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PubMed2006

[DNA methylation: an epigenetic mechanism for tumorigenesis].

DNA methylation is a kind of epigenetic modification in human genome. Both hypermethylation of tumor suppressor gene or DNA repair gene and hypomethylation of repetitious DNA are closely related to different kinds of tumors. Loss of imprinting can also cause tumorigenesis. The recent study confirmed that the level of DNA methylation in genome was not only affected by DNA methyltransferase(DNMT), but also by other factors such as histone modification, diet and environment and RNA interference, etc. DNA methylation has an important role in transcriptional regulation, together with histone modification and chromatin remodeling.

Animals↗
PubMed1997

Biochemical alterations in paromomycin-treated Leishmania donovani promastigotes.

Paromomycin is used for the treatment of leishmaniasis in humans, but little is known about its mechanism of action. Investigating the effect of this antibiotic on promastigotes of Leishmania donovani, we showed that inhibition of the multiplication of these parasites could be related to its effect on RNA synthesis and to modifications of membranous polar lipids and membrane fluidity, leading to altered membrane permeability.

Amebicides↗
PubMed2004

The role of RNA interference in heterochromatic silencing.

Soon after its discovery 75 years ago, heterochromatin, a dense chromosomal material, was found to silence genes. But its importance in regulating gene expression was controversial. Long thought to be inert, heterochromatin is now known to give rise to small RNAs, which, by means of RNA interference, direct the modification of proteins and DNA in heterochromatic repeats and transposable elements. Heterochromatin has thus emerged as a key factor in epigenetic regulation of gene expression, chromosome behaviour and evolution.

Animals↗
PubMed2004

Post-transcriptional regulation of opioid receptors in the nervous system.

Three types of opioid receptors exist in the animals, each is encoded by a single gene, i.e., the mu opioid receptor gene, the delta opioid receptor gene, and the kappa opioid receptor gene. However, each opioid receptor gene produces multiple mRNA variants as a result of alternative promoter usages, splicing and/or polyadenylation. As such, a large reservoir of regulatory events has evolved for the control of the production of mRNA variants or differentially modified proteins from each opioid receptor gene. This review focuses on post-transcriptional events for the regulation of opioid receptor expression or activities, including alternative splicing, mRNA stability, translation, RNA polyadenylation, RNA transport, and covalent modification of the receptors. Variation at the mRNA level contributes, primarily, to the control of spatial and temporal expression of these receptors in different parts of neurons; whereas modification at the receptors is the key for controlling the duration and amplitude of signals generated from these receptors.

Alternative Splicing↗
PubMed1992

Ribosome-bound eukaryotic elongation factor 2 protects 5 S rRNA from modification.

The interaction between eukaryotic elongation factor eEF-2 and reconstituted 80 S ribosomes was investigated by analyzing the accessibility of 5 S ribosomal RNA for chemical and enzymatic modification. Ribosomes reconstituted from derived subunits were modified, and the positions of the modified sites were identified by primer extension using a 5 S rRNA-specific probe. All reactive sites were located between nucleotides 38 and 99, and most of them were found in putative single-stranded regions of the 5 S rRNA. Conversion of the ribosomes to the post-translocation type of particles by treatment with the translational inhibitor ricin resulted in the exposure of 3 additional bases for chemical modification, suggesting that the 5 S rRNA was more exposed in this type of ribosome. After binding of eEF-2 in complex with the non-hydrolyzable GTP analogue guanosine 5'-(beta, gamma-methylene)-triphosphate, most of the exposed bases in the 5 S rRNA were protected against both chemical and enzymatic modification.

Animals↗
PubMed1995

Structure-function relationships of hammerhead ribozymes: from understanding to applications.

The hammerhead ribozyme is the smallest member of the naturally occurring family of RNA molecules that are capable of catalysing the site-specific cleavage of RNA. Functional-group modifications have led to an identification of groups that are important for catalysis, and have helped in the understanding of the role of Mg2+, which is required for catalysis. Recent studies on the three-dimensional structure of the hammerhead ribozyme, including X-ray analysis, have contributed significantly towards an understanding of its mode of action. In addition to contributing to our understanding of RNA catalysis, these studies have also stimulated investigations into the possibility of using ribozymes in gene therapy to cleave specific mRNAs.

Animals↗
PubMed2003

[Assessment of the habits of physicians involved in the management of HIV-infected patients. A clinical audit on the biological follow-up].

BACKGROUND: The aim of this study was to assess the habits of hospital and community-based physicians involved in the management of HIV-infected patients and to measure the gap between their practice and follow-up guidelines. METHOD: The guidelines considered as reference were the 1998 Dormont report. Data were prospectively collected from the medical files of the first 10 HIV-infected patients who presented for an out-patient visit (laboratory tests at initial consultation, type and frequency of follow-up during the previous year, relation between biological data and treatment strategy). RESULTS: 22 physicians (14 hospital-based physicians (HP) and 8 community-based general practitioners (GP) participated in the survey. Initial biological data were available for 211 patients; 45% had tests strictly conforming to the recommendations (HP: 57%, GP 23%; p<0.001). Among patients followed by a GP, the initial biological assessment was adequate in 7% of cases when an opiate substitute was prescribed versus 33% in the absence of opiate substitute prescription (p=0.05). For all patients, syphilis serology was the test most frequently lacking (38%). Among 78 patients with HIV-RNA levels>5,000 copies/ml, 18% did not benefit from a change in treatment. Among the patients treated by a GP, 15% had a three-fold increase in HIV-RNA, compared to their initial measurement. Of these, 3/4 were redirected to a hospital out-patient unit. CONCLUSION: This study highlights the discrepancy between initial laboratory testing and expert recommendations, particularly concerning patients attended by a GP. Improvement in data collection is essential. However, recommendations concerning patients' biological follow-up are applied, with the exception of the delay between the initial prescription or treatment modification and HIV-RNA measurement, which should be shortened.

Diagnostic Tests, Routine↗
PubMedDate not supplied

8-Aminoguanine: a base modification produced in rat liver nucleic acids by the hepatocarcinogen 2-nitropropane.

2-Nitropropane (2-NP), an important industrial chemical and a hepatocarcinogen in rats, had previously been found to produce several modifications of nucleosides in rat liver RNA and DNA that are discernible using HPLC with electrochemical detection. While one of these modifications has been identified as an increase in the levels of 8-oxoguanosine and 8-oxo-2'-deoxyguanosine in RNA and DNA, respectively, the others had not been identified. We now present evidence that a major modification in rat liver nucleic acids due to the administration of 2-NP is the amination of guanine at C8, apparently a completely novel in vivo reaction. 8-Aminoguanosine, isolated from hydrolysates of liver RNA from 2-NP-treated rats, cochromatographed with synthetic or commercially-obtained standard on reverse-phase as well as cation-exchange HPLC, and its UV spectral characteristics at acidic, neutral, and basic pH were identical to those of the standard. Acid hydrolysis produced 8-aminoguanine, which had a retention time and fragmentation pattern identical to that of the standard on gas chromatography-mass spectrometry of the trimethylsilyl derivatives. Evidence for the presence of 8-aminodeoxyguanosine in liver DNA of rats treated with 2-NP was also obtained by cochromatography with synthetic standard on HPLC. Hydroxylamine-O-sulfonic acid was found to react with RNA and DNA to give 8-oxo- and 8-amino-substituted guanines. We propose, as a working hypothesis, that 2-NP may be metabolized to hydroxylamine-O-sulfonate or acetate, which yield the reactive nitrenium ion, NH2+, capable of aminating cellular macromolecules in vivo.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1991

Recognition of the highly conserved GTPase center of 23 S ribosomal RNA by ribosomal protein L11 and the antibiotic thiostrepton.

The antibiotic thiostrepton, a thiazole-containing peptide, inhibits translation and ribosomal GTPase activity by binding directly to a limited and highly conserved region of the large subunit ribosomal RNA termed the GTPase center. We have previously used a filter binding assay to examine the binding of ribosomal protein L11 to a set of ribosomal RNA fragments encompassing the Escherichia coli GTPase center sequence. We show here that thiostrepton binding to the same RNA fragments can also be detected in a filter binding assay. Binding is relatively independent of monovalent salt concentration and temperature but requires a minimum Mg2+ concentration of about 0.5 mM. To help determine the RNA features recognized by L11 and thiostrepton, a set of over 40 RNA sequence variants was prepared which, taken together, change every nucleotide within the 1051 to 1108 recognition domain while preserving the known secondary structure of the RNA. Binding constants for L11 and thiostrepton interaction with these RNAs were measured. Only a small number of sequence variants had more than fivefold effects on L11 binding affinities, and most of these were clustered around a junction of helical segments. These same mutants had similar effects on thiostrepton binding, but more than half of the other sequence changes substantially reduced thiostrepton binding. On the basis of these data and chemical modification studies of this RNA domain in the literature, we propose that L11 makes few, if any, contacts with RNA bases, but recognizes the three-dimensional conformation of the RNA backbone. We also argue from the data that thiostrepton is probably sensitive to small changes in RNA conformation. The results are discussed in terms of a model in which conformational flexibility of the GTPase center RNA is functionally important during the ribosome elongation cycle.

Base Composition↗
PubMed1980

Photoinduced protein-RNA cross-linking in mammalian 80-S ribosomes.

RNA-protein interactions in the 80-S rat liver ribosomes were studied by measuring cross-linking of proteins to rRNAs induced by ultraviolet radiation, as already reported for free 40-S and 60-S subunits. Our results are compatible with the model in which most of the ribosomal proteins are accessible to rRNAs in the native conformational state of the ribosomes. Subunit association in 80-S ribosomes does not seem to induce modifications in protein-RNA interactions as measured by this irradiation technique. However, two proteins, S9 and S13, appeared to be significantly less cross-linked with RNA in ribosomes than in free subunits. Ribosomes which had been frozen and thawed several times were highly sensitive to ultraviolet radiation. Such treatment in the cold chiefly modified their 60-S subunit moiety.

Animals↗
PubMed1988

Structure of the rat insulin-like growth factor II transcriptional unit: heterogeneous transcripts are generated from two promoters by use of multiple polyadenylation sites and differential ribonucleic acid splicing.

The rat insulin-like growth factor II (rIGF-II) gene, which exists as a single copy in the genome, is expressed as a multitranscript family of mRNA molecules ranging in size from 4.6 to 1 kilobases. Part of this heterogeneity can be ascribed to the presence of two different promoters, each transcribing alternative 5'-noncoding regions which are spliced to common coding exons. In the present study we use a combination of DNA sequence analysis of the gene, mapping of the mRNA molecules by Northern analysis and ribonuclease protection experiments, and DNA sequence analysis of cDNA clones complementary to different regions of the genome to establish the structure of several rIGF-II mRNA species. These results indicate that RNA heterogeneity also arises from the use of different polyadenylation sites. In addition, a variant 2 kilobases RNA was observed that was colinear with the distal 1700 base pairs of the 3147 base pair long exon 3, and may arise by alternative RNA splicing. These posttranscriptional modifications of RNAs arising from the rIGF-II transcription unit may generate molecules with different functional potential.

Animals↗
PubMed2003

Systematic, genome-wide identification of host genes affecting replication of a positive-strand RNA virus.

Positive-strand RNA viruses are the largest virus class and include many pathogens such as hepatitis C virus and the severe acute respiratory syndrome coronavirus (SARS). Brome mosaic virus (BMV) is a representative positive-strand RNA virus whose RNA replication, gene expression, and encapsidation have been reproduced in the yeast Saccharomyces cerevisiae. By using traditional yeast genetics, host genes have been identified that function in controlling BMV translation, selecting BMV RNAs as replication templates, activating the replication complex, maintaining a lipid composition required for membrane-associated RNA replication, and other steps. To more globally and systematically identify such host factors, we used engineered BMV derivatives to assay viral RNA replication in each strain of an ordered, genome-wide set of yeast single-gene deletion mutants. Each deletion strain was transformed to express BMV replicase proteins and a BMV RNA replication template with the capsid gene replaced by a luciferase reporter. Luciferase expression, which is dependent on viral RNA replication and RNA-dependent mRNA synthesis, was measured in intact yeast cells. Approximately 4500 yeast deletion strains ( approximately 80% of yeast genes) were screened in duplicate and selected strains analyzed further. This functional genomics approach revealed nearly 100 genes whose absence inhibited or stimulated BMV RNA replication and/or gene expression by 3- to >25-fold. Several of these genes were shown previously to function in BMV replication, validating the approach. Newly identified genes include some in RNA, protein, or membrane modification pathways and genes of unknown function. The results further illuminate virus and cell pathways. Further refinement of virus screening likely will reveal contributions from additional host genes.

Bromovirus↗
PubMed2000

Functional anatomy of a dsRNA trigger: differential requirement for the two trigger strands in RNA interference.

In RNA-mediated interference (RNAi), externally provided mixtures of sense and antisense RNA trigger concerted degradation of homologous cellular RNAs. We show that RNAi requires duplex formation between the two trigger strands, that the duplex must include a region of identity between trigger and target RNAs, and that duplexes as short as 26 bp can trigger RNAi. Consistent with in vitro observations, a fraction of input dsRNA is converted in vivo to short segments of approximately 25 nt. Interference assays with modified dsRNAs indicate precise chemical requirements for both bases and backbone of the RNA trigger. Strikingly, certain modifications are well tolerated on the sense, but not the antisense, strand, indicating that the two trigger strands have distinct roles in the interference process.

Animals↗
PubMed1994

RNA polymerase II is aberrantly phosphorylated and localized to viral replication compartments following herpes simplex virus infection.

During lytic infection, herpes simplex virus subverts the host cell RNA polymerase II transcription machinery to efficiently express its own genome while repressing the expression of most cellular genes. The mechanism by which RNA polymerase II is directed to the viral delayed-early and late genes is still unresolved. We report here that RNA polymerase II is preferentially localized to viral replication compartments early after infection with herpes simplex virus type 1. Concurrent with recruitment of RNA polymerase II into viral compartments is a rapid and aberrant phosphorylation of the large subunit carboxy-terminal domain (CTD). Aberrant phosphorylation of the CTD requires early viral gene expression but is not dependent on viral DNA replication or on the formation of viral replication compartments. Localization of RNA polymerase II and modifications to the CTD may be instrumental in favoring transcription of viral genes and repressing specific transcription of cellular genes.

Animals↗
PubMed1990

Transition of the mRNA sequence downstream from the initiation codon into a single-stranded conformation is strongly promoted by binding of the initiator tRNA.

Using an RNA footprinting technique, accessible sites on the mRNA initiation region bound to the ribosome have been determined. Chemical probing experiments have been done both in the presence and absence of the initiator tRNA with dimethyl sulfate, kethoxal and carbodiimide as reagent probes. As an mRNA, a mini-mRNA containing the initiation region of bacteriophage lambda gene cro has been used. This region is characterized by a long single-stranded Shine-Dalgarno (SD) sequence followed by two hairpin structures of which the first one comprises in its loop the initiation codon. As compared to a free mRNA, the only nucleotides additionally protected in the binary mRNA-ribosome complex have been those which belong to the S-D sequence and the initiation codon. The protection of other nucleotides has not changed. Addition of the initiator RNA results in the modification of nucleotides in the stems of the downstream hairpin structures of the initiation region. This reflects their transition into a single-stranded conformation promoted by tRNA. A possible implication of these findings for the decoding process is discussed.

Base Sequence↗
PubMed2005

Increased parathyroid hormone gene expression in secondary hyperparathyroidism of experimental uremia is reversed by calcimimetics: correlation with posttranslational modification of the trans acting factor AUF1.

Most patients with chronic kidney disease develop secondary hyperparathyroidism with disabling systemic complications. Calcimimetic agents are effective tools in the management of secondary hyperparathyroidism, acting through allosteric modification of the calcium-sensing receptor (CaR) on the parathyroid gland (PT) to decrease parathyroid hormone (PTH) secretion and PT cell proliferation. This study showed that rats that were fed an adenine high-phosphorus diet had increased serum PTH and PTH mRNA levels at 7 and 21 d. For studying the effect of activation of the CaR by the calcimimetics R-568 on PTH gene expression, R-568 was given by gavage to uremic rats for the last 4 d of a 7-d adenine high-phosphorus diet. R-568 decreased both PTH mRNA and serum PTH levels. The effect of the calcimimetic on PTH gene expression was posttranscriptional and correlated with differences in protein-RNA binding and posttranslational modifications of the trans acting factor AUF1 in the PT. The AUF1 modifications as a result of uremia were reversed by treatment with R-568 to those of normal rats. Therefore, uremia and activation of the CaR mediated by calcimimetics modify AUF1 posttranslationally. These modifications in AUF1 correlate with changes in protein-PTH mRNA binding and PTH mRNA levels.

Aniline Compounds↗
PubMed1997

Detection of human immunodeficiency virus type 1 (HIV-1) DNA and RNA sequences in HIV-1 antibody-positive blood donors in Uganda by the Roche AMPLICOR assay.

The ability of commercially available PCR-based assays to accurately detect or quantitate human immunodeficiency virus type 1 (HIV-1) DNA or RNA in individuals predominantly infected with HIV-1 subtypes A and D is not known. Therefore, peripheral leukocytes from 43 individuals in Kampala, Uganda, positive for HIV by the Western blot (immunoblot) assay were tested by using the Roche AMPLICOR HIV-1 assay for the detection of DNA gag sequences. Plasma from these same individuals was tested by using the Roche HIV-1 AMPLICOR MONITOR HIV-1 assay for the quantitation of HIV-1 RNA gag sequences. In addition, peripheral leukocytes were tested for HIV-1 DNA by using a lower annealing temperature or a different primer pair for the HIV-1 pol region. The proportions of individuals with detectable HIV-1 DNA and RNA gag sequences by the Roche assays were 74 and 90%, respectively. The proportions positive for HIV-1 DNA sequences by using a 50 degrees C annealing temperature or the pol primer pair were 71 and 98%, respectively. In summary, the standard Roche assay did not detect HIV-1 DNA sequences in a significant number of HIV-1-infected individuals in Uganda. However, use of a pol primer pair increased the sensitivity of the assay to 98%. The sensitivity of the Roche AMPLICOR MONITOR assay for the detection and quantitation of HIV-1 RNA sequences was significantly higher than that of the DNA-based assay, but the efficiency of the assay, and hence, the accuracy of the values obtained with RNA, is not known. Modifications to existing assays are needed to enhance the sensitivities and accuracies of these commercially available assays for use in developing countries where non-B HIV-1 subtypes predominate.

DNA, Viral↗
PubMed1974

Three-dimensional tertiary structure of yeast phenylalanine transfer RNA.

The 3-angstrom electron density map of crystalline yeast phenylalanine transfer RNA has provided us with a complete three-dimensional model which defines the positions of all of the nucleotide residues in the moleclule. The overall features of the molecule are virtually the same as those seen at a resolution of 4 angstroms except that many additional details of tertiary structure are now visualized. Ten types of hydrogen bonding are identified which define the specificity of tertiary interactions. The molecule is also stabilized by considerable stacking of the planar purines and pyrimidines. This tertiary structure explains, in a simple and direct fashion, chemical modification studies of transfer RNA. Since most of the tertiary interactions involve nucleotides which are common to all transfer RNA 's, it is likely that this three-dimensional structure provides a basic pattern of folding which may help to clarify the three-dimensional structure of all transfer RNA's.

Base Sequence↗