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PubMed2002

RNomics: identification and function of small, non-messenger RNAs.

In the past few years, our knowledge about small non-mRNAs (snmRNAs) has grown exponentially. Approaches including computational and experimental RNomics have led to a plethora of novel snmRNAs, especially small nucleolar RNAs (snoRNAs). Members of this RNA class guide modification of ribosomal and spliceosomal RNAs. Novel targets for snoRNAs were identified such as tRNAs and potentially mRNAs, and several snoRNAs were shown to be tissue-specifically expressed. In addition, previously unknown classes of snmRNAs have been discovered. MicroRNAs and small interfering RNAs of about 21-23 nt, were shown to regulate gene expression by binding to mRNAs via antisense elements. Regulation of gene expression is exerted by degradation of mRNAs or translational regulation. snmRNAs play a variety of roles during regulation of gene expression. Moreover, the function of some snmRNAs known for decades, has been finally elucidated. Many other RNAs were identified by RNomics studies lacking known sequence and structure motifs. Future challenges in the field of RNomics include identification of the novel snmRNA's biological roles in the cell.

Animals↗

PubMed1986

Molecular cloning of cDNA for rat mitochondrial 3-hydroxyacyl-CoA dehydrogenase.

Messenger RNA for 3-hydroxyacyl-CoA dehydrogenase, a mitochondrial matrix enzyme of fatty acid beta-oxidation, was purified from livers of di(2-ethylhexyl)phthalate-treated rats by immunoadsorption of hepatic free polysomes to fixed cells of Staphylococcus aureus and enrichment for poly(A)-rich RNA by oligo(dT)-cellulose chromatography. Plasmid cDNA was constructed from this poly(A)-rich RNA by a modification of the method of Okayama and Berg and was transformed into the Escherichia coli DH1 strain. Plasmids containing cDNA sequences coding for 3-hydroxyacyl-CoA dehydrogenase were screened by differential colony hybridization, and were identified by hybrid-arrested translation and hybrid-selected translation. Plasmid pHADH-1, which contains a 1400-base-pair insert, hybridized to rat 3-hydroxyacyl-CoA dehydrogenase mRNA with a length of 1700 bases. Determination of the dehydrogenase mRNA by in vitro translation and dot-blot analysis with the cDNA probe showed that the induction of the enzyme in rat liver by di(2-ethylhexyl)phthalate could be attributed to an increase in the mRNA concentration.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed1983

Tumor markers derived from nucleic acid components.

It was known for some time that cancer patients excrete in their urine elevated levels of modified nucleosides. From earlier work, we were able to show that most of these modified nucleosides originate from transfer RNA (tRNA). The modifications are achieved at the macromolecular level by enzymes after primary synthesis. Such modifications are highly specific and, therefore, when the modified nucleosides accumulate from the tRNA breakdown, they cannot be reinserted randomly by the polymerases and must be excreted. We found that the modifying enzymes are aberrantly hyperactive in every malignant tissue. We also found that there is abnormally high turnover of tRNA in malignant tissues, which is probably the source of the elevated levels of excretion products. Since these products originate from a cardinal component of the molecular biology of every cell, the determination of markers in the urine may be a universal indicator of malignancy. We are focusing on the use of these markers in syndromes whose diagnoses are otherwise difficult. Since the marker levels return to normal very soon after chemotherapy, such determinations can be used to monitor the effectiveness of therapy. Therefore, the clinical oncologists can adapt their protocols to the specific need of a patient.

Chorionic Gonadotropin↗

PubMed1994

Pseudouridine formation in small nuclear RNAs.

Recent in vitro studies on the formation of pseudouridine (psi) in the spliceosomal small nuclear RNAs (snRNA) are reviewed. Multiple psi synthase activities, in some cases more that one per snRNA, are responsible for this modification of uridine. There is a requirement for Sm protein binding for the efficient formation of psi in U5 RNA but not for the modification of U2 RNA. The inhibition of psi formation by the incorporation of 5-fluorouridine in the snRNA is also reviewed.

Animals↗

PubMed2006

Post-translational modifications, but not transcriptional regulation, of major chloroplast RNA-binding proteins are related to Arabidopsis seedling development.

Chloroplast RNA-binding proteins are involved in stabilizing stored chloroplast mRNAs and in recruiting site-specific factors that mediate RNA metabolism. In the present study, we characterized two major chloroplast RNA-binding proteins, cp29A and cp29B, by MALDI-TOF MS, N-terminal sequencing, and ESI-MS/MS following 2D-PAGE separation. Polypeptides derived from cp29A were recovered with free N-terminus or with N-terminal acetylation. In addition to the two isoforms found for cp29A, an isoform derived from cp29B was also observed to have five amino acids cleaved from its N-terminus. Results of quantitative real-time RT-PCR indicate that both genes reached maximal rates of transcription 96 h after commencement of germination and maintained relatively high levels throughout the whole life cycle. Transcription of cp29A and cp29B did not vary significantly under light or dark conditions, although production of the acetylated and N-terminally cleaved protein isoforms exhibited light dependence. Exposure of etiolated Arabidopsis seedlings to light conditions for as short as 9 h restored the modified isoforms to levels similar to those found in green plants. Identification of post-translational modifications in major chloroplast RNA-binding proteins may help elucidate their roles in seedling development and in plant RNA stabilization during the greening process.

Amino Acid Sequence↗

PubMed1997

Association of herpes simplex virus regulatory protein ICP22 with transcriptional complexes containing EAP, ICP4, RNA polymerase II, and viral DNA requires posttranslational modification by the U(L)13 proteinkinase.

The expression of herpes simplex virus 1 gamma (late) genes requires functional alpha proteins (gamma1 genes) and the onset of viral DNA synthesis (gamma2 genes). We report that late in infection after the onset of viral DNA synthesis, cell nuclei exhibit defined structures which contain two viral regulatory proteins (infected cell proteins 4 and 22) required for gamma gene expression, RNA polymerase II, a host nucleolar protein (EAP or L22) known to be associated with ribosomes and to bind small RNAs, including the Epstein-Barr virus small nuclear RNAs, and newly synthesized progeny DNA. The formation of these complexes required the onset of viral DNA synthesis. The association of infected cell protein 22, a highly posttranslationally processed protein, with these structures did not occur in cells infected with a viral mutant deleted in the genes U(L)13 and U(S)3, each of which specifies a protein kinase known to phosphorylate the protein.

DNA, Viral↗

PubMed2006

Mechanisms of genomic rearrangements and gene expression changes in plant polyploids.

Polyploidy is produced by multiplication of a single genome (autopolyploid) or combination of two or more divergent genomes (allopolyploid). The available data obtained from the study of synthetic (newly created or human-made) plant allopolyploids have documented dynamic and stochastic changes in genomic organization and gene expression, including sequence elimination, inter-chromosomal exchanges, cytosine methylation, gene repression, novel activation, genetic dominance, subfunctionalization and transposon activation. The underlying mechanisms for these alterations are poorly understood. To promote a better understanding of genomic and gene expression changes in polyploidy, we briefly review origins and forms of polyploidy and summarize what has been learned from genome-wide gene expression analyses in newly synthesized auto-and allopolyploids. We show transcriptome divergence between the progenitors and in the newly formed allopolyploids. We propose models for transcriptional regulation, chromatin modification and RNA-mediated pathways in establishing locus-specific expression of orthologous and homoeologous genes during allopolyploid formation and evolution.

Chromosomes, Plant↗

PubMed1980

Inhibitory effect of cyclic adenosine 2',3'-monophosphate on leucine incorporation by L5178Y cells.

The specificity of the reported stimulation of protein synthesis affected by dibutyryl adenosine cyclic 3',5'-monophosphate in L5178Y cells was tested by assaying the effect of adenosine cyclic 2',3'-monophosphate. Protein synthesis was assayed as total acid precipitable 3H-leucine. Leucine incorporation was inhibited by adenosine cyclic 2',3'-monophosphate. Alone, and in combination with actinomycin, 2',3'-cAMP inhibited leucine incorporation more rapidly and to a greater degree than did actinomycin alone. Since a similar potentiating effect was not observed with cordycepin, the hypothesis has been suggested that adenosine cyclic 2',3'-monophosphate inhibits protein synthesis by interfering with some post transcriptional event, perhaps modification of existing RNA. The results further suggest that 2,3 cyclic AMP may be antagonistic of the effects of 3,5 cyclic AMP, and as such may be useful as an inhibitor of that nucleotide's action.

Animals↗

PubMed2000

X-ray crystallographic analysis of pokeweed antiviral protein-II after reductive methylation of lysine residues.

Pokeweed antiviral protein II (PAP-II) is a naturally occurring protein isolated from early summer leaves of the pokeweed plant (Phytolacca americana). PAP-II belongs to a family of ribosome-inactivating proteins which catalytically deadenylate ribosomal and viral RNA. The chemical modification of PAP-II by reductive methylation of its lysine residues significantly improved the crystal quality for X-ray diffraction studies. Hexagonal crystals of the modified PAP-II, with unit cell parameters a = b = 92.51 A, c = 79.05 A, were obtained using 1.8 M Na/K phosphate as the precipitant. These crystals contained one enzyme molecule per asymmetric unit and diffracted up to 2.4 A, when exposed to a synchroton source.

Crystallography, X-Ray↗

PubMed2000

HSP70 is involved in the control of chromosomal transcription in the amphibian oocyte.

The amphibian oocyte represents an excellent model for the study of transcription regulation. Indeed, any modification of transcriptional activity is directly reflected in lampbrush chromosome structure by concomitant morphological changes. Previous studies have led to the hypothesis of a putative role for heat-shock proteins HSP70 and/or HSC70 in transcriptional processes in the oocyte. In order to dissect out the relative role of HSP70 or HSC70 in these processes, we used an oligo-antisense strategy to specifically inhibit the function of the targeted protein. Effects of hsc70 and hsp70 antisense oligodeoxynucleotides were analyzed in terms of both mRNA quantity and protein synthesis. Their effects on oocyte transcription were analyzed at the level of structural organization of lampbrush chromosomes and nucleolar transcriptional activity. Our results show that specific inactivation of hsc70 mRNA by hsc70 antisense oligos led to a reversible inhibition of lampbrush chromosome transcription. However, such reversible inhibition of transcription is considered non-sequence specific since it is also induced by any oligo. In contrast, specific inactivation of hsp70 mRNA by hsp70 antisense oligos, which is correlated with a drop of HSP70 neosynthesis, results in an irreversible inhibition of lampbrush chromosome transcription. Furthermore, our results show that the inactivation of hsp70 or hsc70 mRNAs does not affect nucleolar transcription. Such data suggest a role for HSP70 in the control of chromatin modifications related to RNA polymerase II transcriptional activity.

Animals↗

PubMed2006

Epigenetic regulation in Drosophila.

Epigenetic regulation of gene transcription relies on molecular marks like DNA methylation or histone modifications. Here we review recent advances in our understanding of epigenetic regulation in the fruit fly Drosophila melanogaster. In the past, DNA methylation research has primarily utilized mammalian model systems. However, several recent landmark discoveries have been made in other organisms. For example, the interaction between DNA methylation and histone methylation was first described in the filamentous fungus Neurospora crassa. Another example is provided by the interaction between epigenetic modifications and the RNA interference (RNAi) machinery that was first reported in the fission yeast Schizosaccharomyces pombe. Another organism with great experimental power is the fruit fly Drosophila. Epigenetic regulation by chromatin has been extensively analyzed in the fly and several of the key components have been discovered in this organism. In this chapter, we will focus on three aspects that represent the complexity of epigenetic gene regulation. (1) We will discuss the available data about the DNA methylation system, (2) we will illuminate the interaction between DNA methylation and chromatin regulation, and (3) we will provide an overview over the Polycomb system of epigenetic chromatin modifiers that has proved to be an important paradigm for a chromatin system regulating epigenetic programming.

Acetylation↗

PubMed1983

The role of 2-methylthio-N6-isopentenyladenosine in readthrough and suppression of nonsense codons in Escherichia coli.

Readthrough and suppression of nonsense codons was compared in Escherichia coli strains with and without a miaA mutation, which confers a loss of the isopentenyladenosine modification in transfer RNA. Generally speaking, our results conform to predictions based on previous literature. In addition, we showed that the miaA mutation in strain TRPX is itself a UAA mutation. An antagonism between miaA and rpsL mutations, which confer streptomycin resistance, was also discovered. Our data further suggest that slight alterations of the translation apparatus are easily detectable by monitoring readthrough and suppression of nonsense codons. Our findings are discussed in the context of old and recent reports.

Adenosine↗

PubMed1990

Protein kinase C modulation of queuine uptake in cultured human fibroblasts.

Protein kinase C modulates the activity of a highly specific uptake mechanism for queuine in cultured human fibroblasts. Activators of protein kinase C induce an increased uptake rate for the radiolabeled analog of queuine, rQT3. The protein kinase C inhibitors, H-7, staurosporine and sphingosine all induced a dramatic decrease in the uptake rate of rQT3. This suggests that protein kinase C is tied to efficient cellular uptake of queuine. Uptake is prerequisite to the modification of transfer RNA with queuine. Perturbation of queuine-modified transfer RNA levels has been associated with neoplastic transformation, differentiation and growth control.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMedDate not supplied

Age-dependent gene induction in quail oviduct X. Alterations on the post-transcriptional level (enzymic aspect).

In quail oviducts the rate of synthesis of avidin, the biological end-point marker for the molecular events caused by progesterone, decreases with age. The cause of the reduced capacity of avidin induction has been studied on the molecular biological level polyadenylation of RNA which is one step in the process of post-transcriptional modification of heterogeneous nuclear RNA resulting in the formation of functional mRNA molecules. This novel approach was biochemically possible after the discovery of the poly(A) anabolic enzyme (poly(A) polymerase) and the two poly(A) catabolic enzymes (endoribonuclease IV and 5'-exoribonuclease). These enzymes are involved in the synthesis and degradation of the poly(A) segment of mRNA in vitro and most likely also in poly(A) metabolism in intact cell systems. Enzymatically controlled poly(A) metabolism of mRNA is regulated by the following interrelations: poly(A)-associated proteins and endoribonuclease IV; labilizing factor and poly(A)-associated proteins; 5'-exoribonuclease in cooperation with endoribonuclease IV and poly(A) polymerase. A close correlation between high levels of poly(A) catabolic enzymes and low rate of protein synthesis which was established in cell culture systems, seems also to be partially the biochemical cause for the reduced avidin synthesis in aging quail oviduct.

Aging↗

PubMed2006

Microarray-based gene expression profiling to elucidate cellular responses to nitric oxide--a review from an analytical and biomedical point of view.

Nitric oxide (NO) produced by NO synthases (NOS) regulates a wide range of cellular functions. Analysis by gene arrays provides valuable information for identifying important elements of the cellular responses to NO. Such screening tools might be useful to elucidate NO-responsive regulators, which play a central role in mediating NO effects. Although the final importance of a particular gene is determined by the encoded protein and further protein modifications, measurements of RNA levels have proven to be partly valuable in identifying the molecular changes that occur in cells. Microarray technology permits large-scale and genome-wide analysis of gene expression from multiple samples. We review the current knowledge of the use of microarray gene expression screening in elucidating the effects of NO on various cells and tissues. We also point out the limitations of general microarray-based gene expression analyses and especially when investigating the effects of NO.

Animals↗

PubMed2004

Pathogenic molecular mechanisms in an animal model of fulminant hepatic failure: rabbit hemorrhagic viral disease.

In this study we sought to determine whether molecular mechanisms involved in the pathogenesis of fulminant hepatic failure are present in rabbits experimentally infected with rabbit hemorrhagic disease virus (RHDV). The activities of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, as well as bilirubin concentration, were found to be significantly increased 36 hours after infection. Infected animals also demonstrated significant decreases in factor VII activity, in the Fischer index, and in the deterioration of prothrombin time. The concentration of reduced glutathione was significantly decreased 36 hours after infection, and we noted a marked increase in the ratio of oxidized to reduced glutathione. Infected animals showed progressive decreases in liver activity of the antioxidant enzyme superoxide dismutase. Expression of hepatocyte growth factor and c-met was found to be progressively reduced from 24 hours after infection, during which time we detected no modification in messenger RNA (mRNA) levels of transforming growth factor (TGF)-alpha. TFG-beta 1 was overexpressed 24 and 36 hours after infection, and 36 hours after infection we detected a significant increase in TNF-alpha mRNA levels. Experimental RHDV infection also induced marked activation of nuclear factor-kappaB and a significant increase in inducible nitric oxide synthase mRNA levels from 24 hours after infection. Data obtained from this animal model support its usefulness in the investigation of potential novel therapeutical modalities aimed at neutralizing reactive oxygen species and hepatocyte growth inhibitors or enhancing hepatocyte responsiveness to mitogens.

Alanine Transaminase↗

PubMed2005

Complete genome sequence of bacteriophage T5.

The 121,752-bp genome sequence of bacteriophage T5 was determined; the linear, double-stranded DNA is nicked in one of the strands and has large direct terminal repeats of 10,139 bp (8.3%) at both ends. The genome structure is consistently arranged according to its lytic life cycle. Of the 168 potential open reading frames (ORFs), 61 were annotated; these annotated ORFs are mainly enzymes involved in phage DNA replication, repair, and nucleotide metabolism. At least five endonucleases that believed to help inducing nicks in T5 genomic DNA, and a DNA ligase gene was found to be split into two separate ORFs. Analysis of T5 early promoters suggests a probable motif AAA{3, 4 T}nTTGCTT{17, 18 n}TATAATA{12, 13 W}{10 R} for strong promoters that may strengthen the step modification of host RNA polymerase, and thus control transcription of phage DNA. The distinct protein domain profile and a mosaic genome structure suggest an origin from the common genetic pool.

Bacteriophages↗

PubMed2003

Polycomb, epigenomes, and control of cell identity.

In development, cell identity is maintained by epigenetic functions that prevent changes in cell type-specific transcription programs. Recent insights into gene silencing mechanisms by Polycomb group (PcG) and trithorax group (trxG) proteins reveal that the memory system involves a concerted process of chromatin modification, blocking of RNA polymerase II, and synthesis of noncoding RNA. Remarkably, cell memory is regulated by a balance between repressors and activators that maintains both transcription status and at the same time the possibility of switching to a different state.

Animals↗