When DArcy Wentworth Thompsons On Growth and Form was published 100 years ago, it raised the question of how biological forms arise during development and across evolution. In light of the advances in molecular and cellular biology since then, a succinct modern view of the question states: how do genes encode geometry? Our new special issue is packed with articles that use mathematical and physical approaches to gain insights into cell and tissue patterning, morphogenesis and dynamics, and that provide a physical framework to capture these processes operating across scales.. Read the Editorial by guest editors Thomas Lecuit and L. Mahadevan, as they provide a perspective on the influence of DArcy Thompsons work and an overview of the articles in this issue.. ...
Author Summary Almost all eukaryotic messenger RNAs (mRNAs) have a string of 150-200 adenylates at the 3′ end. This poly(A) tail has been implicated as important for regulating mRNA translation, stability and export. During the lytic phase of infection of Kaposis Sarcoma-Associated Herpesvirus (KSHV), a noncoding viral RNA is synthesized that resembles an mRNA in that it is transcribed by RNA polymerase II, is methyl-G capped at the 5′ end, and is polyadenylated at the 3′ end; yet this RNA is never exported to the cytoplasm for translation. Rather, it builds up in the nucleus to exceedingly high levels. We present evidence that the function of this abundant, polyadenylated nuclear (PAN) RNA is to bind poly(A) binding protein, which normally binds poly(A) tails of mRNAs in the cytoplasm but is re-localized into the nucleus during lytic KSHV infection. The interaction between PAN RNA and re-localized poly(A) binding protein is important for formation of new virus, in particular for the synthesis of
RNA-Protein Complexes: Roles in Gene Expression Noncoding RNAs are important for every step of gene expression. We concentrate on nuclear noncoding RNAs complexed with proteins, where the most famous small nuclear RNPs (snRNPs) participate in pre-mRNA splicing. Current efforts are aimed at understanding how splicing influences downstream events in gene expression via the exon junction complex (EJC), how microRNA biogenesis is regulated during the nuclear maturation steps, and what is the mechanism and function of readthrough transcripts that arise from ~10% of human genes when cells are exposed to stress (osmotic, heat shock or oxidative). Some primate herpesviruses [Epstein-Barr virus (EBV), Herpesvirus saimiri (HVS), and Kaposi sarcoma virus (KSHV)] produce noncoding RNAs that associate with host cell proteins to form snRNPs. Recent investigations have uncovered an unexpected function for an abundant EBV snRNP in the production of viral particles - which is essential for oncogenesis, have ...
Much of our work has focused on the MALAT1 locus, which is over-expressed in many human cancers and produces a long nuclear-retained noncoding RNA as well as a tRNA-like cytoplasmic small RNA (known as mascRNA). Despite being an RNA polymerase II transcript, the 3 end of MALAT1 is produced not by canonical cleavage/polyadenylation but instead by recognition and cleavage of the tRNA-like structure by RNase P. Mature MALAT1 thus lacks a poly(A) tail yet is expressed at a level higher than many protein-coding genes in vivo. We recently showed that the 3 end of MALAT1 is protected from 3-5 exonucleases by a highly conserved triple helical structure. Surprisingly, when this structure is placed downstream from an open reading frame, the transcript is efficiently translated in vivo despite the lack of a poly(A) tail. This result challenges the common paradigm that long poly(A) tails are required for efficient protein synthesis and suggests that non-polyadenylated RNAs may produce functional ...
Antisense oligonucleotides (ASOs) targeting pathologic RNAs have shown promising therapeutic corrections for many genetic diseases including myotonic dystrophy (DM1). Thus, ASO strategies for DM1 can abolish the toxic RNA gain-of-function mechanism caused by nuclear-retained mutant transcripts containing CUG expansions (CUGexp). However, systemic use of ASOs for this muscular disease remains challenging due to poor drug distribution to skeletal muscle. To overcome this limitation, we test an arginine-rich Pip6a cell-penetrating peptide and show that Pip6a-conjugated morpholino phosphorodiamidate oligomer (PMO) dramatically enhanced ASO delivery into striated muscles of DM1 mice following systemic administration in comparison with unconjugated PMO and other ASO strategies. Thus, low-dose treatment of Pip6a-PMO-CAG targeting pathologic expansions is sufficient to reverse both splicing defects and myotonia in DM1 mice and normalizes the overall disease transcriptome. Moreover, treated DM1 ...
In fact, the observation by DeJesus-Hernandez et al. (2011) that C90RF72 nuclear RNA foci can be detected in ALS/FTD patient tissue is an important first step and starts this ball rolling. Among the more crucial. next points will be to determine whether the C90RF72 RNA is pathogenic and, if so, identify proteins to which it binds. Given that TDP-43 pathology is a feature of ALS/FTD and TDP-43 is a RNA-binding protein, it would be very parsimonious if TDP-43 were to bind the C90RF72 transcript. However, based on what is known about the binding of TDP-43 to target RNAs, i.e., TDP-43 prefers long clusters of uridine, guanine dinucleotide-rich regions Ipatasertib cell line ( Tollervey et al., 2011 and Polymenidou et al., 2011), it seems unlikely that it binds directly to the C90RF72 GGGGCC repeat. Alternatively, TDP-43 might bind to other regions of the C90RF72 transcript or be in a complex with another RNA-binding protein that. does bind to the C90RF72 transcript. What about UBQLN2 and the X-linked ...
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TY - JOUR. T1 - ADAR2 regulates RNA stability by modifying access of decay-promoting RNA-binding proteins. AU - Anantharaman, Aparna. AU - Tripathi, Vidisha. AU - Khan, Abid. AU - Yoon, Je Hyun. AU - Singh, Deepak K.. AU - Gholamalamdari, Omid. AU - Guang, Shuomeng. AU - Ohlson, Johan. AU - Wahlstedt, Helene. AU - Öhman, Marie. AU - Jantsch, Michael F.. AU - Conrad, Nicholas K.. AU - Ma, Jian. AU - Gorospe, Myriam. AU - Prasanth, Supriya G.. AU - Prasanth, Kannanganattu V.. PY - 2017/4/20. Y1 - 2017/4/20. N2 - Adenosine deaminases acting on RNA (ADARs) catalyze the editing of adenosine residues to inosine (A-to-I) within RNA sequences, mostly in the introns and UTRs (un-translated regions). The significance of editing within non-coding regions of RNA is poorly understood. Here, we demonstrate that association of ADAR2 with RNA stabilizes a subset of transcripts. ADAR2 interacts with and edits the 3Î.,UTR of nuclear-retained Cat2 transcribed nuclear RNA (Ctn RNA). In absence of ADAR2, the ...
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Background: Long non-coding RNAs (LncRNAs) are non-protein coding transcripts longer than 200 nucleotides in length. Instead of being
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Eukaryotic cells contain a set of low molecular weight nuclear RNAs. One of the more abundant of these is termed U2 RNA. The possibility that U2 RNA is hydrogen-bonded to complementary sequences in other nuclear RNAs was investigated. Cultured human (HeLa) cells were treated with a psoralen derivative that cross-links RNA chains that are base-paired with one another. High molecular weight heterogeneous nuclear RNA was isolated under denaturing conditions, and the psoralen cross-links were reversed. Electrophoresis of the released RNA and hybridization with a human cloned U2 DNA probe revealed that U2 is hydrogen-bonded to complementary sequences in heterogeneous nuclear RNA in vivo. In contrast, U2 RNA is not base-paired with nucleolar RNA, which contains the precursors of ribosomal RNA. The results suggest that U2 RNA participates in messenger RNA processing in the nucleus. ...
DDX3 is a DEAD-box protein (Figure 3A). Although DDX3 has been shown to interact with RNA transport factors TAP/NXF1 and REF/Aly, it does not appear to play a role in bulk mRNA export [32-34]. It is interesting to note that Ded1 (yeast DDX3 homolog) modulates translation by controlling the conformation of eIF4F-mRNA complex [35], suggesting a role of Ded1/DDX3 in translation. The function of DDX3 in RNA export was not recognized until DDX3 was found to participate in the Rev-dependent export of unspliced and partially spliced HIV-1 RNAs [3]. Rev is co-immunoprecipitated with DDX3, but a direct interaction between the two proteins has not been experimentally demonstrated. Rather, the purified GST-CRM1 is able to pull down the in vitro translated DDX3. This direct interaction depends on the DDX3 fragment at amino acid positions 260 to 517 that does not include the NES (nuclear export signal) sequence, and is Ran-GTP independent (Figure 3A, 3C), which suggests that instead of a cargo, DDX3 acts as ...
The large majority of genes encoded by humans and other metazoans contain introns. In general, mRNAs containing introns give rise to a higher level of the encoded protein than do the equivalent intronless, cDNA-derived mRNAs. The mechanisms underlying this difference are complex because splicing can strongly influence not only the efficiency of mRNA 3′ end formation but also mRNA stability and even translation (Ryu and Mertz, 1989; Niwa et al., 1990; Matsumoto et al., 1998). Nevertheless, for most human genes, splicing is not essential for detectable mRNA and protein synthesis. In fact, a recent survey of 15 genes showed that the presence of an excisable intron enhanced gene expression in human cells by an average of 6.3±4.7 fold with a range of from 1.5- to over 20-fold (S. Lu and B. R. Cullen, unpublished).. The first evidence suggesting that splicing also enhances the efficiency of mRNA export came from the demonstration that several intron-containing mRNAs are exported more efficiently ...
Polyadenylate-binding protein 4 (PABPC4) is a protein that in humans is encoded by the PABPC4 gene. Poly(A)-binding proteins (PABPs) bind to the poly(A) tail present at the 3-prime ends of most eukaryotic mRNAs. PABPC4 or IPABP (inducible PABP) was isolated as an activation-induced T-cell mRNA encoding a protein. Activation of T cells increased PABPC4 mRNA levels in T cells approximately 5-fold. PABPC4 contains 4 RNA-binding domains and proline-rich C terminus. PABPC4 is localized primarily to the cytoplasm. It is suggested that PABPC4 might be necessary for regulation of stability of labile mRNA species in activated T cells. PABPC4 was also identified as an antigen, APP1 (activated-platelet protein-1), expressed on thrombin-activated rabbit platelets. PABPC4 may also be involved in the regulation of protein translation in platelets and megakaryocytes or may participate in the binding or stabilization of polyadenylates in platelet dense granules. Model organisms have been used in the study of ...
Nuclear RNA processing is a critical stage in eukaryotic gene expression, and is controlled in part by the expression and concentration of nuclear RNA-binding proteins. Different nuclear RNA-binding proteins are differentially expressed in different cells, helping the spliceosome to decode pre-mRNAs into alternatively spliced mRNAs. Recent post-genomic technology has exposed the complexity of nuclear RNA processing, and is starting to reveal the mechanisms and rules through which networks of RNA-binding proteins can regulate multiple parallel pathways. Identification of multiple parallel processing pathways regulated by nuclear RNA-binding proteins is leading to a systems-wide understanding of the rules and consequences of alternative nuclear RNA processing.. ...
(= hnRNA) Originally identified as a class of RNA, found in the nucleus but not the nucleolus, which is rapidly labelled and with a very wide range of sizes, 2 40 kilobases. It represents the primary transcripts of RNA polymerase II and includes…
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The most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is intronic hexanucleotide (G4C2) repeat expansions (HRE) in the C9orf72 gene. The non-exclusive pathogenic mechanisms by which C9orf72 repeat expansions contribute to these neurological disorders include loss of C9orf72 function and gain-of-function determined by toxic RNA molecules and dipeptides repeats protein toxicity.The expanded repeats are transcribed bidirectionally and forms RNA foci in the central nervous system, and sequester key RNA-binding proteins (RBPs) leading to impairment in RNA processing events. Many studies report widespread transcriptome changes in ALS carrying a C9orf72 repeat expansion. Here we review the contribution of RNA foci interaction with RBPs as well as transcriptome changes involved in the pathogenesis of C9orf72- associated FTD/ALS. These informations are essential to elucidate the pathology and therapeutic intervention of ALS and/or FTD.
Only relatively recently has it become clear that mammalian genomes encode tens of thousands of long non-coding RNAs (lncRNAs). A striking 40% of these are expressed specifically in the brain, where they show precisely regulated temporal and spatial expression patterns. This begs the question, what is the functional role of these many lncRNA transcripts in the brain? Here we canvass a growing number of mechanistic studies that have elucidated central roles for lncRNAs in the regulation of nervous system development and function. We also survey studies indicating that neurological and psychiatric disorders may ensue when these mechanisms break down. Finally, we synthesize these insights with evidence from comparative genomics to argue that lncRNAs may have played important roles in brain evolution, by virtue of their abundant sequence innovation in mammals and plausible mechanistic connections to the adaptive processes that occurred recently in the primate and human lineages.
It has been less than half a century since Robert W. Holley et al. used 140 kg of commercial bakers yeast to characterize the first noncoding RNA (ncRNA), alanine tRNA. Now, 48 years later, advanceme
Evidence for age-dependent impairment of ovalbumin heterogeneous nuclear RNA (HnRNA) processing in hen oviduct.: The expression of the ovalbumin gene in hen ovi
Polyadenylate-binding protein 1 is a protein that in humans is encoded by the PABPC1 gene. The protein PABP1 binds mRNA and facilitates a variety of functions such as transport out of the nucleus, degradation, translation, and stability. There are two separate PABP1 proteins, one which is located in the nucleus (PABPN1) and the other which is found in the cytoplasm (PABPC1). The location of PABP1 affects the role of that protein and its function with RNA. The poly(A)-binding protein (PAB or PABP), which is found complexed to the 3 poly(A) tail of eukaryotic mRNA, is required for poly(A) shortening and translation initiation. In humans, the PABPs comprise a small nuclear isoform and a conserved gene family that displays at least 3 functional proteins: PABP1 (PABPC1), inducible PABP (iPABP, or PABPC4; MIM 603407), and PABP3 (PABPC3; MIM 604680). In addition, there are at least 4 pseudogenes, PABPCP1 to PABPCP4.[supplied by OMIM] PABPC1 is usually diffused within the cytoplasm and concentrated at ...
Long Non-Coding RNAs為一種不會轉譯成protein的transcripts,長度通常大於200bp,最長可超過10000bp,部分的lncRNA跟mRNA一樣會有alternati
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Expression of PABPC1 (PAB1, PABP1, PABPC2, PABPL1) in cerebral cortex tissue. Antibody staining with HPA045423 and CAB011536 in immunohistochemistry.
Expression of PABPC1 (PAB1, PABP1, PABPC2, PABPL1) in placenta tissue. Antibody staining with HPA045423 and CAB011536 in immunohistochemistry.
In this issue Begg reviews the role of metal ions in the virulence and viability of bacterial pathogens. The author gives an overview of the roles of iron, manganese, copper and zinc during infection. The cover image illustrates strategies employed by hosts to limit metal ions during bacterial infection.. ...
LSM1 antibody (LSM1 homolog, U6 small nuclear RNA associated (S. cerevisiae)) for IP, WB. Anti-LSM1 pAb (GTX130104) is tested in Human samples. 100% Ab-Assurance.
With the multitude of green choices available, how can moms determine what will be best for their families-and the environment? Terra Wellington has the an...
Long non-coding RNAs (long ncRNAs, lncRNA) are non-protein coding transcripts longer than 200 nucleotides. This somewhat arbitrary limit distinguishes long ncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short ...
Recent studies show that only a small part of the human transcriptome is involved in the protein-coding process [1]. Long non-coding RNAs (lncRNAs) comprise the majority of transcripts; however, little is known about the function of lncRNAs [2]. The GENCODE project discovered more than 14,000 lncRNA transcripts from approximately 9,000 gene loci [3]. The lncRNA database collected a few hundred of high-confidence, experimentally validated lncRNAs [4]. For example, the Xist RNA of humans is a large RNA sequence (19 kb) that has remained untranslated [5]. Xist RNA has been proven to have an important function in regulating X-inactivation [6, 7]. Although an increasing list of evidence demonstrates that lncRNAs may be involved in multiple biological processes, including epigenetic regulation, chromatin remodeling, and cell proliferation and differentiation, the molecular mechanisms underlying the functions of lncRNAs still remain largely elusive.. In general, lncRNAs function with their binding ...
Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. LncRNAs have been recently recognized as the hallmark features in various diseases. In hematopoiesis, they regulate development at almost every stage of cell lineage differentiation; therefore, abnormal expression of lncRNAs may lead to different hematopoietic disorders. Until now there has been almost no information available about lncRNA deregulation and role in myelodysplastic syndromes (MDS).. We perform genome-wide screening of lncRNA levels in MDS patients and compare expression profiles between various risk groups of patients and healthy subjects, to find lncRNAs with altered levels in MDS. This knowledge will help us to better understand the pathogenesis of MDS and identify lncRNAs that may represent candidate diagnostic and prognostic molecular markers of the disease.. ...
Complete information for SNAPC2 gene (Protein Coding), Small Nuclear RNA Activating Complex Polypeptide 2, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
The molecular mechanism underlying Parkinsons disease (PD), an increasingly common neurodegenerative disease, remains unclear. Long non-coding RNA (lncRNA) plays essential roles in gene expression and human diseases. We hypothesize that lncRNAs are involved in neuronal degeneration of PD. Using microarray, we identified 122 differentially expressed (DE) lncRNAs and 48 DE mRNAs between the circulating leukocytes from PD patients and healthy controls. There were 714 significant correlations (r ≥ 0.8 or ≤−0.8, p
Nuclear proteins are often segregated into distinct subnuclear compartments that can be visualized by immunofluorescence or live imaging (Zimber et al., 2004). These nuclear bodies are reorganized in cells in response to stresses and signaling. Some of these compartments, such as speckles, contain pre-mRNA splicing factors (Lamond and Sleeman, 2003). For speckles, there are approximately 25 to 50 nuclear domains located throughout a mammalian cell that contain serine/arginine (SR) proteins (Zimber et al., 2004). Although there are regions of increased SF2/ASF concentration in the nucleoplasm, protein molecules in these regions are under constant flux (Misteli et al., 1997; Phair and Misteli, 2000). Splicing factors continuously shuttle in and out, leading to variations in size and shape of the speckles (Kruhlak et al., 2000; Phair and Misteli, 2000).. Of particular interest is the relationship of splicing factors to human disease (Zimber et al., 2004). Splicing defects can be caused by ...
The main function of lncRNA in regulation is to control expression of defined genes. For their role in development, they modulate chromatin structure recruiting epigenetic modification proteins to defined sites of the genome. Examples of this function are HOTAIR, Xist and Kcnqot1. HOTAIR is involved in limb formation and cancer meanwhile Kcnqot1 is involved with the imprinting of its loci…. ...
While widely seen as junk RNA, human non-coding RNAs may actually be functional, according to findings resulting from the recently completed atlas of human long non-coding RNAs.