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At least 1,099 records · Page 61Linked to original sources
PubMed2003

Detection of tRNA-like structure through RNase P cleavage of viral internal ribosome entry site RNAs near the AUG start triplet.

The 9600-base RNA genome of hepatitis C virus (HCV) has an internal ribosome entry site (IRES) in its first 370 bases, including the AUG start triplet at bases 342-344. Structural elements of this and other IRES domains substitute for a 5' terminal cap structure in protein synthesis. Recent work (Nadal, A., Martell, M., Lytle, J. R., Lyons, A. J., Robertson, H. D., Cabot, B., Esteban, J. I., Esteban, R., Guardia, J., and Gomez, J. (2002) J. Biol. Chem. 277, 30606-30613) has demonstrated that the host pre-tRNA processing enzyme, RNase P, can cleave the HCV RNA genome at a site in the IRES near the AUG initiator triplet. Although this step is unlikely to be part of the HCV life cycle, such a reaction could indicate the presence of a tRNA-like structure in this IRES. Because susceptibility to cleavage by mammalian RNase P is a strong indicator of tRNA-like structure, we have conducted the studies reported here to test whether such tRNA mimicry is unique to HCV or is a general property of IRES structure. We have assayed IRES domains of several viral RNA genomes: two pestiviruses related to HCV, classical swine fever virus and bovine viral diarrhea virus; and two unrelated viruses, encephalomyocarditis virus and cricket paralysis virus. We have found similarly placed RNase P cleavage sites in these IRESs. Thus a tRNA-like domain could be a general structural feature of IRESs, the first IRES structure to be identified with a functional correlate. Such tRNA-like features could be recognized by pre-existing ribosomal tRNA-binding sites as part of the IRES initiation cycle.

Animals↗
PubMed2005

A more complex isoleucine aptamer with a cognate triplet.

The simplest RNA that can meet a column affinity selection for isoleucine was previously defined using selection amplification with decreasing numbers of randomized nucleotides. This simplest UAUU motif was a small asymmetric internal loop. Conserved positions of the loop include isoleucine codon and anticodon triplets (Lozupone C., Changayil, S., Majerfeld, I., and Yarus, M. (2003) RNA (N. Y.) 9, 1315-1322). Using new primer sequences, we now select a somewhat more complex isoleucine binding RNA, requiring 4.7 more bits of information to describe. The newly selected structure is a terminal or hairpin loop of 20 nucleotides, 15 being invariant. An information profile shows that the new binding site contains five short functional loop regions joined by less significant single nucleotide positions. Among the important nucleotides is a conserved isoleucine anticodon, supporting the escaped triplet theory, which posits a stereochemical genetic code originating in RNA amino acid binding sites.

Anticodon↗
PubMed1999

Identification of a good c-myc antisense oligodeoxynucleotide target site and the inactivity at this site of novel NCH triplet--targeting ribozymes.

A region of c-myc mRNA was identified which permitted very efficient antisense effects to be achieved in living cells using chimeric methylphosphonate--phosphodiester antisense effectors. Novel inosine--containing ribozymes (which cleave after NCH triplets) were directed to an ACA triplet within this region and delivered into living cells. No ribozyme intracellular activity could be identified. Very low ribozyme function was also observed in in vitro assays using a 1700nt substrate RNA.

Bacterial Proteins↗
PubMed2000

Genetic instabilities of triplet repeat sequences by recombination.

The expansion of triplet repeat sequences is an initial step in the disease etiology of a number of hereditary neurological disorders in humans. Diseases such as myotonic dystrophy, Huntington's, several spinocerebellar ataxias, fragile X syndrome, and Friedreich's ataxia are caused by the expansions of CTG.CAG, CGG.CCG, or GAA.TTC repeats. The mechanisms of the expansion process have been investigated intensely in E. coli, yeast, transgenic mice, mammalian cell culture, and in human clinical cases. Whereas studies from 1994-1999 have implicated DNA replication and repair at the paused synthesis sites due to the unusual conformations of the triplet repeat sequences, recent work has shown that homologous recombination (gene conversion) is a powerful mechanism for generating massive expansions, in addition to, or in concert with, replication and repair.

Animals↗
PubMed1999

A novel frequency domain fluorescence technique for determination of triplet decay times.

Frequency domain fluorescence measurement using two diode lasers with amplitude modulation in the kHz range yields a signal component at the sum frequency. This intermodulation phenomenon was observed in an aqueous solution of haematoporphyrin (HP) and could be related to triplet state population kinetics. This indirect measurement technique may allow triplet decay time measurement during photodynamic therapy (PDT) enabling monitoring of the type II phototoxic damage rate.

Biophysical Phenomena↗
PubMed2002

Oxaliplatin plus irinotecan and leucovorin-modulated 5-fluorouracil triplet regimen every other week: a dose-finding study in patients with advanced gastrointestinal malignancies.

BACKGROUND: Oxaliplatin (OXA) and irinotecan (IRI) are active drugs in first-line as well as second-line treatment of advanced colorectal cancer patients, their toxicity profiles are not overlapping, and both drugs have shown synergism with folinic acid-modulated 5-fluorouracil (5-FU). We planned this phase I study to define the dose-limiting toxicities (DLTs), the maximum tolerated doses (MTDs), and the recommended doses (RDs) for a triplet regimen including OXA plus IRI on day 1, and 6S-folinic acid (LFA) plus 5-FU on day 2, every 2 weeks. PATIENTS AND METHODS: At least three patients had to be treated at each dose level, and the trial proceeded if no more than 33% of patients showed a DLT after the first cycle. Starting from OXA 85 mg/m(2) (over 2 h) and IRI 150 mg/m(2) (over 1 h), an alternated escalation was planned up to 110 mg/m(2) and 200 mg/m(2), respectively. Thereafter, a fixed dose of LFA, 250 mg/m(2) (as 2-h infusion), plus an escalating dose of 5-FU (from 650 to 800 mg/m(2) as an intravenous bolus) was added on day 2 to the previous dose level of OXA and IRI. RESULTS: Forty-six patients, all but four affected by advanced colorectal primaries, entered this study. The MTDs for OXA and IRI given on the same day were 110 and 200 mg/m(2): these doses caused a DLT in three of six patients. The previous dose level (110 and 175 mg/m(2), respectively) on day 1 was safely followed on day 2 by LFA plus 5-FU up to 800 mg/m(2). Indeed, only one of three patients treated at this last level had a DLT. This cohort was then expanded including a total of 14 patients, and on the whole series five cases of DLT occurred: WHO grade 4 neutropenia (two patients), grade 3 or 4 diarrhoea (three patients). Cumulative toxicity was analysed in 43 patients for a total of 347 cycles: grade 4 neutropenia was detected in 13 patients (30%); it was not dose-related, nor was it exacerbated by the addition of modulated 5-FU. Febrile neutropenia occurred in four patients. Grade 3 or 4 diarrhoea was suffered by nine (21%) and five (12%) patients, respectively. Two complete and nine partial responses were reported on 40 evaluable patients (six patients were disease-free at study entry), giving a response rate of 27.5% (95% confidence interval 15% to 44%); nine of 18 (50%) assessable patients of the two last cohorts treated with the triplet regimen achieved a complete response (two patients) or a partial response (seven patients). CONCLUSIONS: The RDs for this biweekly regimen were: OXA 110 mg/m(2) plus IRI 175 mg/m(2) on day 1, and LFA 250 mg/m(2) plus 5-FU 800 mg/m(2) on day 2. This regimen appeared active in pretreated gastrointestinal malignancies, and it is worthy of being evaluated in advanced colorectal carcinoma after failure of 5-FU-based adjuvant or palliative treatment.

Adolescent↗
PubMed1994

Precursor arrays for triplet repeat expansion at the fragile X locus.

To determine factors governing triplet repeat expansion at FMR1, we need to understand the basis of normal variation. We have sequenced the FMR1 repeat from 102 normal X chromosomes and show that most are interrupted with a regularly spaced AGG trinucleotide giving an ordered structure to the array. Five types of arrays were identified consisting of varying numbers of a core unit with consensus [AGG(CGG)9]. Additional variation in the length of the (CGG)n portion within each unit generates the continuum of lengths seen on normal chromosomes. Ten per cent contain long, uninterrupted tracts of (CGG)n, and their lengths suggest they have arisen by the loss of AGG triplets from longer interrupted arrays. Haplotype analysis of arrays carrying long, uninterrupted (CGG)n tracts suggests that they occur more frequently on genetic backgrounds which are more highly represented on fragile X chromosomes. These arrays may well be precursors from which the larger fragile X associated arrays have arisen by further expansion.

Base Sequence↗
PubMed1987

The nucleotide sequence of a 3.2 kb segment of mitochondrial maxicircle DNA from Crithidia fasciculata containing the gene for cytochrome oxidase subunit III, the N-terminal part of the apocytochrome b gene and a possible frameshift gene; further evidence for the use of unusual initiator triplets in trypanosome mitochondria.

A 3.2 kb segment of the maxicircle of Crithidia fasciculata mitochondrial (mt) DNA contains the gene for cytochrome oxidase subunit III (coxIII), the N-terminal portion of the gene for apocytochrome b (cytb) and two partially overlapping Unassigned Reading Frames (C.URF2/1). Transcript analysis of the segment reveals that both the coxIII gene and the C.URF2/1 area are transcribed into a pair of RNA products. With the C. fasciculata gene version as a probe, a coxIII gene could not be detected in nuclear and mtDNA of Trypanosoma brucei, indicating that the cytochrome oxidases of these two closely related trypanosome species may differ. The nucleotide homology in the N-terminal region of the coxIII and cytb genes in T. brucei, Leishmania tarentolae and C. fasciculata starts at a UUA leucine codon, which adds further support to the hypothesis that apart from AUG, other initiator triplets are used in trypanosomal mitochondria: UUG, CUG and UUA, all triplets coding for leucine in the universal code. Finally, the possibility is discussed that the two overlapping URFs (C.URF2/1) in fact represent a single, frameshift containing, gene.

Amino Acid Sequence↗
PubMed1993

A single trinucleotide, 5'AGC3'/5'GCT3', of the triplet-repeat disease genes confers metal ion-induced non-B DNA structure.

Expansion of (AGC)n repeats has been associated with genetic disorders called triplet-repeat diseases such as Huntington's disease (HD), myotonic muscular dystrophy (DM) and Kennedy's disease. To gain insight into the abnormal behavior of these repeats, we studied their structural properties in supercoiled DNA. Chemical probing revealed that, under physiological salt and pH conditions, Zn2+ or Co2+ ions induce (AGC)n repeats to adopt a novel non-B DNA structure in which all cytosine but none of adenine residues in either strand become unpaired. The minimum size of (AGC)n repeat that could form this structure independently of neighboring sequences is a single unit of double-stranded trinucleotide, 5'AGC3'/5'GCT3'. Other trinucleotide units of the same nucleotide composition, 5'CAG3'/5'CTG3' or 5'GCA3'/5'TGC3', do not form non-B DNA structures. This unusual DNA structural properly adopted by a single 5'AGC3'/5'GCT3' trinucleotide may contribute to expansion of (AGC)n sequences in triplet-repeat diseases.

Base Sequence↗
PubMed1995

DNA CTG triplet repeats involved in dynamic mutations of neurologically related gene sequences form stable duplexes.

DNA triplet repeats, 5'-d(CTG)n and 5'-d(CAG)n, are present in genes which have been implicated in several neurodegenerative disorders. To investigate possible stable structures formed by these repeating sequences, we have examined d(CTG)n, d(CAG)n and d(CTG).d(CAG)n (n = 2 and 3) using NMR and UV optical spectroscopy. These studies reveal that single stranded (CTG)n (n > 2) forms stable, antiparallel helical duplexes, while the single stranded (CAG)n requires at least three repeating units to form a duplex. NMR and UV melting experiments show that the Tm increases in the order of [(CAG)3]2 < [(CTG)3]2 << (CAG)3.(CTG)3. The (CTG)3 duplex is stable and exhibits similar NMR spectra in solutions containing 0.1-4 M NaCl and at a pH range from 4.6 to 8.8. The (CTG)3 duplex, which contains multiple-T.T mismatches, displays many NMR spectral characteristics similar to those of B-form DNA. However, unique NOE and 1H-31P coupling patterns associated with the repetitive T.T mismatches in the CTG repeats are discerned. These results, in conjunction with recent in vitro studies suggest that longer CTG repeats may form hairpin structures, which can potentially cause interruption in replication, leading to dynamic expansion or deletion of triplet repeats.

Base Composition↗
PubMed1995

Discordant expression and variable numbers of neighboring GGA- and GAA-rich triplet repeats in the 3' untranslated regions of two groups of messenger RNAs encoded by the rat polymeric immunoglobulin receptor gene.

An unusual S1-nuclease sensitive microsatellite (STMS) has been found in the single copy, rat polymeric immunoglobulin receptor gene (PIGR) terminal exon. In Fisher rats, elements within or beyond the STMS are expressed variably in the 3' untranslated regions (3'UTRs) of two 'Groups' of PIGR-encoded hepatic mRNAs (pIg-R) during liver regeneration. STMS elements include neighboring constant regions (a 60-bp d[GA]-rich tract with a chi-like octamer, followed by 15 tandem d[GGA] repeats) that merge directly with 36 or 39 tandem d[GAA] repeats (Fisher or Wistar strains, respectively) interrupted by d[AA] between their 5th-6th repeat units. The Wistar STMS is flanked upstream by two regions of nearly contiguous d[CA] or d[CT] repeats in the 3' end of intron 8; and downstream, by a 283 bp 'unit' containing several inversions at its 5' end, and two polyadenylation signals at its 3' end. The 283 nt unit is expressed in Group 1 pIg-R mRNAs; but it is absent in the Group 2 family so that their GAA repeats merge with their poly A tails. In contrast to genomic sequence, GGA triplet repeats are amplified (n > or = 24-26), whereas GAA triplet repeats are truncated variably (n < or = 9-37) and expressed uninterruptedly in both mRNA Groups. These results suggest that 3' end processing of the rat PIGR gene may involve misalignment, slippage and premature termination of RNA polymerase II. The function of this unusual processing and possible roles of chi-like octamers in quiescent or extrahepatic tissues are discussed.

Animals↗
PubMed1996

Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy.

Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease that is associated with a (CTG)n repeat expansion in the 3'-untranslated region of the myotonin protein kinase (Mt-PK) gene. This study reports the isolation and characterization of a (CUG)n triplet repeat pre-mRNA/mRNA binding protein that may play an important role in DM pathogenesis. Two HeLa cell proteins, CUG-BP1 and CUG-BP2, have been purified based upon their ability to bind specifically to (CUG)8 oligonucleotides in vitro. While CUG-BP1 is the major (CUG)8-binding activity in normal cells, nuclear CUG-BP2 binding activity increases in DM cells. Both CUG-BP1 and CUG-BP2 have been identified as isoforms of a novel heterogeneous nuclear ribonucleoprotein (hnRNP), hNab50. The CUG-BP/hNab50 protein is localized predominantly in the nucleus and is associated with polyadenylated RNAs in vivo. In vitro RNA-binding/photocrosslinking studies demonstrate that CUG-BP/hNab50 binds to RNAs containing the Mt-PK 3'-UTR. We propose that the (CUG)n repeat region in Mt-PK mRNA is a binding site for CUG-BP/hNab50 in vivo, and triplet repeat expansion leads to sequestration of this hnRNP on mutant Mt-PK transcripts.

Amino Acid Sequence↗
PubMed1997

Transcription increases the deletion frequency of long CTG.CAG triplet repeats from plasmids in Escherichia coli.

Induction of transcription into long CTG.CAG repeats contained on plasmids in Escherichia coli is shown to increase the frequency of deletions within the repeat sequences. This elevated genetic instability was detected because active transcription into the triplet repeat influenced the growth transitions of the host cell, allowing advantageous growth for cells harboring plasmids with deleted repeat sequences. The variety of deletion products observed in separate cultures suggests that transcription altered the metabolism of the DNA in a manner that produced random length changes in the repeat sequence. For cultures containing plasmids without active transcription into the triplet repeat, or those maintained in exponential growth, deletions occurred within the repeat at a lower frequency (5-20-fold lower). In these incubations the extent of deletions was proportional to the number of cell divisions and many repeat lengths were observed within each culture, suggesting that the decrease in average repeat length at long incubation times was due to multiple small deletions. These observations show that deletions within long CTG.CAG repeats contained on plasmids in E.coli occur via more than one pathway and their level of genetic instability is altered by the enzymatic processes occurring upon the DNA.

Escherichia coli↗
PubMed2005

Evolutionary conservation suggests a regulatory function of AUG triplets in 5'-UTRs of eukaryotic genes.

By comparing sequences of human, mouse and rat orthologous genes, we show that in 5'-untranslated regions (5'-UTRs) of mammalian cDNAs but not in 3'-UTRs or coding sequences, AUG is conserved to a significantly greater extent than any of the other 63 nt triplets. This effect is likely to reflect, primarily, bona fide evolutionary conservation, rather than cDNA annotation artifacts, because the excess of conserved upstream AUGs (uAUGs) is seen in 5'-UTRs containing stop codons in-frame with the start AUG and many of the conserved AUGs are found in different frames, consistent with the location in authentic non-coding sequences. Altogether, conserved uAUGs are present in at least 20-30% of mammalian genes. Qualitatively similar results were obtained by comparison of orthologous genes from different species of the yeast genus Saccharomyces. Together with the observation that mammalian and yeast 5'-UTRs are significantly depleted in overall AUG content, these findings suggest that AUG triplets in 5'-UTRs are subject to the pressure of purifying selection in two opposite directions: the uAUGs that have no specific function tend to be deleterious and get eliminated during evolution, whereas those uAUGs that do serve a function are conserved. Most probably, the principal role of the conserved uAUGs is attenuation of translation at the initiation stage, which is often additionally regulated by alternative splicing in the mammalian 5'-UTRs. Consistent with this hypothesis, we found that open reading frames starting from conserved uAUGs are significantly shorter than those starting from non-conserved uAUGs, possibly, owing to selection for optimization of the level of attenuation.

5' Untranslated Regions↗
PubMed2001

New quadruplex structure of GGA triplet repeat DNA--an intramolecular quadruplex composed of a G:G:G:G tetrad and G(:A):G(:A):G(:A):G heptad, and its dimerization.

The structure of d(GGAGGAGGAGGA) containing four tandem repeats of a GGA triplet sequence has been determined under physiological K+ conditions by NMR. d(GGAGGAGGAGGA) folds into an intramolecular quadruplex composed of a G:G:G:G tetrad and a G(:A):G(:A):G(:A):G heptad. Four G-G segments of d(GGAGGAGGAGGA) are aligned parallel to each other due to seven successive turns of the main chain at each of the GGA and GAGG segments. Two quadruplexes form a dimer stabilized through a stacking interaction between the heptads of the two quadruplexes. On the basis of these results, the biological implications of naturally occurring GGA triplet repeat DNA are discussed.

Adenosine↗
PubMed2006

A knowledge-based scoring function based on residue triplets for protein structure prediction.

One of the general paradigms for ab initio protein structure prediction involves sampling the conformational space such that a large set of decoy (candidate) structures are generated and then selecting native-like conformations from those decoys using various scoring functions. In this study, based on a physical/geometric approach first suggested by Banavar and colleagues, we formulate a knowledge-based scoring function, which uses the radii of curvature formed among triplets of residues in a protein conformation. By analyzing its performance on various decoy sets, we determine a good set of parameters--the distance cutoff and the number of distance bins--to use for configuring such a function. Furthermore, we investigate the effect of using various approaches for compiling the prior distribution on the performance of the knowledge-based function. Possible extensions to the current form of the residue triplet scoring function are discussed.

Algorithms↗
PubMed1996

Analysis of the DRPLA triplet repeat in brain tissue and leukocytes from schizophrenics.

An expansion of the CAG triplet in the human gene called atrophin-1 or CTG-B37 causes the neuropsychiatric disease known as dentatorubral-pallidoluysian atrophy (DRPLA). We have examined the genomic DNA from brains and peripheral blood leukocytes (PBLs) of schizophrenic and non-schizophrenic individuals and PBLs from a cohort of monozygotic twins discordant or concordant for schizophrenia, for expansions of the CTG-B37 region. All samples, including non-schizophrenic/normal controls, had 7-22 CAG repeats in this region. Thus we found no evidence for an expansion of the DRPLA triplet repeat associated with schizophrenia when compared to controls. Our data suggest that an expansion in the CTG-B37 gene is not linked to or responsible for the disease schizophrenia.

Alleles↗