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At least 1,783 records · Page 99Linked to original sources
PubMed1998

Metaphase fragility of the human RNU1 and RNU2 loci is induced by actinomycin D through a p53-dependent pathway.

Infection of human cells with adenovirus 12 (Ad12), but not Ad2 or 5, induces four specific sites of metaphase chromosome fragility: the U1 small nuclear RNA (snRNA) genes (the RNU1 locus), the U2 snRNA genes (RNU2), the U1 snRNA pseudogenes (PSU1) and the 5S rRNA genes (RN5S). Significantly, each of these sites corresponds to a multigene family encoding a small, abundant structural RNA. We and others have shown previously that Ad12-induced fragility of the RNU2 locus requires U2 snRNA promoter elements, viral early functions and p53 function, but not viral replication or integration, Rb function or chromosomal sequences flanking the RNU2 locus. Remarkably, we now find that very low doses of actinomycin D (5-50 ng/ml) can phenocopy Ad12 infection: metaphase fragility of the RNU1 and RNU2 loci is induced specifically in the absence of virus, and induction also requires U2 promoter elements and p53 function. Concurrently, it has been found by others that treatment with cytosine arabinoside (araC), but not aphidicolin, can also phenocopy Ad12 infection. We propose that Ad12 infection, actinomycin D and araC all induce a similar or identical global damage arrest signal (perhaps a modification or altered conformation of p53) that preferentially interferes with metaphase condensation of the RNU1 and RNU2 loci. The RNU1 and RNU2 loci could be especially sensitive to this global signal either because specialized U snRNA transcription factors interact uniquely with the signal, or because the high concentration of short, active transcription units hinders chromatin condensation.

Chromosome Fragility↗
PubMed1989

HIV trans-activation and transcription control mechanisms.

Promoter-specific transcription factors, whose function was once thought to be limited to initiation, are now known to have more diverse roles in RNA metabolism, including the cellular localization of transcripts and the integration of RNA initiation with attenuation and RNA 3' end formation. The human immunodeficiency viruses (HIV-1 and HIV-2) provide a useful system to study such proteins, since distinct DNA and RNA elements downstream of the site of transcription initiation act in conjunction with the promoter to regulate the induction and attenuation of RNA synthesis. Sequences corresponding to the 5' untranslated leader of HIV-1 and HIV-2 harbor at least three distinct elements: (i) a DNA domain that binds LBP-1, a cellular activator of initiation; (ii) a structured RNA element critical for the function of the HIV-1 trans-activating protein, Tat; and (iii) an RNA element required for the production of attenuated RNAs from the basal (uninduced) promoter. These attenuated leader RNAs seem to be created in vitro by stalled RNA polymerase II complexes that may be uniquely capable of rapidly processing RNA. Tat-mediated increases in steady-state levels of viral transcripts appear from nuclear run-on experiments to involve a control mechanism at both initiation and early post-initiation steps. Studies that implicate a role for Tat in post-transcriptional control suggest the existence of a mechanism for the coordination of eukaryotic transcription and translation, possibly through the assembly of nuclear regulatory factors at the 5' end of the RNA.

Base Sequence↗
PubMed1994

Suppression of mutations in the core of the Tetrahymena ribozyme by spermidine, ethanol and by substrate stabilization.

We have previously described a collection of mutations in conserved residues of the core of the Tetrahymena self-splicing intron. Most of these single base substitutions have less than 10% of the activity of their parental intron derivative [Couture, S., et al., (1990) J. Mol. Biol., 215, 345-358]. We examined the effect of two agents known to stabilize RNA structure, spermidine and ethanol, on the activity of many of these mutant RNAs. In the presence of either 5 mM spermidine or 20% ethanol most substitution mutations were partially or completely suppressed. These conditions also increased the temperature optima of both wild-type and mutant ribozymes. In addition, we find that mutations are also suppressed by a high concentration of GTP, a substrate in the reaction which is bound specifically by the intron. Thus we observe a general suppression of mutations in an RNA enzyme (ribozyme) by spermidine, ethanol and by substrate stabilization. These results are consistent with the idea that most mutations destabilize the folded structure of the ribozyme and can be suppressed by any of a variety of stabilizing influences.

Animals↗
PubMed1983

Differential stringent control of the tandem E. coli ribosomal RNA promoters from the rrnA operon expressed in vivo in multicopy plasmids.

The tandem P1, P2 promoter region of the rrnA ribosomal operon has been fused to the t1, t2 terminator region of the rrnB operon in pBR322 plasmid derivatives. This deletes most internal RNA structural elements ordinarily processed out of ribosomal operon transcripts. In vivo as well as in vitro transcripts arising from both promoters terminate predominantly in the t1 terminator region about 40 base pairs beyond the mature rrnB 5S RNA gene. Stringent control of the P1 and P2 promoted transcripts has been assessed in vivo. In these plasmid fusions, the upstream (P1) promoter activity was subject to stringent control, while the downstream (P2) promoter activity was inhibited by amino acid starvation in both stringent and relaxed hosts. A plasmid with an additional deletion of the P2 region also showed stringent regulation of the P1 promoter.

Amino Acids↗
PubMed2002

Genetic control by a metabolite binding mRNA.

Messenger RNAs are typically thought of as passive carriers of genetic information that are acted upon by protein- or small RNA-regulatory factors and by ribosomes during the process of translation. We report that the 5'-untranslated sequence of the Escherichia coli btuB mRNA assumes a more proactive role in metabolic monitoring and genetic control. The mRNA serves as a metabolite-sensing genetic switch by selectively binding coenzyme B(12) without the need for proteins. This binding event establishes a distinct RNA structure that is likely to be responsible for inhibition of ribosome binding and consequent reduction in synthesis of the cobalamin transport protein BtuB. This finding, along with related observations, supports the hypothesis that metabolic monitoring through RNA-metabolite interactions is a widespread mechanism of genetic control.

5' Untranslated Regions↗
PubMed2006

Physical interaction of apoptosis-inducing factor with DNA and RNA.

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein, which upon apoptosis induction translocates to the nucleus where it interacts with DNA by virtue of positive charges clustered on the AIF surface. Here we show that the AIF interactome, as determined by mass spectroscopy, contains a large panel of ribonucleoproteins, which apparently bind to AIF through the RNA moiety. However, AIF is devoid of any detectable RNAse activity both in vitro and in vivo. Recombinant AIF can directly bind to DNA as well as to RNA. This binding can be visualized by electron microscopy, revealing that AIF can condense DNA, showing a preferential binding to single-stranded over double-stranded DNA. AIF also binds and aggregates single-stranded and structured RNA in vitro. Single-stranded poly A, poly G and poly C, as well double-stranded A/T and G/C RNA competed with DNA for AIF binding with a similar efficiency, thus corroborating a computer-calculated molecular model in which the binding site within AIF is the same for distinct nucleic acid species, without a clear sequence specificity. Among the preferred electron donors and acceptors of AIF, nicotine adenine dinucleotide phosphate (NADP) was particularly efficient in enhancing the generation of higher-order AIF/DNA and AIF/RNA complexes. Altogether, these data support a model in which a direct interaction of AIF contributes to the compaction of nucleic acids within apoptotic cells.

Amino Acid Sequence↗
PubMed2004

Hybridization of antisense oligonucleotides with alpha-sarcin loop region of Escherichia coli 23S rRNA.

Binding of complementary oligonucleotides (ONs) with alpha-sarcin loop region (2638-2682) of Escherichia coli 23S rRNA was investigated. Four of the tested pentadecanucleotides efficiently bound to target sequences with association rate and equilibrium constants approximately 10(3) M(-1)s(-1) and 10(7) M(-1), respectively. ON S5 (CGAGAGGACCGGAGU) complementary to the sequence 2658-2672 displayed the highest affinity to the target. Activation energy for binding of ON S5 was measured to be 11 kcal/mol; this value corresponds to approximately 10% of the calculated enthalpy of the local RNA structure unfolding in the presence of this oligonucleotide. The activation energy value is evidence for the heteroduplex formation to occur via strand displacement pathway; the initiation of heteroduplex formation requires disruption of 1-2 base pairs in RNA hairpin.

Base Sequence↗
PubMed2002

Endogenous and silencing-associated small RNAs in plants.

A large set of endogenous small RNAs of predominantly 21 to 24 nucleotides was identified in Arabidopsis. These small RNAs resembled micro-RNAs from animals and were similar in size to small interfering RNAs that accumulated during RNA silencing triggered by multiple types of inducers. Among the 125 sequences identified, the vast majority (90%) arose from intergenic regions, although small RNAs corresponding to predicted protein-coding genes, transposon-like sequences, and a structural RNA gene also were identified. Evidence consistent with the derivation of small RNAs of both polarities, and from highly base-paired precursors, was obtained through the identification and analysis of clusters of small RNA loci. The accumulation of specific small RNAs was regulated developmentally. We propose that Arabidopsis small RNAs participate in a wide range of post-transcriptional and epigenetic events.

Arabidopsis↗
PubMed2005

Focus issue: RNA, a multifunctional molecule.

This week's issues of Science, Science's STKE, and SAGE KE (www.sciencemag.org/sciext/rna/) focus on the increasing complexity that RNA brings to cellular biology. STKE resources include Reviews, Perspectives, and Teaching Resources. STKE specifically looks at the roles for small RNAs in regulation of gene expression and how mRNAs can be selectively activated from cytoplasmic macromolecular structures, RNA granules, to contribute to such processes as synaptic plasticity.

Animals↗
PubMed1998

Effects of polyvalent cations on the folding of an rRNA three-way junction and binding of ribosomal protein S15.

The Bacillus stearothermophilus ribosomal protein S15 binds to a phylogenetically conserved three-way junction formed by the intersection of helices 20, 21, and 22 of eubacterial 16S ribosomal RNA, inducing a large conformational change in the RNA. Like many RNA structures, this three-way junction can also be folded by the addition of polyvalent cations such as magnesium, as demonstrated by comparing the mobilities of the wild-type and mutant junctions in the absence and presence of polyvalent cations in nondenaturing polyacrylamide gels. Using a modification interference assay, critical nucleotides for folding have been identified as the phylogenetically conserved nucleotides in the three-way junction. NMR spectroscopy of the junction reveals that the conformations induced by the addition of magnesium or S15 are extremely similar. Thus, the folding of the junction is determined entirely by RNA elements within the phylogenetically conserved junction core, and the role of Mg2+ and S15 is to stabilize this intrinsically unstable structure. The organization of the junction by Mg2+ significantly enhances the bimolecular association rate (k(on)) of S15 binding, suggesting that S15 binds specifically to the folded form of the three-way junction via a tertiary structure capture mechanism.

Bacterial Proteins↗
PubMed1988

Vasopressin mRNA in the suprachiasmatic nuclei: daily regulation of polyadenylate tail length.

Daily variation has been found in the length of the polyadenylate tail attached to vasopressin messenger RNA in the suprachiasmatic nuclei, which is the location of an endogenous circadian pacemaker in mammals. No such variation was found in the supraoptic or paraventricular nuclei. This variation in the length of the polyadenylate tail may underlie the circadian rhythm of vasopressin peptide levels in cerebrospinal fluid and is a unique example of a daily rhythm in messenger RNA structure.

Animals↗
PubMed1988

RNA splicing and genes.

The splicing of long transcripts of RNA (copied from DNA in the cell nucleus) into smaller, specific mRNA (ready for export to the protein-producing machinery in the cytoplasm) is an important event in the regulation of gene expression in eukaryotic cells. The splicing reaction occurs as a late step in the nuclear pathway for synthesis of mRNAs. This pathway commences with initiation of transcription by RNA polymerase II and probably involves an integrated series of steps each dependent on previous events. Splicing of precursors to mRNAs involves the formation of a spliceosome complex containing the 5' and 3' splice sites. This complex contains the evolutionarily highly conserved small nuclear RNAs (snRNAs) U2, U4, U5, and U6. The most abundant snRNA, U1, is required to form the spliceosome and may be a part of the spliceosome. Analogues of these snRNAs have been identified in yeast. Assembly of the spliceosome probably involves the binding of a multi-snRNA complex containing U4, U5, and U6 snRNAs. Several observations suggest that the association of snRNAs in such complexes is quite dynamic. It is argued that the snRNAs in the spliceosome form a catalytic RNA structure that is responsible for the cleavage and ligation steps during splicing.

Animals↗
PubMed1998

Structure of an RNA internal loop consisting of tandem C-A+ base pairs.

The crystal structure of the RNA octamer 5'-CGC(CA)GCG-3' has been determined from X-ray diffraction data to 2.3 A resolution. In the crystal, this oligomer forms a self-complementary double helix in the asymmetric unit. Tandem non-Watson-Crick C-A and A-C base pairs comprise an internal loop in the middle of the duplex, which is incorporated with little distortion of the A-form double helix. From the geometry of the C-A base pairs, it is inferred that the adenosine imino group is protonated and donates a hydrogen bond to the carbonyl group of the cytosine. The wobble geometry of the C-A+ base pairs is very similar to that of the common U-G non-Watson-Crick pair.

Adenine↗
PubMed1993

Mutations affecting pseudoknot control of the replication of B group plasmids.

The translational initiation region of the mRNA for the replication initiation protein (RepA) of pMU720 is predicted to be sequestered in an inhibitory secondary structure designated stem-loop III. Activation of repA translation requires both the disruption of stem-loop III by ribosomes involved in the translation and termination of the leader peptide RepB and the formation of a pseudoknot, a tertiary RNA structure. Disruption of stem-loop III by site-directed mutagenesis was found to be insufficient to allow high repA expression in the absence of pseudoknot formation, indicating that the pseudoknot acts as an enhancer of repA translation. Furthermore, extending the length of the leader peptide RepB and changing the distance between the pseudoknot and repA Shine-Dalgarno sequence were found to have major effects on the translation of repA.

Amino Acid Sequence↗
PubMed1998

Phylogenetic evidence for the improved RNA higher-order structure in internal ribosome entry sequences of HCV and pestiviruses.

The strong requirement for a small segment of the 5'-proximal coding sequence of hepatitis C virus (HCV) is one of the most remarkable features in the internal initiation of HCV mRNA translation. Phylogenetic analysis and RNA folding indicate a common RNA structure of the 5' untranslated region (UTR) of HCV and the animal pestiviruses, including HCV types 1-11, bovine viral diarrhea (BVDV), border disease virus (BDV) and hog cholera (HoCV). Although the common RNA structure shares similar features to that proposed for the internal ribosome entry sequence (IRES) of picornavirus, phylogenetic evidence suggests four new tertiary interactions between conserved terminal hairpin loops and between the terminal hairpin loop of F2b and the short coding sequence for HCV and pestiviruses. We suggest that the higher-order structures of IRES cis-acting elements for HCV and animal pestivirus are composed of stem-loop structures B-C, domains E-H, stem-loop structure J and four additional tertiary interactions. The common structure of IRES elements for these viruses forms a compact structure by these tertiary interactions and stem stacking. The active structural core is centered in the junction domain of E-H that is also conserved in all members of picornaviruses. Our model suggests that the requirement for a small segment of the 5' coding sequence is to form the distinct tertiary structure that facilitates the cis-acting function of the HCV IRES in the internal initiation of the translational control.

5' Untranslated Regions↗
PubMed1998

RNA editing of brain glutamate receptor channels: mechanism and physiology.

Glutamate-gated cation selective channels mediate fast excitatory neurotransmission in the mammalian brain. Functionally critical channel positions contain amino acid residues not predicted from the exonic sequence for the channel subunits. The codons for these residues are created in the respective primary gene transcripts by the site selective deamination of adenosine to inosine. This type of RNA editing requires a short double-stranded RNA structure formed by the exonic sequence around the adenosine targeted for deamination with a complementary sequence in the downstream intron and hence, it precedes splicing. Candidate enzymes for nuclear transcript editing currently comprise three molecularly cloned mammalian RNA-dependent adenosine deaminases. Two of these are expressed in most body tissues, perhaps indicating that adenosine deamination in transcripts is more global than has been recognized. Indeed, numerous mRNAs in different tissues may contain inosine residues and encode proteins with amino acid substitutions and different properties relative to the exonically encoded forms. If so, RNA editing by adenosine deamination may significantly enlarge the functional repertoire of the mammalian genome.

Amino Acid Sequence↗
PubMed1999

The importance of internal loops within RNA substrates of ADAR1.

Adenosine deaminases that act on RNA (ADARs) are a family of RNA editing enzymes that convert adenosines to inosines within double-stranded RNA (dsRNA). Although ADARs deaminate perfectly base-paired dsRNA promiscuously, deamination is limited to a few, selected adenosines within dsRNA containing mismatches, bulges and internal loops. As a first step in understanding how RNA structural features promote selectivity, we investigated the role of internal loops within ADAR substrates. We observed that a dsRNA helix is deaminated at the same sites whether it exists as a free molecule or is flanked by internal loops. Thus, internal loops delineate helix ends for ADAR1. Since ADAR1 deaminates short RNAs at fewer adenosines than long RNAs, loops decrease the number of deaminations within an RNA by dividing a long RNA into shorter substrates. For a series of symmetric internal loops related in sequence, larger loops (>/=six nucleotides) acted as helix ends, whereas smaller loops (</=four nucleotides) did not. Our work provides the first information about how secondary structure within ADAR substrates dictates selectivity, and suggests a rational approach for delineating minimal substrates for RNAs deaminated by ADARs in vivo.

Adenosine Deaminase↗
PubMedDate not supplied

RNA-sequence-mediated gene regulation in HIV-1.

The quantity and quality of human immunodeficiency virus type 1 (HIV-1) gene expression is controlled in large part by the action of two small nuclear viral regulatory proteins termed Tat and Rev. Tat is unique among transcriptional trans-activators in that it acts via a structured RNA target sequence, termed TAR, to induce high levels of transcription from the HIV-1 long terminal repeat promoter element. The activity of the viral Rev protein is also unprecedented in that this protein functions to induce the nuclear export of a specific class of viral RNA species that are otherwise sequestered in the nucleus by the action of cellular factors. Like Tat, Rev also interacts with a highly specific cis-acting target sequence termed, in this case, the Rev Response Element. In this review, I provide an outline of our current understanding of the roles and mechanisms of action of these two novel RNA-sequence-dependent regulatory proteins.

Base Sequence↗