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PubMed2006

A novel class of small RNAs in mouse spermatogenic cells.

Small noncoding RNAs, including small interfering RNAs (siRNAs) and micro RNAs (miRNAs) of approximately 21 nucleotides (nt) in length, have emerged as potent regulators of gene expression at both transcriptional and post-transcriptional levels in diverse organisms. Here we report the identification of a novel class of small RNAs in the mouse male germline termed piwi-interacting RNAs (piRNAs). piRNAs are approximately 30 nt in length. They are expressed during spermatogenesis, mostly in spermatids. piRNAs are associated with MIWI, a spermatogenesis-specific PIWI subfamily member of the Argonaute protein family, and depend on MIWI for their biogenesis and/or stability. Furthermore, a subpopulation of piRNAs are associated with polysomes, suggesting their potential role in translational regulation.

Animals↗
PubMed2005

Detection of 5'- and 3'-UTR-derived small RNAs and cis-encoded antisense RNAs in Escherichia coli.

Evidence is accumulating that small, noncoding RNAs are important regulatory molecules. Computational and experimental searches have led to the identification of approximately 60 small RNA genes in Escherichia coli. However, most of these studies focused on the intergenic regions and assumed that small RNAs were >50 nt. Thus, the previous screens missed small RNAs encoded on the antisense strand of protein-coding genes and small RNAs of <50 nt. To identify additional small RNAs, we carried out a cloning-based screen focused on RNAs of 30-65 nt. In this screen, we identified RNA species corresponding to fragments of rRNAs, tRNAs and known small RNAs. Several of the small RNAs also corresponded to 5'- and 3'-untranslated regions (UTRs) and internal fragments of mRNAs. Four of the 3'-UTR-derived RNAs were highly abundant and two showed expression patterns that differed from the corresponding mRNAs, suggesting independent functions for the 3'-UTR-derived small RNAs. We also detected three previously unidentified RNAs encoded in intergenic regions and RNAs from the long direct repeat and hok/sok elements. In addition, we identified a few small RNAs that are expressed opposite protein-coding genes and could base pair with 5' or 3' ends of the mRNAs with perfect complementarity.

3' Untranslated Regions↗
PubMed1988

Characterization of Novikoff hepatoma small RNAs homologous to repetitive DNAs.

Three minor small RNA species from Novikoff hepatoma cells, with homology to repetitive DNA sequences, have been identified and characterized. These small RNAs, designated 5.1S, 6S and T3 RNAs, show homology to Alu 1, Alu 2, and Alu 3 sequences, respectively. 6S and T3 RNAs were found both in the nucleus and cytoplasm, whereas 5.1S RNA was not found in the nucleus. Neural tissues were found to contain a 6S-sized BC1 RNA with homology to I.D. sequences; in contrast, the current study shows that Novikoff hepatoma cells contain a 75-80 nucleotide long (T3) RNA, homologous to I.D. sequences. These data suggest that BC1 and T3 small RNAs, homologous to I.D. sequences, are expressed in a tissue-specific manner. These results also show that in addition to the abundant 7SL, 4.5S and 4.5S1 RNAs having homology to repetitive DNA, Novikoff hepatoma cells also contain several minor small RNAs with homology to repetitive sequences.

Animals↗
PubMed2005

The role of small RNAs in human diseases: potential troublemaker and therapeutic tools.

Small RNAs, including short interfering RNAs (siRNAs) and microRNAs (miRNAs), are ubiquitous, versatile repressors of gene expression in plants, animals, and many fungi. They can trigger destruction of homologous mRNA or inhibition of cognate mRNA translation and play an important role in maintaining the stable state of chromosome structure and regulating the expression of protein-coding genes. Furthermore, the recent research showed that there exists close relationship between small RNAs and human diseases. Several human diseases have surfaced in which miRNAs or their machinery might be implicated, such as some neurological diseases and cancers. The specificity and potency of small RNAs suggest that they might be promising as therapeutic agents. This article will review the role of small RNAs in some human diseases etiology and investigations of taking siRNAs as therapeutic tools for treating viral infection, cancer, and other diseases. We also discuss the potential of miRNAs in gene therapy.

Animals↗
PubMed2000

Evolutionary conservation of post-transcriptional 3' end adenylation of small RNAs: S. cerevisiae signal recognition particle RNA and U2 small nuclear RNA are post-transcriptionally adenylated.

The 3' terminal nucleotide of several human small RNAs, including Signal Recognition Particle (SRP) RNA, 7SK RNA, U2 small nuclear RNA and ribosomal 5S RNA was previously characterized and a fraction of these RNAs was found to contain a single post-transcriptionally added adenylic acid residue on their 3' ends. Here we report the development of a reverse transcription-polymerase chain reaction (RT-PCR) assay for determining and quantifying the extent of post-transcriptional adenylation of RNAs from different species. Using this assay, we found that a fraction of S. cerevisiae U2 small nuclear RNA and S. cerevisiae SRP RNA contain a post-transcriptionally added adenylic acid residue on their 3' ends. Sequencing analysis confirmed this adenylation to be post-transcriptional. Corresponding small RNAs in Xenopus oocytes also contained this post-transcriptional adenylation on their 3' ends. These data show that post-transcriptional adenylation on the 3' end of several small RNA molecules is conserved through evolution. Xenopus SRP RNA from both cytoplasmic and nuclear compartments contained post-transcriptionally added adenylic acid residue on its 3' end. In addition, the Alu portion of SRP RNA was adenylated, when injected into the cytoplasm of frog oocytes. These data show that this novel adenylating machinery, capable of specifically adding a single adenylic acid to the 3' end of some RNA molecules, is present and functional in both nucleus and cytoplasm.

Adenosine Monophosphate↗
PubMed2006

Small RNAs and non-small cell lung cancer.

Patients with non-small cell lung cancer (NSCLC) are commonly diagnosed with advanced disease and have limited therapeutic options. Experimental treatment approaches including small molecule targeted therapeutics, gene modified tumor vaccines, and viral-based gene therapy have induced tumor regression in a small proportion of patients, suggesting that advanced NSCLC is susceptible to molecular perturbations. RNA interference (RNAi) has generated considerable excitement as a potential cancer therapeutic application. RNAi is the process by which small, double stranded RNA molecules (small interfering RNA, or siRNA) can initiate sequence-specific, post-transcriptional gene silencing (PTGS). Cancer growth inhibition was attained through siRNA-knockdown of unique or overexpressed cancer oncogenetic messages that are relevant to NSCLC pathophysiology. As with other loss-of-function cancer gene therapy approaches, clinical efficacy of siRNA depends largely on the extent of cell target coverage at the locoregional and/or systemic level. Cationic liposomes as well as viral vectors have been used successfully for siRNA delivery. However, viral delivery may have more immediate relevance due to its wider clinical acceptance in the cancer gene therapy arena. We advocate the use of conditional replicative, oncolytic adenovirus for siRNA delivery, which offers potential benefits of restricted and renewable siRNA expression within the tumor microenvironment, and an additive anti-tumor outcome through viral oncolysis and siRNA-mediated oncogene-silencing, which we have demonstrated with the A549 NSCLC cell line. Several oncolytic adenoviral constructs are potentially applicable clinical platforms with proven infectivity and safety, which are feasible also for the delivery of microRNAs (miRNA), a recently discovered group of endogenous, small RNA with PTGS activity that is downregulated in lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed2006

A germline-specific class of small RNAs binds mammalian Piwi proteins.

Small RNAs associate with Argonaute proteins and serve as sequence-specific guides to regulate messenger RNA stability, protein synthesis, chromatin organization and genome structure. In animals, Argonaute proteins segregate into two subfamilies. The Argonaute subfamily acts in RNA interference and in microRNA-mediated gene regulation using 21-22-nucleotide RNAs as guides. The Piwi subfamily is involved in germline-specific events such as germline stem cell maintenance and meiosis. However, neither the biochemical function of Piwi proteins nor the nature of their small RNA guides is known. Here we show that MIWI, a murine Piwi protein, binds a previously uncharacterized class of approximately 29-30-nucleotide RNAs that are highly abundant in testes. We have therefore named these Piwi-interacting RNAs (piRNAs). piRNAs show distinctive localization patterns in the genome, being predominantly grouped into 20-90-kilobase clusters, wherein long stretches of small RNAs are derived from only one strand. Similar piRNAs are also found in human and rat, with major clusters occurring in syntenic locations. Although their function must still be resolved, the abundance of piRNAs in germline cells and the male sterility of Miwi mutants suggest a role in gametogenesis.

Animals↗
PubMed2006

A PCR-based method for detection and quantification of small RNAs.

Recent cloning efforts have identified hundreds of thousands of small RNAs including micro RNAs (miRNAs), Piwi-interacting RNAs (piRNAs), and small nucleolar RNAs (snoRNAs). These non-coding small RNAs need to be further validated and characterized by detecting and quantifying their expression in different tissues and during different developmental courses. A simple, accurate, and sensitive method for small RNA expression profiling is in high demand. Here, we report such a PCR-based method.

Animals↗
PubMed2000

Malignant transformation of B lymphoma cell line BJAB by Epstein-Barr virus-encoded small RNAs.

EBV-encoded small RNAs (EBERs) are non-polyadenylated and abundantly transcribed RNAs, whose functions have not yet been fully elucidated. Here, we report that the EBV-negative B lymphoma cell line, BJAB, was rendered more malignant and resistant to apoptosis by EBERs. EBER-transfected cells exhibited enhanced growth potential in SCID mice as well as in soft agar, and showed resistance to apoptotic stimuli in comparison with the vector control. EBERs inhibited the activity of the double-stranded RNA-dependent protein kinase, PKR, which is reputed to act as a tumor-suppressor. These results suggest that EBERs play an important role in the pathogenesis of EBV-associated malignancies through the inhibition of PKR.

Apoptosis↗
PubMed2004

Small RNAs shed some light.

Small regulatory RNAs can act by pairing with their target messages, targeting themselves and the mRNA for degradation; Lenz et al. (this issue of Cell) now report that multiple small RNAs are essential regulators of the quorum-sensing systems of Vibrio species, including the regulation of virulence in V. cholerae.

Gene Expression Regulation, Bacterial↗
PubMed2004

Conjugation-specific small RNAs in Tetrahymena have predicted properties of scan (scn) RNAs involved in genome rearrangement.

We proposed a scan-RNA model for genome rearrangement based on finding small RNAs that hybridized preferentially to micronuclear-specific sequences and on the properties of Twi1p, a PPD protein required for both sequence elimination and small RNA accumulation in Tetrahymena. Here we show that Twi1p interacts with the small RNAs in both the old and the developing macronucleus, and is required for their stability. We show that the specificity of the small RNAs for micronuclear-limited sequences increases during conjugation. These results indicate that the small RNAs observed in conjugating cells have the properties predicted for scan RNAs.

Animals↗
PubMed1986

Occurrence of novel small RNAs with concomitant inhibition of host cellular U small nuclear RNA synthesis in Vero cells infected with herpes simplex virus type 1.

In eukaryotic cells, small nuclear and small cytoplasmic RNAs (sn- or scRNAs) are associated with distinct proteins, forming ribonucleoproteins (snRNPs or scRNPs). In the present study we analysed the protein composition as well as the small RNA pattern in non-infected and herpes simplex virus type 1 (HSV)-infected Vero cells. We found that concomitantly with the shut-off of host cell mRNA synthesis, synthesis of U-snRNAs was stopped. Due to their stability, however, U-snRNAs were still present in cells 36 h after HSV infection. Besides these RNAs, two novel small RNAs which we termed HVR1 and HVR2 were detected in infected cells. On the basis of their relative mobilities in urea gels, the apparent chain lengths of these newly synthesized RNAs were determined to be 255 and 154 nucleotides respectively. The small RNA-binding proteins Sm, RNP, Ro and La were found to increase up to 15-fold after HSV infection. The data presented suggest that new, virus-coded small RNPs are synthesized which might play a role in the maturation and regulation of HSV-coded RNA transcripts.

Animals↗
PubMed2005

Two classes of endogenous small RNAs in Tetrahymena thermophila.

Endogenous small RNAs function in RNA interference (RNAi) pathways to guide RNA cleavage, translational repression, or methylation of DNA or chromatin. In Tetrahymena thermophila, developmentally regulated DNA elimination is governed by an RNAi mechanism involving approximately 27-30-nucleotide (nt) RNAs. Here we characterize the sequence features of the approximately 27-30-nt RNAs and a approximately 23-24-nt RNA class representing a second RNAi pathway. The approximately 23-24-nt RNAs accumulate strain-specifically manner and map to the genome in clusters that are antisense to predicted genes. These findings reveal the existence of distinct endogenous RNAi pathways in the unicellular T. thermophila, a complexity previously demonstrated only in multicellular organisms.

Animals↗
PubMed2006

MicroRNAs and other small RNAs enriched in the Arabidopsis RNA-dependent RNA polymerase-2 mutant.

The Arabidopsis genome contains a highly complex and abundant population of small RNAs, and many of the endogenous siRNAs are dependent on RNA-Dependent RNA Polymerase 2 (RDR2) for their biogenesis. By analyzing an rdr2 loss-of-function mutant using two different parallel sequencing technologies, MPSS and 454, we characterized the complement of miRNAs expressed in Arabidopsis inflorescence to considerable depth. Nearly all known miRNAs were enriched in this mutant and we identified 13 new miRNAs, all of which were relatively low abundance and constitute new families. Trans-acting siRNAs (ta-siRNAs) were even more highly enriched. Computational and gel blot analyses suggested that the minimal number of miRNAs in Arabidopsis is approximately 155. The size profile of small RNAs in rdr2 reflected enrichment of 21-nt miRNAs and other classes of siRNAs like ta-siRNAs, and a significant reduction in 24-nt heterochromatic siRNAs. Other classes of small RNAs were found to be RDR2-independent, particularly those derived from long inverted repeats and a subset of tandem repeats. The small RNA populations in other Arabidopsis small RNA biogenesis mutants were also examined; a dcl2/3/4 triple mutant showed a similar pattern to rdr2, whereas dcl1-7 and rdr6 showed reductions in miRNAs and ta-siRNAs consistent with their activities in the biogenesis of these types of small RNAs. Deep sequencing of mutants provides a genetic approach for the dissection and characterization of diverse small RNA populations and the identification of low abundance miRNAs.

Arabidopsis↗
PubMed1979

Comparison of the small RNAs of polymerase-deficient and polymerase-positive Rous sarcoma virus and another species of avian retrovirus.

The small RNAs contained in virions of avian leukosis and sarcoma viruses are a virus-specific subset of the total small RNA population of the host cell. The reverse transcriptase protein must be present in the budding virion for this selection to take place. Virions of the alpha form of the Bryan strain of Rous sarcoma virus, which lack detectable reverse transcriptase, incorporated an unselected population of small RNAs identical to total chicken cell small RNA. Virions of reticuloendotheliosis virus, which contain a reverse transcriptase unrelated to that of the avian leukosis and sarcoma viruses, contained a distinctly different population of small RNAs although both the avian leukosis and sarcoma and the reticuloendotheliosis viruses were grown in chicken cells. Because the primer for avian leukosis and sarcoma virus RNA-dependent DNA synthesis is a host cell tRNA, the differences in reverse transcriptase small RNA selection may help explain the failure of different species of retrovirus to complement for the reverse transcriptase.

Animals↗
PubMed2005

Small RNAs: classification, biogenesis, and function.

Eukaryotes produce various types of small RNAs of 19-28 nt in length. With rapidly increasing numbers of small RNAs listed in recent years, we have come to realize how widespread their functions are and how diverse the biogenesis pathways have evolved. At the same time, we are beginning to grasp the common features and rules governing the key steps in small RNA pathways. In this review, I will summarize the current classification, biogenesis, action mechanism and function of these fascinating molecules.

Animals↗
PubMed1986

Viral-encoded small RNAs in herpes virus saimiri induced tumors.

DNA sequences from the left terminus of herpes virus saimiri L-DNA are essential for the oncogenic and transforming potential of the virus, but these sequences are not required for replication. RNA derived from 0.0 to 6.7 map units (7.4 kbp) on the herpes virus saimiri genome was studied by Northern blot hybridization and by nuclease protection analyses. Although several poly(A)-containing RNAs were detected from this region in permissively-infected monolayer cells in vitro, these RNAs could not be detected in cells taken directly from viral-induced lymphomas nor in the lymphoblastoid tumor cell line 1670. Instead, these transformed T-cells expressed four small RNAs of approximately 73, 105, 110 and 135 nt derived from this region. These small RNAs were not detected at all during the course of lytic infection of monolayer cells. Thus, synthesis of these RNAs is stringently regulated in a cell-type specific manner. Genomic coding sequences for each of these small RNAs were mapped to 0.5-1.2 kbp DNA fragments stretched over 4.3 kbp of viral genetic information. These findings together with the biological properties of mutants with deletions in this region have led us to speculate that one or more of these small RNAs play an essential role in cell growth transformation by herpes virus saimiri.

Animals↗
PubMed1987

Analysis of intracellular small RNAs of mouse hepatitis virus: evidence for discontinuous transcription.

We have previously shown the presence of multiple small leader-containing RNA species in mouse hepatitis virus (MHV)-infected cells. In this paper, we have analyzed the origin, structure, and mechanism of synthesis of these small RNAs. Using cDNA probes specific for leader RNA and genes A, D, and F, we demonstrate that subsets of these small RNAs were derived from the various viral genes. These subsets have discrete and reproducible sizes, varying with the gene from which they are derived. The size of each subset correlates with regions of secondary structure, whose free energy ranges from -1.6 to -77.1 kcal/mol, in each of the mRNAs examined. In addition, identical subsets were detected on the replicative intermediate (RI) RNA, suggesting that they represent functional transcriptional intermediates. The biological significance of these small RNAs is further supported by the detection of leader-containing RNAs of 47, 50, and 57 nucleotides in length, which correspond to the crossover sites in two MHV recombinant viruses. These data, coupled with the high frequency of RNA recombination during MHV infection, suggest that the viral polymerase may pause in or around regions of secondary structure, thereby generating pools of free leader-containing RNA intermediates which can reassociate with the template, acting as primers for the synthesis of full-length or recombinant RNAs. These data suggest that MHV transcription uses a discontinuous and nonprocessive mechanism in which RNA polymerase allows the partial RNA products to be dissociated from the template temporarily during the process of transcription.

DNA↗