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At least 19 recordsLinked to original sources
PubMed2002

Comparative genomics and evolution of proteins involved in RNA metabolism.

RNA metabolism, broadly defined as the compendium of all processes that involve RNA, including transcription, processing and modification of transcripts, translation, RNA degradation and its regulation, is the central and most evolutionarily conserved part of cell physiology. A comprehensive, genome-wide census of all enzymatic and non-enzymatic protein domains involved in RNA metabolism was conducted by using sequence profile analysis and structural comparisons. Proteins related to RNA metabolism comprise from 3 to 11% of the complete protein repertoire in bacteria, archaea and eukaryotes, with the greatest fraction seen in parasitic bacteria with small genomes. Approximately one-half of protein domains involved in RNA metabolism are present in most, if not all, species from all three primary kingdoms and are traceable to the last universal common ancestor (LUCA). The principal features of LUCA's RNA metabolism system were reconstructed by parsimony-based evolutionary analysis of all relevant groups of orthologous proteins. This reconstruction shows that LUCA possessed not only the basal translation system, but also the principal forms of RNA modification, such as methylation, pseudouridylation and thiouridylation, as well as simple mechanisms for polyadenylation and RNA degradation. Some of these ancient domains form paralogous groups whose evolution can be traced back in time beyond LUCA, towards low-specificity proteins, which probably functioned as cofactors for ribozymes within the RNA world framework. The main lineage-specific innovations of RNA metabolism systems were identified. The most notable phase of innovation in RNA metabolism coincides with the advent of eukaryotes and was brought about by the merge of the archaeal and bacterial systems via mitochondrial endosymbiosis, but also involved emergence of several new, eukaryote-specific RNA-binding domains. Subsequent, vast expansions of these domains mark the origin of alternative splicing in animals and probably in plants. In addition to the reconstruction of the evolutionary history of RNA metabolism, this analysis produced numerous functional predictions, e.g. of previously undetected enzymes of RNA modification.

Animals↗
PubMed1978

RNA metabolism, manganese, and RNA polymerases of zinc-sufficient and zinc-deficient Euglena gracilis.

The three major RNA classes from zinc-sufficient [(+Zn)] and zinc-deficient [(=Zn)] Euglena gracilis have been separated by affinity chromatography on oligo(dT)- and N-[N'-[m-(dihydroxyboryl)phenyl]succinamoyl]aminoethyl (DBAE)-celluloses. The total RNA content and the ribosomal and transfer RNA fractions are the same in (+Zn) and (=Zn) cells. IN (-Zn) cells, the messenger RNA fraction increases, and its altered base composition reveals additional bases and a 2-fold increase in the (G+C)/(A+U) ratio. Since the intracellular content of manganese increases in (-Zn) cells, we have examined its role in determining these changes in RNA composition. An increase in the Mn2+ content from 1 to 10 mM in assays with RNA polymerases I and II from (+Zn) cells and those with the single RNA polymerase from (-Zn) cells decreases the ratio of UMP to CMP incorporated from 1.7 to 1.0, 2.1 to 0.8 and 3.5 to 0.4, respectively. Thus, Mn2+ concentration can significantly alter the products of the enzymatic action of RNA polymerases from both (+Zn) and (-Zn) E. gracilis cells.

Base Sequence↗
PubMed1978

Interferon-mediated effect on ribosomal RNA metabolism.

Ribosomal RNA (rRNA) has been shown to be involved in the binding of bacterial messenger RNA (mRNA) and an analogous 18 S rRNA.mRNA complex has been reported in eukaryotic systems. Thus, qualitative changes in host rRNA may be involved in the development of the interferon mediated antiviral state, a process thought to involve the inability of host ribosomes to bind and recognize viral mRNA. Data are reported which suggest that trisomy 21 human fibroblasts respond to human interferon with a marked reduction in cytoplasmic rRNA. [3H]Uridine was used to radioactively label the polysomal RNAs for 24 h beginning 12 h after interferon addition. Subsequent sucrose gradient analysis of the phenol or SDS-extracted RNA revealed that the reduction in radioactive rRNA was nearly complete for the 28 S rRNA. In contrast, considerable residual uridine incorporation was found in the 18 S rRNA species. Corollary data suggesting a net increase in mRNA synthesis and a net decrease in protein synthesis are reported.

Cell Line↗
PubMed1997

RNA metabolism in myotonic dystrophy: patient muscle shows decreased insulin receptor RNA and protein consistent with abnormal insulin resistance.

Myotonic dystrophy is a dominantly inherited clinically variable multisystemic disorder, and has been found to be caused by heterozygosity for a trinucleotide repeat expansion mutation in the 3' untranslated region of a protein kinase gene (DM kinase). The mechanisms by which the expanded repeat in DNA results in a dominant biochemical defect and the varied clinical phenotype, is not known. We have recently proposed a model where disease pathogenesis may occur at the RNA level in myotonic dystrophy: the mutant DM kinase RNA with the expansion mutation may disrupt cellular RNA metabolism in some general manner, as evidenced by defects in RNA processing of the normal DM kinase gene in heterozygous patients (dominant negative RNA mutation). Here we further test this hypothesis by measuring RNA metabolism of other genes in patient muscle biopsies (nine adult onset myotonic dystrophy patients, two congenital muscular dystrophy patients, four normal controls, and four myopathic controls). We focused on the insulin receptor gene because of the documented insulin resistance of DM patients. We show that there is a significant decrease in insulin receptor RNA in both total RNA and RNA polyA+ pools relative to normal and myopathic control muscles (P < 0.002), measured relative to both dystrophin RNA and muscle sodium channel RNA. We also show reductions in insulin receptor protein. Our results reinforce the concept of a generalized RNA metabolism defect in myotonic dystrophy, and offer a possible molecular mechanism for the increased insulin resistance observed in many myotonic dystrophy patients.

Adolescent↗
PubMed1978

RNA metabolism in M1 adrenergic neuroblastoma cells.

RNA metabolism of M1 adrenergic neuroblastoma cells was investigated in logarithmic proliferating, stationary and differentiated states. [3h] uridine labelling experiments showed that in the stationary phase (10 days of culture) the cells incorporated less radioactive precursors into RNA than in the logarithmic phase (3 days of culture). Cells differentiated by bromodeoxyuridine treatment were compared with proliferating cells. At short labelling time, the BrdU-treated cells incorporated more [3H] uridine in RNA than the controls. But when morphological differentiation became irreversible, the treated cells incorporated less [3H] uridine into RNA. Our results show that morphological differentiation by BrdU-treatment of neuroblastoma M1 cells is not accompanied by striking changes in RNA metabolism.

Adenosine↗
PubMed2000

The balance sheet for transcription: an analysis of nuclear RNA metabolism in mammalian cells.

The control of RNA synthesis from protein-coding genes is fundamental in determining the various cell types of higher eukaryotes. The activation of these genes is driven by promoter complexes, and RNA synthesis is performed by an enzyme mega-complex-the RNA polymerase II holoenzyme. These two complexes are the fundamental components required to initiate gene expression and generate the primary transcripts that, after processing, yield mRNAs that pass to the cytoplasm where protein synthesis occurs. But although this gene expression pathway has been studied intensively, aspects of RNA metabolism remain difficult to comprehend. In particular, it is unclear why >95% of RNA polymerized by polymerase II remains in the nucleus, where it is recycled. To explain this apparent paradox, this review presents a detailed description of nuclear RNA (nRNA) metabolism in mammalian cells. We evaluate the number of active transcription units, discuss the distribution of polymerases on active genes, and assess the efficiency with which the products mature and pass to the cytoplasm. Differences between the behavior of mRNAs on this productive pathway and primary transcripts that never leave the nucleus lead us to propose that these represent distinct populations. We discuss possible roles for nonproductive RNAs and present a model to describe the metabolism of these RNAs in the nuclei of mammalian cells.-Jackson, D. A., Pombo, A., Iborra, F. The balance sheet for transcription: an analysis of nuclear RNA metabolism in mammalian cells.

Animals↗
PubMed1984

Nuclear RNA metabolism in rat hippocampal slices incubated in vitro.

Rat hippocampal slices were incubated with [3H]uridine in vitro to analyze the metabolism of nuclear RNA and the RNA precursor fractions. Labeling of total nuclear RNA was linear for 4 h of incubation and proportional to the concentration of labeled uridine in the incubation medium. Addition of 3.5 X 10(-8) M corticosterone to the incubation medium produced an enhancement of nuclear RNA labeling with no significant effect on the labeling of the RNA precursor fraction. Progesterone and dexamethasone, at the same concentration, had no effect on either variable. Labeling of RNA by cerebellar slices under the same conditions was approximately one-half the value obtained using hippocampal slices and the cerebellar RNA precursor fraction accumulated only 65% of the radioactivity from [3H]uridine found in the hippocampal pool. Corticosterone had no effect on the labeling of total nuclear RNA in cerebellar slices. Nuclear poly(A)-containing RNA constituted 19% of the total labeled nuclear RNA in these incubations, as estimated by oligo (dT)-cellulose chromatography. Cordycepin (3'-deoxyadenosine) at a concentration of 25 micrograms/ml inhibited to some extent the labeling of total nuclear RNA and the RNA precursor fraction, but preferentially diminished the amount of labeled RNA bound to oligo (dT)-cellulose. Corticosterone increased the amount of [3H]RNA which bound to oligo (dT)-cellulose, while progesterone had no effect. These results show that hippocampal slices maintained in vitro, can be used to analyze nuclear RNA metabolism, one positive regulator of which in the rat hippocampus is the adrenal steroid, corticosterone.

Adrenalectomy↗
PubMed1975

Method of examining viral RNA metabolism in cells in culture: metabolism of vesicular stomatitis virus RNA.

A method is described for radioactively labeling viral RNA and then quickly halting further incorporation of radioactive precursor into RNA so that the fate of the labeled RNA can be followed. Small complementary RNAs synthesized during vesicular stomatitis virus infection in the presence of cycloheximide do not metabolize to virion length molecules when protein synthesis inhibition is reversed.

Animals↗
PubMed1975

Ribosomal RNA metabolism in cucumber leaf mesophyll protoplasts.

Aspects of the metabolism of RNA have been studied in enzymatically isolated protoplasts from cotyledon and first leaf mesophyll tissue of two cultivars of cucumber. The first leaf mesophyll protoplasts incorporated (3H)-uridine into ribosomal RNA at a constant rate for up to 25 hr in a simple salts medium and for up to 45 hr in a growth medium. Pulse-chase labelling experiments on such preparations showed a rapid dilution of the intracellular (3H)-uridine pool(s) and a high metabolic rate in the cells in one cultivar but not in another. Gel electrophoretic analysis of the RNA from both cotyledon and first leaf protoplasts showed that both protoplast types incorporated either (14C)- or (3H)-uridine into ribosomal RNA species. Incorporation of (3H)-uridine into chloroplasts RNA was minimal in cotyledon protoplasts, but significant in leaf protoplasts. Greater incorporation into the chloroplast RNA species could be achieved by longer pulses. Synthesis of all of the ribosomal RNA species was sensitive to actinomycin D at 10 and 25 mug/ml concentrations in all protoplasts tested.

Cells, Cultured↗
PubMed1993

A three-dimensional view of precursor messenger RNA metabolism within the mammalian nucleus.

A quantitative three-dimensional analysis of nuclear components involved in precursor messenger RNA metabolism was performed with a combination of fluorescence hybridization, immunofluorescence, and digital imaging microscopy. Polyadenylate [poly(A)] RNA-rich transcript domains were discrete, internal nuclear regions that formed a ventrally positioned horizontal array in monolayer cells. A dimmer, sometimes strand-like, poly(A) RNA signal was dispersed throughout the nucleoplasm. Spliceosome assembly factor SC-35 localized within the center of individual domains. These data support a nuclear model in which there is a specific topological arrangement of noncontiguous centers involved in precursor messenger RNA metabolism, from which RNA transport toward the nuclear envelope radiates.

Cell Nucleus↗
PubMed1977

Differential RNA metabolism in rat brain cells fractionated by zonal centrifugation.

Combined fractionation and RNA metabolism studies were made on homoiogous cell types (neurons and glia) banded from rat brain cerebral cortex and hippocampus tissue at 40,000 rev/min for 50 minutes in a Beckman Ti 14 zonal rotor loaded with a discontinuous methyl cellulose (Methocel) and sucrose density gradient. Comparisons were made on the cellular fractions recovered from animals intracisternally injected with 15 muCi tritiated cytidine (3HCR) RNA precursor one hour before sacrifice and tissue cellular filtrate preparation. Immediate 3H pool-correction of extracted 3HRNA from the three cellular Bands recovered made possible a mathematically valid measure of 3HCR-precursor incorporation into RNA of the different cell types. Comparison of the cellular 3HRNA data by analysis of variance revealed the occurrence of differential tritium labelling of RNA in the same cell types banded from different brain regions. In particular, an important advance was demonstrated by the procedures developed in these studies for the quantitative cellular assay of brain in vivo (differential) RNA metabolism.

Analysis of Variance↗
PubMed1988

[Mechanism of action of anti-cancer drugs from the viewpoint of RNA metabolism].

The mechanism of action of anti-cancer drugs, especially 5-FU, was discussed on the basis of RNA metabolism. After its incorporation into cells, 5-FU is metabolized through the uracil pathway, and finally incorporated into various species of RNA. On the other hand, 5-FU metabolized to FdUMP forms a covalent ternary complex among TS and mTHF, and inhibits de novo TMP synthesis, resulting in the inhibition of DNA synthesis. However, 5-FU was found to exert an effect on TS- mutant FM3A cells which was almost as lethal as the effect on wild-type FM3A cells in the presence of thymidine. Therefore, this lethal effect could be attributable to the inhibition of RNA metabolism, rather than DNA metabolism. The effects of 5-FU on RNA metabolism in L1210 cells are as follows: (1) inhibition of the processing of preribosomal RNA to ribosomal RNA (2) inhibition of the synthesis of poly(A) RNA of mRNA (3) inhibition of tRNA methylation (4) impaired synthesis of snRNA, U4, U6. (5) inhibition of pre-rRNA methylation (6) enhancement of poly(A) RNA translation. With reference to the items listed above, a discussion was made on the basis of our experimental results.

Animals↗