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PubMed2006

Functional proteomics reveals the biochemical niche of C. elegans DCR-1 in multiple small-RNA-mediated pathways.

In plants, animals, and fungi, members of the Dicer family of RNase III-related enzymes process double-stranded RNA (dsRNA) to initiate small-RNA-mediated gene-silencing mechanisms. To learn how C. elegans Dicer, DCR-1, functions in multiple distinct silencing mechanisms, we used a mass-spectrometry-based proteomics approach to identify DCR-1-interacting proteins. We then generated and characterized deletion alleles for the corresponding genes. The interactors are required for production of three species of small RNA, including (1) small interfering RNAs (siRNAs), derived from exogenous dsRNA triggers (exo-siRNAs); (2) siRNAs derived from endogenous triggers (endo-siRNAs); and (3) developmental regulatory microRNAs (miRNAs). One interactor, the conserved RNA-phosphatase homolog PIR-1, is required for the processing of a putative amplified DCR-1 substrate. Interactors required for endo-siRNA production include ERI-1 and RRF-3, whose loss of function enhances RNAi. Our findings provide a first glimpse at the complex biochemical niche of Dicer and suggest that competition exists between DCR-1-mediated small-RNA pathways.

Amino Acid Sequence↗
PubMed2025

A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy.

Transfer RNA-derived small RNAs (tsRNAs or tDRs) perform a range of cellular functions. Here, we showed that tRNA-Asp-GTC-3'tDR, a hypoxia-induced tDR derived from the 3' end of tRNA-Asp-GTC, activated autophagic flux in kidney cells and its silencing blocked autophagic flux. Functional gain-/loss-of-function studies in murine kidney disease models demonstrated a substantial renoprotective function of tRNA-Asp-GTC-3'tDR. Mechanistically, tRNA-Asp-GTC-3'tDR assembled stable G-quadruplex structures and sequestered pseudouridine synthase 7 (PUS7), preventing catalytic pseudouridylation of histone mRNAs. The resulting pseudouridylation deficiency directed histone mRNAs to the autophagosome-lysosome pathway, triggering RNA autophagy. This tDR-induced RNA autophagy pathway was activated during murine and human kidney diseases, suggesting clinical relevance. Thus, tRNA-Asp-GTC-3'tDR plays a role in regulating RNA autophagy, which helps to maintain homeostasis in kidney cells and protects against kidney injury.

Animals↗
PubMed2006

Base-pairing requirement for RNA silencing by a bacterial small RNA and acceleration of duplex formation by Hfq.

SgrS is an Hfq-binding small antisense RNA that is induced upon phosphosugar stress. It forms a ribonucleoprotein complex with RNase E through Hfq to mediate silencing of the target ptsG mRNA encoding the membrane component of the glucose-specific phosphoenolpyruvate phosphotransferase system. Although SgrS is believed to act on ptsG mRNA through base pairing between complementary regions, this was not previously tested experimentally. We addressed the question of whether SgrS indeed forms an RNA-RNA duplex with ptsG mRNA to exert its regulatory function. Specific single nucleotide substitutions around the Shine-Dalgarno (SD) sequence of ptsG completely eliminated SgrS action while compensatory mutations in SgrS restored it. A systematic mutational analysis of both ptsG and SgrS RNAs revealed that six base pairs around SD sequence of ptsG are particularly important for SgrS action. We also showed in vitro that SgrS forms a stable duplex with the ptsG mRNA, and that Hfq markedly facilitates the rate of duplex formation.

Base Pairing↗
PubMed2006

Induction of gene silencing by hairpin RNA expression in Tetrahymena thermophila reveals a second small RNA pathway.

Unlike in other eukaryotes, in which it causes gene silencing, RNA interference (RNAi) has been linked to programmed DNA deletion in the ciliate Tetrahymena thermophila. Here we have developed an efficient method to inducibly express double-stranded RNA hairpins and demonstrated that they cause gene silencing through targeted mRNA degradation in all phases of the life cycle, including growth, starvation, and mating. This technique offers a new tool for gene silencing in this model organism. Induction of RNA hairpins causes dramatic upregulation of Dicer and Argonaute family genes, revealing a system capable of rapidly responding to double-stranded RNA. These hairpins are processed into 23- to 24-nucleotide (nt) small RNAs, which are distinctly different from the 28- to 30-nt small RNAs known to be associated with DNA deletion. Thus, two different small RNA pathways appear to be responsible for gene silencing and DNA deletion. Surprisingly, expression of the RNA hairpin also causes targeted DNA deletion during conjugation, although at low efficiencies, which suggests a possible crossover of these two molecular paths.

Animals↗
PubMed2004

Sequence-specific inhibition of small RNA function.

Hundreds of microRNAs (miRNAs) and endogenous small interfering RNAs (siRNAs) have been identified from both plants and animals, yet little is known about their biochemical modes of action or biological functions. Here we report that 2'-O-methyl oligonucleotides can act as irreversible, stoichiometric inhibitors of small RNA function. We show that a 2'-O-methyl oligonucleotide complementary to an siRNA can block mRNA cleavage in Drosophila embryo lysates and HeLa cell S100 extracts and in cultured human HeLa cells. In Caenorhabditis elegans, injection of the 2'-O-methyl oligonucleotide complementary to the miRNA let-7 can induce a let-7 loss-of-function phenocopy. Using an immobilized 2'-O-methyl oligonucleotide, we show that the C. elegans Argonaute proteins ALG-1 and ALG-2, which were previously implicated in let-7 function through genetic studies, are constituents of a let-7-containing protein-RNA complex. Thus, we demonstrate that 2'-O-methyl RNA oligonucleotides can provide an efficient and straightforward way to block small RNA function in vivo and furthermore can be used to identify small RNA-associated proteins that mediate RNA silencing pathways.

Animals↗
PubMed1985

Identification and characterization of a polyadenylated small RNA (s-poly A+ RNA) in dinoflagellates.

A 104 nucleotide-long small RNA, referred to as s-poly A+ RNA, containing 30 adenosine residues on its 3' -end was found in dinoflagellates, purified and its nucleotide sequence was determined. The sequence is: (sequence text) The polyadenylation signal AAUAAA was not found in this RNA; this result indicates that the 30 nucleotide-long poly A on the 3' -end is either coded for by this gene, or the poly A chain is added on this small RNA by a mechanism different from that for polyadenylation of messenger RNAs. Two polyadenylated small RNAs identified previously were implicated in differentiation of chicken heart muscle cells (Deshpande, A. K., Jakowlew, S. B., Arnold, H., Crawford, P. A. and Siddiqui, M. A. Q. (1977) J. Biol. Chem. 252, 6521-6527), and in brain specific mRNA transcription (Sutcliffe, J. G., Milner, R. J., Gottesfeld, J. M. and Lerner, R. A. (1984) Nature 309, 237-241). This RNA is the first polyadenylated small RNA to be sequenced.

Animals↗
PubMed2001

Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans.

Double-stranded RNAs can suppress expression of homologous genes through an evolutionarily conserved process named RNA interference (RNAi) or post-transcriptional gene silencing (PTGS). One mechanism underlying silencing is degradation of target mRNAs by an RNP complex, which contains approximately 22 nt of siRNAs as guides to substrate selection. A bidentate nuclease called Dicer has been implicated as the protein responsible for siRNA production. Here we characterize the Caenorhabditis elegans ortholog of Dicer (K12H4.8; dcr-1) in vivo and in vitro. dcr-1 mutants show a defect in RNAi. Furthermore, a combination of phenotypic abnormalities and RNA analysis suggests a role for dcr-1 in a regulatory pathway comprised of small temporal RNA (let-7) and its target (e.g., lin-41).

Alleles↗
PubMed1979

Synthesis of a small RNA in cells coinfected by standard and defective interfering particles of vesicular stomatitis virus.

A small RNA, containing approximately 50 nucleotides, is synthesized by cells coinfected with standard vesicular stomatitis virus and its defective interfering (DI) particles. Infection of cells by standard virus or DI particles alone does not lead to synthesis of significant amounts of small RNA. The RNA is initiated at its 5' end with (p)ppXp and is not polyadenylylated at the 3' end despite a content of 51% adenosine. It has sequences complementary to the genome of a DI particle. The synthesis of the small RNA correlates with the replication of the genome of DI particles with molar ratio small RNA/genome RNA of DI particles greater than 50. When replication of DI genomes is prevented by the addition of cycloheximide or prior UV irradiation of DI particles, small RNA is not synthesized in coinfected cells. These results indicate that the small RNA is not the result of transcriptional initiation and that it may relate to interference mediated by DI particles.

Animals↗
PubMed1994

Identification of a small RNA that interacts with the 5' splice site of the Trypanosoma brucei spliced leader RNA in vivo.

In vivo psoralen cross-linking of the trypanosome spliced leader (SL) RNA has led to the discovery of a small RNA that we provisionally call the spliced leader-associated (SLA) RNA. The 72 nt SLA RNA is unlike any known small RNA except for a small region that resembles U5 snRNA. The SL/SLA RNA cross-links map to two regions, the predominant interactions occurring between the 5' splice site region of the SL RNA and a CUUUUA sequence in the SLA RNA. The resemblance between these cross-links and interactions of U5 snRNA with cis-spliced pre-mRNAs suggests that the SLA RNA may be the trans-splicing analog of U5 snRNA in trypanosomes.

Animals↗
PubMed2001

RNA interference: it's a small RNA world.

Short RNAs regulate gene expression in many species. Some are generated from any double-stranded RNA and degrade complementary RNAs; others are encoded by genes and repress specific mRNAs. Both, it turns out, are processed and handled by similar proteins. These pathways offer a glimpse into a world of small RNAs.

Animals↗
PubMed2004

MicC, a second small-RNA regulator of Omp protein expression in Escherichia coli.

In a previous bioinformatics-based search for novel small-RNA genes encoded by the Escherichia coli genome, we identified a region, IS063, located between the ompN and ydbK genes, that encodes an approximately 100-nucleotide small-RNA transcript. Here we show that the expression of this small RNA is increased at a low temperature and in minimal medium. Twenty-two nucleotides at the 5' end of this transcript have the potential to form base pairs with the leader sequence of the mRNA encoding the outer membrane protein OmpC. The deletion of IS063 increased the expression of an ompC-luc translational fusion 1.5- to 2-fold, and a 10-fold overexpression of the small RNA led to a 2- to 3-fold repression of the fusion. Deletion and overexpression of the IS063 RNA also resulted in increases and decreases, respectively, in OmpC protein levels. Taken together, these results suggest that IS063 is a regulator of OmpC expression; thus, the small RNA has been renamed MicC. The antisense regulation was further demonstrated by the finding that micC mutations were suppressed by compensatory mutations in the ompC mRNA. MicC was also shown to inhibit ribosome binding to the ompC mRNA leader in vitro and to require the Hfq RNA chaperone for its function. We suggest that the MicF and MicC RNAs act in conjunction with the EnvZ-OmpR two-component system to control the OmpF/OmpC protein ratio in response to a variety of environmental stimuli.

Base Sequence↗
PubMed1990

Posttranscriptional control of plasmid ColIb-P9 repZ gene expression by a small RNA.

The replication frequency of plasmid ColIb-P9 depends on the level of repZ gene expression, which is negatively regulated by the action of the inc gene (C. Hama, T. Takizawa, H. Moriwaki, Y. Urasaki, and K. Mizobuchi, J. Bacteriol. 172:1983-1991, 1990). To further understand the mechanism of this regulation, we analyzed transcripts of the ColIb-P9 replication control region. Four RNA species, designated RNAI to RNAIV, were observed in plasmid pCH11, which contained the whole inc gene region and the 5' portion of the repZ gene. RNAII, RNAIII, and RNAIV, with sizes of approximately 200, 500, and 1,500 bases, respectively, were identified as rightward transcripts that shared common transcription initiation sites; RNAIV was determined to be equivalent to a part of repZ mRNA, which was observed in pCH10, a plasmid that contained sufficient information for replication and control of ColIb-P9. Conversely, RNAI, with a size of about 70 bases, was transcribed leftward and was identified as the product of the inc gene and hence equivalent to inc RNA detected by in vitro RNA synthesis. This small RNA was found to be complementary to a part of repZ mRNA. These results and quantitative analyses of the transcripts in Inc- mutants indicate that the inc RNA negatively regulates repZ expression mainly at the posttranscriptional level through the possible formation of an inc RNA-repZ mRNA hybrid in the host cells.

Bacterial Proteins↗
PubMed1991

Brain-specific small RNA transcript of the identifier sequences is present as a 10 S ribonucleoprotein particle.

BC-1 RNA is a small RNA transcript of the identifier repetitive sequences present in rodent genomes. The RNA has been reported to be specific to the brain and confined to the cytoplasm. The RNA level increases during the 1st month after birth. To understand its cytoplasmic function, it seems important to examine whether BC-1 RNA is present as an RNP. It is believed that the protein component may govern the functions of BC-1 RNA in the brain cells. In the present report, we have demonstrated that BC-1 RNA is not free but complexed with proteins to form a 10 S RNP in the cytoplasm. We have also shown that the 10 S RNP is not associated with cytoplasmic structures such as polysomes/ribosomes or microsomes. The buoyant density of the RNP was 1.26 g/cm3 in metrizamide. Furthermore, some of the protein components were shown to be in direct contact with RNA, since photo-cross-linking adducts of protein to BC-1 RNA were identified upon UV irradiation of the 10 S BC-1 RNP.

Animals↗
PubMed2002

Electron paramagnetic resonance dynamic signatures of TAR RNA-small molecule complexes provide insight into RNA structure and recognition.

Electron paramagnetic resonance (EPR) spectroscopy was utilized to investigate the correlation between RNA structure and RNA internal dynamics in complexes of HIV-1 TAR RNA with small molecules. TAR RNAs containing single nitroxide spin-labels in the 2'-position of U23, U25, U38, or U40 were incubated with compounds known to inhibit TAR-Tat complex formation. The combined changes in nucleotide mobility at all four sites, as monitored by their EPR spectral width, yield a dynamic signature for each compound. The multicyclic dyes Hoechst 33258, DAPI, and berenil bind to TAR RNA in a similar manner and gave nearly identical signatures. Different signatures were obtained for the acridine derivative CGP 40336A and the aminoglycoside antibiotic neomycin, which bind to different regions of the RNA. The dynamic signature for guanidinoneomycin was remarkably similar to that obtained for argininamide and is evidence for guanidinoneomycin binding to the same site as arginine 52 of the Tat protein, rather than to the neomycin binding site. The data presented here show that the dynamic signatures provide strong insights into RNA structure and recognition and demonstrate the value of EPR spectroscopy for the investigation of small molecule binding to RNA.

Acridines↗