstrated in a 16 week old fetus whereas there was no evidence for such a somatic heterogeneity in a 13 week old fetus. Dilution plating of cultured cells from an adult patient and a fetus resulted in isolation of clones showing single expanded restriction fragments when the donor showed a heterogeneous smear of expansions or a single expanded fragment. During proliferation in vitro to 45 doublings, DM cells experienced highly synchronous further repeat expansion which first became evident at approximately 15 cell generations and reached a plateau of maximum expansion at approximately 200 days. When mathematically expressed as a function of culture time the dynamics of expansion of restriction fragments followed a sigmoid curve. This unstable behaviour of CTG repeat expansions in DM was compared to the mitotically stable patterns of full mutation in fragile X fetal tissues and led to the hypothesis that methylation of CpGs within the repeat sequence is a stabilizing factor of largely expanded CGG and GCC repeats allowing for efficient methyl-directed strand-specific DNA mismatch repair.

Adult↗
PubMed1991

The highly variable pentameric repeats of the AT-rich germline limited DNA in Parascaris univalens are the telomeric repeats of somatic chromosomes.

We have characterized the organization of the germline limited DNA of P. univalens by means of sequence analysis. The repeat unit of this satellite DNA is the pentanucleotide 5'TTGCA, although there is a high degree of sequence variation. Repeat variants are not arranged in tandem but in a disperse, nonrandom manner. In the somatic genome which arises from the germline genome through extensive genomic rearrangement early in development, copies of these pentamers represent the telomeric repeats, indicated by their sensitivity to Bal 31 and their presence in a somatic endlibrary. Unlike telomeric sequences from other species the P. univalens telomeres do not display consecutive guanines and no strand bias for that base, recently suggested as universal features of eukaryotic telomeres. Investigation of fragments that carry pentameric repeats along with sequences of different type identifies a 5 bp consensus sequence at the junction point. We suggest a model in which pentameric repeats originate via amplification by a terminal transferase (telomerase) in both the germline and the somatic genome.

Animals↗
PubMed2006

Characterization of two potentially universal turn motifs that shape the repeated five-residues fold--crystal structure of a lumenal pentapeptide repeat protein from Cyanothece 51142.

The genome of the diurnal cyanobacterium Cyanothece sp. PCC 51142 has recently been sequenced and observed to contain 35 pentapeptide repeat proteins (PRPs). These proteins, while present throughout the prokaryotic and eukaryotic kingdoms, are most abundant in cyanobacteria. The sheer number of PRPs in cyanobacteria coupled with their predicted location in every cellular compartment argues for important, yet unknown, physiological and biochemical functions. To gain biochemical insights, the crystal structure for Rfr32, a 167-residue PRP with an N-terminal 29-residue signal peptide, was determined at 2.1 A resolution. The structure is dominated by 21 tandem pentapeptide repeats that fold into a right-handed quadrilateral beta-helix, or Rfr-fold, as observed for the tandem pentapeptide repeats in the only other PRP structure, the mycobacterial fluoroquinoline resistance protein MfpA from Mycobacterium tuberculosis. Sitting on top of the Rfr-fold are two short, antiparallel alpha-helices, bridged with a disulfide bond, that perhaps prevent edge-to-edge aggregation at the C terminus. Analysis of the main-chain (Phi,Psi) dihedral orientations for the pentapeptide repeats in Rfr32 and MfpA makes it possible to recognize the structural details for the two distinct types of four-residue turns adopted by the pentapeptide repeats in the Rfr-fold. These turns, labeled type II and type IV beta-turns, may be universal motifs that shape the Rfr-fold in all PRPs.

Amino Acid Motifs↗
PubMed1984

The tandem direct repeats within the long terminal repeat of murine leukemia viruses are the primary determinant of their leukemogenic potential.

To map the viral sequences encoding the leukemogenic determinant(s) of nondefective murine leukemia viruses (MuLVs), we constructed chimeric viral genomes in vitro between cloned viral DNAs from the highly leukemogenic Gross passage A (Gross A) MuLV and from the related nonleukemogenic BALB/c N-tropic MuLV. Infectious chimeric MuLVs, recovered from murine cells microinjected with these DNAs, were inoculated into newborn mice to test the leukemogenic potential of these viruses. We found that the U3 long terminal repeat region from Gross A genomes was sufficient to confer an intermediate leukemogenic potential to chimeric MuLVs. Sequencing data indicated that the U3 tandem direct repeat was responsible for this effect. Adding most of the Gross A p15E-coding sequences to the Gross A U3 long terminal repeat enhanced the leukemogenic potential of chimeric viruses significantly. Adding a larger 3'-end env region (all p15E-coding sequences and 345 base pairs of the carboxy terminus of gp70) to the Gross A U3 long terminal repeat restored the full leukemogenic potential of Gross A MuLV. Chimeric viruses harboring only the Gross A 3'-end env region were, however, nonleukemogenic. Similar chimeric MuLVs, constructed with genomes from the parental weakly leukemogenic BALB/c B-tropic MuLVs and nonleukemogenic BALB/c N-tropic MuLVs, were also studied. Our data indicate that the U3 tandem direct repeat sequences appear to be necessary and sufficient to confer some leukemogenic potential to MuLV. However, env 3'-end sequences, mostly the p15E-encoding sequences, are required for the expression of fully leukemic phenotypes.

AKR murine leukemia virus↗
PubMed2000

G239T mutation in Repeat 1 of human IRBP: possible implications for more than one binding site in a single repeat.

PURPOSE: Interphotoreceptor retinoid-binding protein(IRBP) is a four-repeat protein found in the interphotoreceptor space. Each repeat can bind retinoids and fatty acids. The purpose of this study was to examine the effects of the single amino acid substitution, G239T, versus the wild type sequence of human IRBP Repeat 1, on ligand binding at equilibrium, ligand off rates, and protection of retinol from degradation. METHODS: G239T was created by site-specific mutagenesis, expressed in E. coli, and purified. E. coli expressed wild type Repeat 1 (EcR1) and G239T were subjected to thermal denaturation and analyzed by circular dichroism spectroscopy. We compared the ligand binding properties by fluorescence enhancement of retinol and 16-anthroyloxy-palmitate, tryptophan quenching of the proteins by different ligands, binding competition assays, protection of retinol from degradation, and stopped-flow kinetics to measure transfer of ligands to and from model membranes. RESULTS: Circular dichroism, fluorescence, and absorbance spectroscopy of G239T and EcR1 showed similar wavelength scans. G239T exhibited about three-fold less fluorescence of bound all-trans-retinol or 13-cis-retinol versus EcR1. Retinol quenching of intrinsic protein fluorescence was reduced by 37% in G239T versus EcR1. Other retinoids used as quenchers produced no difference between intrinsic protein fluorescence of either G239T or EcR1; all exhibited saturable high affinity binding to each protein. Docosahexaenoic acid (DHA) served as a competitive inhibitor of retinol fluorescence enhancement with EcR1. However, DHA did not alter retinol fluorescence with G239T. 16-anthroyloxy-palmitate (16-AP) exhibited about 30% higher levels of fluorescence enhancement when bound to G239T versus EcR1. EcR1 prevented oxidative damage of all-trans-retinol, whereas G239T provided much less protection. Each protein could accept 9-cis-retinal from small unilamellar vesicles (SUVs) as measured by stopped flow kinetics. Off rates were the same in comparing G239T and EcR1 as acceptors. CONCLUSIONS: Despite the general similarity in shape between G239T and EcR1 and the nearly identical binding behavior with some ligands, distinct differences exist in the ligand binding properties of G239T and EcR1. Fluorescence enhancement/quenching and retinol protection experiments suggest that retinol binding is reduced by about 50% in G239T versus EcR1. The data suggest that either: (1) EcR1 contains two binding sites for retinol and G239T has lost one site or (2) EcR1 has a single binding site that is altered in G239T to reduce retinol binding. Results of all the experiments were consistent with the first model while some of the data were not consistent with the second model. Thus, it is possible that position 239, found in Domain B2 of IRBP Repeat 1, is located in or near one of two retinol binding sites.

Amino Acid Substitution↗
PubMed2000

Repeat prescribing: a role for community pharmacists in controlling and monitoring repeat prescriptions.

BACKGROUND: Traditional systems of managing repeat prescribing have been criticised for their lack of clinical and administrative controls. AIM: To compare a community pharmacist-managed repeat prescribing system with established methods of managing repeat prescribing. METHOD: A randomised controlled intervention study (19 general medical practices, 3074 patients, 62 community pharmacists). Patients on repeat medication were given sufficient three-monthly scripts, endorsed for monthly dispensing, to last until their next clinical review consultation with their general practitioner (GP). The scripts were stored by a pharmacist of the patient's choice. Each monthly dispensing was authorised by the pharmacist, using a standard protocol. The cost of the drugs prescribed and dispensed was calculated. Data on patient outcomes were obtained from pharmacist-generated patient records and GP notes. RESULTS: A total of 12.4% of patients had compliance problems, side-effects, adverse drug reactions, or drug interactions identified by the pharmacist. There were significantly more problems identified in total in the intervention group. The total number of consultations, deaths, and non-elective hospital admissions was the same in both groups. Sixty-six per cent of the study patients did not require their full quota of prescribed drugs, representing 18% of the total prescribed costs (estimated annual drug cost avoidance of 43 Pounds per patient). CONCLUSION: This system of managing repeat prescribing has been demonstrated to be logistically feasible, to identify clinical problems, and to make savings in the drugs bill.

Adolescent↗
PubMedDate not supplied

[Convergent origin of repeats in genes coding for globular proteins. An analysis of the factors determining the presence of inverted and symmetrical repeats].

The factors, determining the presence of inverted and symmetrical repeats in genes coding for globular proteins, have been analysed. An interesting property of genetical code has been revealed in the analysis of symmetrical repeats: the pairs of symmetrical codons corresponded to pairs of amino acids with mostly similar physical-chemical parameters. This property may explain the presence of symmetrical repeats and palindromes only in genes coding for beta-structural proteins-polypeptides, where amino acids with similar physical-chemical properties occupy symmetrical positions. A stochastic model of evolution of polynucleotide sequences has been used for analysis of inverted repeats. The modelling demonstrated that only limiting of sequences (uneven frequencies of used codons) is enough for arising of nonrandom inverted repeats in genes.

Amino Acid Sequence↗
PubMedDate not supplied

[son Pseudogenes do not contain five repeating elements of the region of complete tandem repeats present in the homologous sequence of the son gene].

Recently we have published a sequence of the coding region of the son gene, containing at least six areas of the tandem repeats [V.V. Bliskovsky, F.B. Berdichevsky, A.V. Tkachenko, M.E. Belova, I.M. Chumakov--Molecularnaya biologiya, 1992, V. 26. P. 793-806; V.V. Bliskovsky, A.V. Kirillov, V.M. Zacharyev, I.M. Chumakov--Molecularnaya biologiya, 1992, V. 26. P. 807-812]. The presence of several areas of tandem repeats with different nucleotide sequences of the repeated elements within one and the same gene supports the proposition that genomic localization of the sequence influences its duplication. Here we present a nucleotide sequence of the son pseudogene isolated as the result of hybridization screening of a human genomic library using the sequence of the son gene as a probe. The comparison of the gene and the pseudogene nucleotide sequences shows that the sequence of pseudogene does not contain five repeated units of an area of the tandem repeats, which are presented in the homology sequence of the son gene. Because the pseudogene was probably generated by the reverse son-gene transcript insertion to the genome, and so the nucleotide sequences of the coding region of the gene and the sequence of the pseudogene were identical at this moment, the differences between the gene and the pseudogene are the results of their evolution after the generation of the pseudogene. Possible factors, influenced the son gene and the son pseudogene evolution are discussed.

Base Sequence↗
PubMed1998

Large CAG/CTG repeat templates produced by PCR, usefulness for the DIRECT method of cloning genes with CAG/CTG repeat expansions.

We report here a simple method for generating large CAG/CTG repeat sequences. We have applied this method to clone the genomic sequence containing the CAG/CTG repeat and its upstream intronic sequence present in spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD) by a modified DIRECT method. With these modifications we have considerably simplified the generation of the repeat probe used to screen for anomalous bands. This method will facilitate the molecular approach to other genetic disorders where expansions of repeat sequences could be involved.

Base Sequence↗
PubMed1996

Mosaicism of a microdeletion of 486 bp involving the CGG repeat of the FMR1 gene due to misalignment of GTT tandem repeats at chi-like elements flanking both breakpoints and a full mutation.

Although the majority of fragile-X patients demonstrate methylation and a much-expanded CGG repeat region in the 5'-untranslated region of exon 1 of the FMR1 gene, exceptional cases have been reported to be due to deletions. However, fine mapping of the deletion breakpoints is still lacking and so far the underlying mechanism is unknown. We identified a fragile-X patient mosaic for a full mutation and a microdeletion. The microdeletion spans 486 bp, involving 168 bp upstream from the CGG repeat region, the entire CGG repeat region, exon 1, and 138 bp of the first intron of the FMR1 gene. In contrast to previous reports, the 5' breakpoint does not fall into the hotspot region. The proximal breakpoint, 5'-GTGGTT/T-3', and the distal breakpoint, 5'-GTTGTT/GG-3', can be characterized as chi-like elements and are flanked by direct tandem repeats. Mosaicism of a full mutation and the microdeletion in the DNA of the patient's leukocytes indicates the mitotic origin of the microdeletion. Since the microdeletion allele is unmethylated, it can be concluded that it is not derived from the methylated full mutation but from an unmethylated premutational allele.

Base Composition↗
PubMed1997

The number of triplet repeats in five brain-expressed loci with CAG repeats is not associated with schizophrenia.

We have previously shown that large expansions of CAG (CTG) triplets are associated both with schizophrenia itself and with an early age-at-onset of the disease. However, the repeat expansion detection (RED) method used did not provide a chromosomal location for the expanded region(s) (Morris et al., 1995). In a further study of our schizophrenic and control patients, we have now examined the length of the repeated sequence in five loci that are expressed in brain and are known to contain CAG repeat regions (Li et al., 1993). No enlarged repeat regions were identified; it is unlikely therefore that expansions at any of these five loci can account for expansions of up to 136 triplets identified by the RED method.

Age of Onset↗
PubMed2001

Polymorphic insertion of additional repeat within an area of direct 8 bp tandem repeats in the 5'-untranslated region of the p53R2 gene and cancer risk.

p53R2 is a recently cloned gene that functions in p53-induced DNA repair. In the 5'-untranslated region of the p53R2 gene two direct tandem 8 bp repeats are located. Within the region of these 8 bp direct repeats we have detected the insertion of an additional repeat. In order to determine a possible association of this novel polymorphism with any cancer or population, we carried out genotyping of 843 European and Asian controls and patients with various cancer types. In addition, 26 cancer cell lines were included in the study. No significant difference in polymorphic frequency could be demonstrated for any of the cancer types, although the allelic frequency in melanoma patients was lower than in controls (chi(2) = 3.28; P = 0.07; OR = 0.32; 95% CI 0.07-1.26). A significantly higher frequency of the polymorphism was detected in the compiled Caucasian individuals compared with Asians (chi(2) = 9.19; P = 0.002; OR = 3.13; 95% CI 1.39-7.43). In one tumour cell line we observed two extra inserted copies of the 8 bp repeat. The functional effect of the insertion polymorphism on the p53R2 gene transcription remains to be determined.

5' Untranslated Regions↗
PubMed2004

Both CAG repeats and inverted DNA repeats stimulate spontaneous unequal sister-chromatid exchange in Saccharomyces cerevisiae.

Genomic regions containing trinucleotide repeats (TNRs) are highly unstable, as the repeated sequences exhibit a high rate of mutational change, in which they undergo either a contraction or an expansion of repeat numbers. Although expansion of TNRs is associated with several human genetic diseases, the expansion mechanism is poorly understood. Extensive studies in model organisms have indicated that instability of TNRs occurs by several mechanisms, including replication slippage, DNA repair and recombination. In all models, the formation of secondary structures by disease-associated TNRs is a critical step in the mutation process. In this report, we demonstrate that TNRs and inverted repeats (IRs) both of which have the potential to form secondary structures in vivo, increase spontaneous unequal sister-chromatid exchange (SCE) in vegetatively growing yeast cells. Our results also show that TNR-mediated SCE events are independent of RAD50, MRE11 and RAD51, whereas IR-stimulated SCEs are dependent on the RAD52 epistasis-group genes. We propose that many TNR expansion mutations occur by SCE.

DNA↗
PubMed2025

Pentatricopeptide repeat protein targeting CUG repeat RNA ameliorates RNA toxicity in a myotonic dystrophy type 1 mouse model.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by the expansion of a CTG-triplet repeat in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. It results in the transcription of toxic RNAs that contain expanded CUG repeats (CUGexp). Splicing factors, such as muscleblind-like 1 (MBNL1), are sequestered by CUGexp, thereby disrupting the normal splicing program that is essential for various cellular functions. Pentatricopeptide repeat (PPR) proteins, originally found in plants, regulate RNA in organelles by binding in a sequence-specific manner. Here, we designed PPR proteins that specifically bind to the hexamer of CUG repeat RNAs (CUG-PPRs) and showed that CUG-PPR1 could ameliorate RNA toxicity induced by CUGexp in cell models of DM1. A single systemic recombinant adeno-associated virus (AAV9) vector-mediated gene delivery of CUG-PPR1 demonstrated long-term therapeutic effects on myotonia and restored splicing activity in a mouse model of DM1. These results highlight the potential of PPR molecules to target pathogenic RNA sequences in DM1 and potentially other RNA-mediated disorders.

Animals↗
PubMed1995

Identification of two human sequence-specific DNA-binding proteins which interact with the direct repeats in the squirrel monkey retrovirus long terminal repeat.

Squirrel monkey retrovirus (SMRV) is a xenotropic endogenous virus of the squirrel monkey. The long terminal repeat of the SMRV contains four direct repeats (43 or 42 bp) with different degrees of perfection in the U3 region. Herein, we found two human nuclear proteins (SMBP1 and SMBP2) which bind specifically to the direct repeats with different affinities. The binding proteins recognize overlapped sequences in the 5' region of the repeats. SMBP1 and 2 are monomeric proteins of 35 and 17 kDa, respectively.

Animals↗