Articoli di riviste: "Messenger RNA-binding proteins"

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Anji, Antje, e Meena Kumari. "Guardian of Genetic Messenger-RNA-Binding Proteins". Biomolecules 6, n. 1 (6 gennaio 2016): 4. http://dx.doi.org/10.3390/biom6010004.

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Yu, Michael C. "The Role of Protein Arginine Methylation in mRNP Dynamics". Molecular Biology International 2011 (7 aprile 2011): 1–10. http://dx.doi.org/10.4061/2011/163827.

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Abstract (sommario):

In eukaryotes, messenger RNA biogenesis depends on the ordered and precise assembly of a nuclear messenger ribonucleoprotein particle (mRNP) during transcription. This process requires a well-orchestrated and dynamic sequence of molecular recognition events by specific RNA-binding proteins. Arginine methylation is a posttranslational modification found in a plethora of RNA-binding proteins responsible for mRNP biogenesis. These RNA-binding proteins include both heterogeneous nuclear ribonucleoproteins (hnRNPs) and serine/arginine-rich (SR) proteins. In this paper, I discuss the mechanisms of action by which arginine methylation modulates various facets of mRNP biogenesis, and how the collective consequences of this modification impart the specificity required to generate a mature, translational- and export-competent mRNP.

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Schuschel, Konstantin, Matthias Helwig, Stefan Hüttelmaier, Dirk Heckl, Jan-Henning Klusmann e Jessica I. Hoell. "RNA-Binding Proteins in Acute Leukemias". International Journal of Molecular Sciences 21, n. 10 (12 maggio 2020): 3409. http://dx.doi.org/10.3390/ijms21103409.

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Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions.

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Dreyfuss, Gideon, V. Narry Kim e Naoyuki Kataoka. "Messenger-RNA-binding proteins and the messages they carry". Nature Reviews Molecular Cell Biology 3, n. 3 (marzo 2002): 195–205. http://dx.doi.org/10.1038/nrm760.

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Zhang, Jing, Fanghui Ding, Dan Jiao, Qiaozhi Li e Hong Ma. "The Aberrant Expression of MicroRNA-125a-5p/IGF2BP3 Axis in Advanced Gastric Cancer and Its Clinical Relevance". Technology in Cancer Research & Treatment 19 (1 gennaio 2020): 153303382091733. http://dx.doi.org/10.1177/1533033820917332.

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RNA-binding proteins have been associated with cancer development. The overexpression of a well-known RNA-binding protein, insulin-like growth factor 2 messenger RNA–binding protein 3, has been identified as an indicator of poor prognosis in patients with various types of cancer. Although gastric cancer is a relatively frequent and potentially fatal malignancy, the mechanism by which insulin-like growth factor 2 messenger RNA–binding protein 3 regulates the development of this cancer remains unclear. This study aimed to investigate the role and regulatory mechanism of insulin-like growth factor 2 messenger RNA–binding protein 3 in gastric cancer. An analysis of IGF2BP3 expression patterns reported in 4 public gastric cancer–related microarray data sets from the Gene Expression Omnibus and The Cancer Genome Atlas-Stomach Adenocarcinoma revealed strong expression of this gene in gastric cancer tissues. Insulin-like growth factor 2 messenger RNA–binding protein 3 expression in gastric cancer was further confirmed via quantitative reverse transcription polymerase chain reaction and immunohistochemistry, respectively, in an in-house gastric cancer cohort (n = 30), and the association of insulin-like growth factor 2 messenger RNA–binding protein 3 expression with clinical parameters and prognosis was analyzed. Notably, stronger IGF2BP3 expression significantly correlated with poor prognosis, and significant changes in insulin-like growth factor 2 messenger RNA–binding protein 3 expression were only confirmed in patients with advanced-stage gastric cancer in an independent cohort. The effects of insulin-like growth factor 2 messenger RNA–binding protein 3 on cell proliferation were confirmed through in vitro experiments involving the HGC-27 gastric cancer cell line. MicroR-125a-5p, a candidate microRNA that target on insulin-like growth factor 2 messenger RNA–binding protein 3, decreased in advanced-stage gastric cancer. Upregulation of microR-125a-5p inhibited insulin-like growth factor 2 messenger RNA–binding protein 3, and dual-luciferase report assay indicated that microR-125a-5p inhibited the translation of IGF2BP3 by directly targeting the 3′ untranslated region. These results indicate that the microR-125a-5p/insulin-like growth factor 2 messenger RNA–binding protein 3 axis contributes to the oncogenesis of advanced gastric cancer.

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Anderson, Paul, e Nancy Kedersha. "RNA granules". Journal of Cell Biology 172, n. 6 (6 marzo 2006): 803–8. http://dx.doi.org/10.1083/jcb.200512082.

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Cytoplasmic RNA granules in germ cells (polar and germinal granules), somatic cells (stress granules and processing bodies), and neurons (neuronal granules) have emerged as important players in the posttranscriptional regulation of gene expression. RNA granules contain various ribosomal subunits, translation factors, decay enzymes, helicases, scaffold proteins, and RNA-binding proteins, and they control the localization, stability, and translation of their RNA cargo. We review the relationship between different classes of these granules and discuss how spatial organization regulates messenger RNA translation/decay.

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Akay, Alper, Ashley Craig, Nicolas Lehrbach, Mark Larance, Ehsan Pourkarimi, Jane E. Wright, Angus Lamond, Eric Miska e Anton Gartner. "RNA-binding protein GLD-1/quaking genetically interacts with the mir-35 and the let- 7 miRNA pathways in Caenorhabditis elegans". Open Biology 3, n. 11 (novembre 2013): 130151. http://dx.doi.org/10.1098/rsob.130151.

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Messenger RNA translation is regulated by RNA-binding proteins and small non-coding RNAs called microRNAs. Even though we know the majority of RNA-binding proteins and microRNAs that regulate messenger RNA expression, evidence of interactions between the two remain elusive. The role of the RNA-binding protein GLD-1 as a translational repressor is well studied during Caenorhabditis elegans germline development and maintenance. Possible functions of GLD-1 during somatic development and the mechanism of how GLD-1 acts as a translational repressor are not known. Its human homologue, quaking (QKI), is essential for embryonic development. Here, we report that the RNA-binding protein GLD-1 in C. elegans affects multiple microRNA pathways and interacts with proteins required for microRNA function. Using genome-wide RNAi screening, we found that nhl-2 and vig-1 , two known modulators of miRNA function, genetically interact with GLD-1. gld-1 mutations enhance multiple phenotypes conferred by mir-35 and let-7 family mutants during somatic development. We used stable isotope labelling with amino acids in cell culture to globally analyse the changes in the proteome conferred by let-7 and gld-1 during animal development. We identified the histone mRNA-binding protein CDL-1 to be, in part, responsible for the phenotypes observed in let-7 and gld-1 mutants. The link between GLD-1 and miRNA-mediated gene regulation is further supported by its biochemical interaction with ALG-1, CGH-1 and PAB-1, proteins implicated in miRNA regulation. Overall, we have uncovered genetic and biochemical interactions between GLD-1 and miRNA pathways.

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Bier, Katja, Ashley York e Ervin Fodor. "Cellular cap-binding proteins associate with influenza virus mRNAs". Journal of General Virology 92, n. 7 (1 luglio 2011): 1627–34. http://dx.doi.org/10.1099/vir.0.029231-0.

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The influenza virus RNA polymerase synthesizes three types of RNA: genomic vRNA, anti-genomic cRNA and mRNA. Both vRNA and cRNA are bound by the viral RNA polymerase and nucleoprotein to form ribonucleoprotein complexes. Viral mRNAs are also proposed to be bound by the RNA polymerase to prevent their endonucleolytic cleavage, regulate the splicing of M1 mRNA, and facilitate translation. Here, we used standard immunoprecipitation, biochemical purification and RNA immunoprecipitation assays to investigate the association of viral and host factors with viral mRNA. We found that viral mRNA associates with the viral non-structural protein 1 (NS1), cellular poly(A)-binding protein 1 (PABP1), the 20 kDa subunit NCBP1 of the nuclear cap-binding complex (CBC), the RNA and export factor-binding protein REF/Aly and the translation initiation factor eIF4E. However, our data suggest that the RNA polymerase might not form part of the viral messenger ribonucleoprotein (mRNP) complex. We propose a model in which viral mRNAs, by associating with cellular cap-binding proteins, follow the pathways normally used by cellular mRNAs for splicing, nuclear export and translation.

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Chabot, Benoit, e Lulzim Shkreta. "Defective control of pre–messenger RNA splicing in human disease". Journal of Cell Biology 212, n. 1 (4 gennaio 2016): 13–27. http://dx.doi.org/10.1083/jcb.201510032.

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Examples of associations between human disease and defects in pre–messenger RNA splicing/alternative splicing are accumulating. Although many alterations are caused by mutations in splicing signals or regulatory sequence elements, recent studies have noted the disruptive impact of mutated generic spliceosome components and splicing regulatory proteins. This review highlights recent progress in our understanding of how the altered splicing function of RNA-binding proteins contributes to myelodysplastic syndromes, cancer, and neuropathologies.

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Idler, R. K., e W. Yan. "Control of Messenger RNA Fate by RNA-Binding Proteins: An Emphasis on Mammalian Spermatogenesis". Journal of Andrology 33, n. 3 (14 luglio 2011): 309–37. http://dx.doi.org/10.2164/jandrol.111.014167.

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Guttridge, Katherine Ladner, e L. Dennis Smith. "Xenopus interspersed RNA families, Ocr and XR, bind DNA-binding proteins". Zygote 3, n. 2 (maggio 1995): 111–22. http://dx.doi.org/10.1017/s0967199400002483.

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SummaryInterspersed RNA makes up two-thirds of cytoplasmic polyadenylated RNA in Xenopus and sea urchin eggs.Although it has no known function, previous work has suggested that at least one family of interspersed RNA, XR, binds Xenopus oocyte proteins, and can influence the rate of translation. We have used two Xenopus repeat families, Ocr and XR, to explore their protein binding abilities. Ocr RNA binds the same pattern of highly abundant oocyte proteins that XR RNA binds, which are believed to be messenger ribonucleoprotein (mRNP) particle proteins. In addition, we show that Ocr RNA binds the Oct-60 protein, a member of the POU-domain family of transcription factors found in Xenopus oocytes. Using a 32 base pair sequence from the XR repeat in a DNA affinity column two proteins were isolated, 66KDa and 92KDa, that together form a complex with XR DNA. One of these proteins (92KDa) also binds XR RNA. We suggest that the role of at least a subset of interspersed RNAs in development may be to bind, and sequester in the cytoplasm, DNA-binding proteins until the end of oogenesis

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Anderson, Kelsi L., e Paul M. Dunman. "Messenger RNA Turnover Processes inEscherichia coli, Bacillus subtilis, and Emerging Studies inStaphylococcus aureus". International Journal of Microbiology 2009 (2009): 1–15. http://dx.doi.org/10.1155/2009/525491.

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The regulation of mRNA turnover is a recently appreciated phenomenon by which bacteria modulate gene expression. This review outlines the mechanisms by which three major classes of bacterialtrans-acting factors, ribonucleases (RNases), RNA binding proteins, and small noncoding RNAs (sRNA), regulate the transcript stability and protein production of target genes. Because the mechanisms of RNA decay and maturation are best characterized inEscherichia coli, the majority of this review will focus on how these factors modulate mRNA stability in this organism. However, we also address the effects of RNases, RNA binding proteins, sRNAs on mRNA turnover, and gene expression inBacillus subtilis, which has served as a model for studying RNA processing in gram-positive organisms. We conclude by discussing emerging studies on the role modulating mRNA stability has on gene expression in the important human pathogenStaphylococcus aureus.

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Dynan, William S., e Robert Tjian. "Control of eukaryotic messenger RNA synthesis by sequence-specific DNA-binding proteins". Nature 316, n. 6031 (agosto 1985): 774–78. http://dx.doi.org/10.1038/316774a0.

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Bose, Sudeep K., Tapas K. Sengupta, Sumita Bandyopadhyay e Eleanor K. Spicer. "Identification of Ebp1 as a component of cytoplasmic bcl-2 mRNP (messenger ribonucleoprotein particle) complexes". Biochemical Journal 396, n. 1 (26 aprile 2006): 99–107. http://dx.doi.org/10.1042/bj20051548.

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The 3′-UTR (untranslated region) of bcl-2 mRNA contains an ARE (AU-rich element) that potentially regulates the stability of bcl-2 mRNA in a cell specific fashion. Previous studies have demonstrated that multiple proteins interact with bcl-2 mRNA in HL-60 (human leukaemia-60) cells, potentially contributing to the overexpression of Bcl-2 protein. Treatment of HL-60 cells with taxol or okadaic acid has been shown to induce destabilization of bcl-2 mRNA, which was associated with decreased binding of trans-acting factors to bcl-2 mRNA. Nucleolin has been identified as one of the bcl-2 mRNA-binding proteins [Sengupta, Bandyopadhyay, Fernandes and Spicer (2004) J. Biol. Chem. 279, 10855–10863]. In an effort to identify additional bcl-2 mRNA-binding proteins, two polypeptides of approx. 45 kDa and 60 kDa were isolated from HL-60 cells by AREbcl-2 (transcripts that contain bcl-2 AREs) RNA affinity chromatography. These proteins were identified as the human proliferation associated protein, Ebp1, and human DRBP76 (double stranded RNA-binding protein 76) respectively, by MALDI (matrix-assisted laser-desorption ionization)-MS. RNA electrophoretic mobility shift assays indicated that recombinant Ebp1 binds to AREbcl-2 RNA but not to the group 1 ARE present in GM-CSF (granulocyte macrophage-colony stimulating factor) mRNA in vitro. Antibody supershift assays demonstrated that Ebp1 is present in protein–AREbcl-2 RNA complexes formed with cytosolic HL-60 extracts. The interaction of Ebp1 with bcl-2 mRNA in HL-60 cells was also demonstrated by RNA co-immunoprecipitation assays. This interaction was not detected in extracts of taxol-treated HL-60 cells. Immunoprecipitation assays further revealed that Ebp1 co-precipitates with nucleolin from HL-60 cytoplasmic extracts. The observation that co-precipitation was decreased when extracts were treated with RNase suggests that Ebp1 and nucleolin are present in the same bcl-2 mRNP (messenger ribonucleoprotein particle) complexes. RNA-decay assays further demonstrated that Ebp1 decreased the rate of decay of β-globin–AREbcl-2 transcripts in HL-60 cell extracts. Collectively, these results indicate a novel function for Ebp1 in contributing to the regulation of bcl-2 expression in HL-60 cells.

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Khandjian, Edouard W. "Biology of the fragile X mental retardation protein, an RNA-binding protein". Biochemistry and Cell Biology 77, n. 4 (25 agosto 1999): 331–42. http://dx.doi.org/10.1139/o99-035.

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The fragile X syndrome, an X-linked disease, is the most frequent cause of inherited mental retardation. The syndrome results from the absence of expression of the FMR1 gene (fragile mental retardation 1) owing to the expansion of a CGG trinucleotide repeat located in the 5prime untranslated region of the gene and the subsequent methylation of its CpG island. The FMR1 gene product (FMRP) is a cytoplasmic protein that contains two KH domains and one RGG box, characteristics of RNA-binding proteins. FMRP is associated with mRNP complexes containing poly(A)+mRNA within actively translating polyribosomes and contains nuclear localization and export signals making it a putative transporter (chaperone) of mRNA from the nucleus to the cytoplasm. FMRP is the archetype of a novel family of cytoplasmic RNA-binding proteins that includes FXR1P and FXR2P. Both of these proteins are very similar in overall structure to FMRP and are also associated with cytoplasmic mRNPs. Members of the FMR family are widely expressed in mouse and human tissues, albeit at various levels, and seem to play a subtle choreography of expression. FMRP is most abundant in neurons and is absent in muscle. FXR1P is strongly expressed in muscle and low levels are detected in neurons. The complex expression patterns of the FMR1 gene family in different cells and tissues suggest that independent, however similar, functions for each of the three FMR-related proteins might be expected in the selection and metabolism of tissue-specific classes of mRNA. The molecular mechanisms altered in cells lacking FMRP still remain to be elucidated as well as the putative role(s) of FXR1P and FXR2P as compensatory molecules.Key words: RNA-binding proteins, polyribosomes, messenger ribonucleoprotein, messenger ribonucleoparticles, nucleocytoplasmic trafficking, mental retardation.

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Aitchison, J. D., G. Blobel e M. P. Rout. "Kap104p: A Karyopherin Involved in the Nuclear Transport of Messenger RNA Binding Proteins". Science 274, n. 5287 (25 ottobre 1996): 624–27. http://dx.doi.org/10.1126/science.274.5287.624.

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Ray, B. K., T. G. Lawson, R. D. Abramson, W. C. Merrick e R. E. Thach. "Recycling of messenger RNA cap-binding proteins mediated by eukaryotic initiation factor 4B." Journal of Biological Chemistry 261, n. 25 (settembre 1986): 11466–70. http://dx.doi.org/10.1016/s0021-9258(18)67267-9.

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Akman, Hasan O., Hong Zhang, M. A. Q. Siddiqui, William Solomon, Eric L. P. Smith e Olcay A. Batuman. "Response to hypoxia involves transforming growth factor-β2 and Smad proteins in human endothelial cells". Blood 98, n. 12 (1 dicembre 2001): 3324–31. http://dx.doi.org/10.1182/blood.v98.12.3324.

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Abstract Oxygen deprivation (hypoxia) is a consistent component of ischemia that induces an inflammatory and prothrombotic response in the endothelium. In this report, it is demonstrated that exposure of endothelial cells to hypoxia (1% O2) increases messenger RNA and protein levels of transforming growth factor-β2 (TGF-β2), a cytokine with potent regulatory effects on vascular inflammatory responses. Messenger RNA levels of the TGF-β2 type II membrane receptor, which is a serine threonine kinase, also increased. The stimulatory effect of hypoxia was found to occur at the level of transcription of the TGF-β2 gene and involves Smad proteins, a class of intracellular signaling proteins that mediates the downstream effects of TGF-β receptors. Transient transfection studies showed that the region spanning −77 and −40 base pairs within the TGF-β2 promoter (harboring a Smad-binding “CAGA box”) is activated in hypoxic cells compared with nonhypoxic controls (P < .01). Hypoxia also stimulated transcription from another promoter, 3TP-Lux, a reporter construct responsive to Smads and TGF-β. In addition, specific binding to a Smad-binding oligonucleotide was observed with nuclear extracts from hypoxic endothelial cells but not from nonhypoxic cells. It is concluded that Smad proteins, which can regulate endothelial responses to mechanical and inflammatory stress, also may play an important role in vascular responses to hypoxia and ischemia.

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Coppin, Lucie, Julie Leclerc, Audrey Vincent, Nicole Porchet e Pascal Pigny. "Messenger RNA Life-Cycle in Cancer Cells: Emerging Role of Conventional and Non-Conventional RNA-Binding Proteins?" International Journal of Molecular Sciences 19, n. 3 (25 febbraio 2018): 650. http://dx.doi.org/10.3390/ijms19030650.

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Calapez, Alexandre, Henrique M. Pereira, Angelo Calado, José Braga, José Rino, Célia Carvalho, João Paulo Tavanez, Elmar Wahle, Agostinho C. Rosa e Maria Carmo-Fonseca. "The intranuclear mobility of messenger RNA binding proteins is ATP dependent and temperature sensitive". Journal of Cell Biology 159, n. 5 (9 dicembre 2002): 795–805. http://dx.doi.org/10.1083/jcb.200203046.

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fAter being released from transcription sites, messenger ribonucleoprotein particles (mRNPs) must reach the nuclear pore complexes in order to be translocated to the cytoplasm. Whether the intranuclear movement of mRNPs results largely from Brownian motion or involves molecular motors remains unknown. Here we have used quantitative photobleaching techniques to monitor the intranuclear mobility of protein components of mRNPs tagged with GFP. The results show that the diffusion coefficients of the poly(A)-binding protein II (PABP2) and the export factor TAP are significantly reduced when these proteins are bound to mRNP complexes, as compared with nonbound proteins. The data further show that the mobility of wild-type PABP2 and TAP, but not of a point mutant variant of PABP2 that fails to bind to RNA, is significantly reduced when cells are ATP depleted or incubated at 22°C. Energy depletion has only minor effects on the intranuclear mobility of a 2,000-kD dextran (which corresponds approximately in size to 40S mRNP particles), suggesting that the reduced mobility of PABP2 and TAP is not caused by a general alteration of the nuclear environment. Taken together, the data suggest that the mobility of mRNPs in the living cell nucleus involves a combination of passive diffusion and ATP-dependent processes.

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Sanchez, Mayka, Bruno Galy, Bjoern Schwanhaeusser, Jonathon Blake, Tomi Bähr-Ivacevic, Vladimir Benes, Matthias Selbach, Martina U. Muckenthaler e Matthias W. Hentze. "Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins". Blood 118, n. 22 (24 novembre 2011): e168-e179. http://dx.doi.org/10.1182/blood-2011-04-343541.

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Abstract Iron regulatory proteins (IRPs) 1 and 2 are RNA-binding proteins that control cellular iron metabolism by binding to conserved RNA motifs called iron-responsive elements (IREs). The currently known IRP-binding mRNAs encode proteins involved in iron uptake, storage, and release as well as heme synthesis. To systematically define the IRE/IRP regulatory network on a transcriptome-wide scale, IRP1/IRE and IRP2/IRE messenger ribonucleoprotein complexes were immunoselected, and the mRNA composition was determined using microarrays. We identify 35 novel mRNAs that bind both IRP1 and IRP2, and we also report for the first time cellular mRNAs with exclusive specificity for IRP1 or IRP2. To further explore cellular iron metabolism at a system-wide level, we undertook proteomic analysis by pulsed stable isotope labeling by amino acids in cell culture in an iron-modulated mouse hepatic cell line and in bone marrow-derived macrophages from IRP1- and IRP2-deficient mice. This work investigates cellular iron metabolism in unprecedented depth and defines a wide network of mRNAs and proteins with iron-dependent regulation, IRP-dependent regulation, or both.

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Burgute, Bhagyashri D., Vivek S. Peche, Anna-Lena Steckelberg, Gernot Glöckner, Berthold Gaßen, Niels H. Gehring e Angelika A. Noegel. "NKAP is a novel RS-related protein that interacts with RNA and RNA binding proteins". Nucleic Acids Research 42, n. 5 (17 dicembre 2013): 3177–93. http://dx.doi.org/10.1093/nar/gkt1311.

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Abstract NKAP is a highly conserved protein with roles in transcriptional repression, T-cell development, maturation and acquisition of functional competency and maintenance and survival of adult hematopoietic stem cells. Here we report the novel role of NKAP in splicing. With NKAP-specific antibodies we found that NKAP localizes to nuclear speckles. NKAP has an RS motif at the N-terminus followed by a highly basic domain and a DUF 926 domain at the C-terminal region. Deletion analysis showed that the basic domain is important for speckle localization. In pull-down experiments, we identified RNA-binding proteins, RNA helicases and splicing factors as interaction partners of NKAP, among them FUS/TLS. The FUS/TLS–NKAP interaction takes place through the RS domain of NKAP and the RGG1 and RGG3 domains of FUS/TLS. We analyzed the ability of NKAP to interact with RNA using in vitro splicing assays and found that NKAP bound both spliced messenger RNA (mRNA) and unspliced pre-mRNA. Genome-wide analysis using crosslinking and immunoprecipitation-seq revealed NKAP association with U1, U4 and U5 small nuclear RNA, and we also demonstrated that knockdown of NKAP led to an increase in pre-mRNA percentage. Our results reveal NKAP as nuclear speckle protein with roles in RNA splicing and processing.

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Chapman, Ria M., Caroline L. Tinsley, Matthew J. Hill, Marc P. Forrest, Katherine E. Tansey, Antonio F. Pardiñas, Elliott Rees et al. "Convergent Evidence That ZNF804A Is a Regulator of Pre-messenger RNA Processing and Gene Expression". Schizophrenia Bulletin 45, n. 6 (29 dicembre 2018): 1267–78. http://dx.doi.org/10.1093/schbul/sby183.

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Abstract Genome-wide association studies have linked common variation in ZNF804A with an increased risk of schizophrenia. However, little is known about the biology of ZNF804A and its role in schizophrenia. Here, we investigate the function of ZNF804A using a variety of complementary molecular techniques. We show that ZNF804A is a nuclear protein that interacts with neuronal RNA splicing factors and RNA-binding proteins including RBFOX1, which is also associated with schizophrenia, CELF3/4, components of the ubiquitin-proteasome system and the ZNF804A paralog, GPATCH8. GPATCH8 also interacts with splicing factors and is localized to nuclear speckles indicative of a role in pre-messenger RNA (mRNA) processing. Sequence analysis showed that GPATCH8 contains ultraconserved, alternatively spliced poison exons that are also regulated by RBFOX proteins. ZNF804A knockdown in SH-SY5Y cells resulted in robust changes in gene expression and pre-mRNA splicing converging on pathways associated with nervous system development, synaptic contact, and cell adhesion. We observed enrichment (P = 1.66 × 10–9) for differentially spliced genes in ZNF804A-depleted cells among genes that contain RBFOX-dependent alternatively spliced exons. Differentially spliced genes in ZNF804A-depleted cells were also enriched for genes harboring de novo loss of function mutations in autism spectrum disorder (P = 6.25 × 10–7, enrichment 2.16) and common variant alleles associated with schizophrenia (P = .014), bipolar disorder and schizophrenia (P = .003), and autism spectrum disorder (P = .005). These data suggest that ZNF804A and its paralogs may interact with neuronal-splicing factors and RNA-binding proteins to regulate the expression of a subset of synaptic and neurodevelopmental genes.

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Wang, Ya-Nan, Chen-Yang Yu e Hong-Zhong Jin. "RNA N6-Methyladenosine Modifications and the Immune Response". Journal of Immunology Research 2020 (21 gennaio 2020): 1–6. http://dx.doi.org/10.1155/2020/6327614.

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N6-methyladenosine (m6A) is the most important modification of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) in higher eukaryotes. Modulation of m6A modifications relies on methyltransferases and demethylases. The discovery of binding proteins confirms that the m6A modification has a wide range of biological effects and significance at the molecular, cellular, and physiological levels. In recent years, techniques for investigating m6A modifications of RNA have developed rapidly. This article reviews the biological significance of RNA m6A modifications in the innate immune response, adaptive immune response, and viral infection.

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Borchardt, Erin K., Nicole M. Martinez e Wendy V. Gilbert. "Regulation and Function of RNA Pseudouridylation in Human Cells". Annual Review of Genetics 54, n. 1 (23 novembre 2020): 309–36. http://dx.doi.org/10.1146/annurev-genet-112618-043830.

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Recent advances in pseudouridine detection reveal a complex pseudouridine landscape that includes messenger RNA and diverse classes of noncoding RNA in human cells. The known molecular functions of pseudouridine, which include stabilizing RNA conformations and destabilizing interactions with varied RNA-binding proteins, suggest that RNA pseudouridylation could have widespread effects on RNA metabolism and gene expression. Here, we emphasize how much remains to be learned about the RNA targets of human pseudouridine synthases, their basis for recognizing distinct RNA sequences, and the mechanisms responsible for regulated RNA pseudouridylation. We also examine the roles of noncoding RNA pseudouridylation in splicing and translation and point out the potential effects of mRNA pseudouridylation on protein production, including in the context of therapeutic mRNAs.

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Ishii, Takashi, Hiroshi Hayakawa, Tatsuhiro Igawa, Takeshi Sekiguchi e Mutsuo Sekiguchi. "Specific binding of PCBP1 to heavily oxidized RNA to induce cell death". Proceedings of the National Academy of Sciences 115, n. 26 (11 giugno 2018): 6715–20. http://dx.doi.org/10.1073/pnas.1806912115.

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In aerobically growing cells, the guanine base of RNA is oxidized to 8-oxo-7,8-dihydroguanine (8-oxoG), which induces alteration in their gene expression. We previously demonstrated that the human AUF1 protein binds to 8-oxoG in RNA to induce the selective degradation of oxidized messenger RNA. We herein report that the poly(C)-binding protein PCBP1 binds to more severely oxidized RNA to activate apoptosis-related reactions. While AUF1 binds to oligoribonucleotides carrying a single 8-oxoG, PCBP1 does not bind to such oligoribonucleotides but instead binds firmly to oligoribonucleotides in which two 8-oxoG residues are located nearby. PCBP1-deficient cells, constructed from the human HeLa S3 line using the CRISPR-Cas9 system, exhibited higher survival rates than HeLa S3 cells when small doses of hydrogen peroxide were applied. The levels of caspase-3 activation and PARP-1 cleavage in the PCBP1-deficient cells were significantly lower than those in wild-type cells. The structure–function relationship of PCBP1 was established with the use of PCBP1 mutant proteins in which the conserved KH domains were defective. Human cells appear to possess two distinct mechanisms, one controlled by AUF1 and the other by PCBP1, with the former functioning when messenger RNA is moderately oxidized and the latter operating when the RNA is more severely damaged.

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López de Silanes, Isabel, María Paz Quesada e Manel Esteller. "Aberrant Regulation of Messenger RNA 3′-Untranslated Region in Human Cancer". Analytical Cellular Pathology 29, n. 1 (1 gennaio 2007): 1–17. http://dx.doi.org/10.1155/2007/586139.

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Abstract (sommario):

The messenger RNA 3′-untranslated region (3′UTR) is emerging as critically important in regulating gene expression at posttranscriptional levels. The 3′UTR governs gene expression via orchestrated interactions between mRNA structural components (cis-elements) and specific trans-acting factors (RNA-binding proteins and non-coding RNAs). Alterations in any of these components can lead to disease. Here, we review the mutations in 3′UTR regulatory sequences as well as the aberrant levels, subcellular localization, and posttranslational modifications of trans-acting factors that can promote or enhance the malignant phenotype of cancer cells. A thorough understanding of these alterations and their impact upon 3′UTR-directed posttranscriptional gene regulation will uncover promising new targets for therapeutic intervention.

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Mamontova, Victoria, Barbara Trifault e Kaspar Burger. "Compartment-Specific Proximity Ligation Expands the Toolbox to Assess the Interactome of the Long Non-Coding RNA NEAT1". International Journal of Molecular Sciences 23, n. 8 (17 aprile 2022): 4432. http://dx.doi.org/10.3390/ijms23084432.

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Abstract (sommario):

The nuclear paraspeckle assembly transcript 1 (NEAT1) locus encodes two long non-coding (lnc)RNA isoforms that are upregulated in many tumours and dynamically expressed in response to stress. NEAT1 transcripts form ribonucleoprotein complexes with numerous RNA-binding proteins (RBPs) to assemble paraspeckles and modulate the localisation and activity of gene regulatory enzymes as well as a subset of messenger (m)RNA transcripts. The investigation of the dynamic composition of NEAT1-associated proteins and mRNAs is critical to understand the function of NEAT1. Interestingly, a growing number of biochemical and genetic tools to assess NEAT1 interactomes has been reported. Here, we discuss the Hybridisation Proximity (HyPro) labeling technique in the context of NEAT1. HyPro labeling is a recently developed method to detect spatially ordered interactions of RNA-containing nuclear compartments in cultured human cells. After introducing NEAT1 and paraspeckles, we describe the advantages of the HyPro technology in the context of other methods to study RNA interactomes, and review the key findings in mapping NEAT1-associated RNA transcripts and protein binding partners. We further discuss the limitations and potential improvements of HyPro labeling, and conclude by delineating its applicability in paraspeckles-related cancer research.

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Anji, A., e M. Kumari. "NR1 MESSENGER RNA BINDING PROTEINS IN FETAL CORTICAL NEURONS AND CEREBRAL CORTEX OF ADULT MOUSE." Alcoholism: Clinical & Experimental Research 28, Supplement (agosto 2004): 38A. http://dx.doi.org/10.1097/00000374-200408002-00191.

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30

Kaneko, Shuji, Ken-ichi Kato, Shun-ichi Yamagishi, Hiroyuki Sugiyama e Yasuyuki Nomura. "GTP-binding proteins Gi and Go transplanted onto Xenopus oocyte by rat brain messenger RNA". Molecular Brain Research 3, n. 1 (dicembre 1987): 11–19. http://dx.doi.org/10.1016/0169-328x(87)90039-8.

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31

Oliveira, Camila, André P. Gerber, Samuel Goldenberg e Lysangela R. Alves. "Characterization of the RNA-Binding Protein TcSgn1 in Trypanosoma cruzi". Microorganisms 9, n. 5 (2 maggio 2021): 986. http://dx.doi.org/10.3390/microorganisms9050986.

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Abstract (sommario):

RNA-binding proteins (RBPs) participate in several steps of post-transcriptional regulation of gene expression, such as splicing, messenger RNA transport, mRNA localization, and translation. Gene-expression regulation in trypanosomatids occurs primarily at the post-transcriptional level, and RBPs play important roles in the process. Here, we characterized the RBP TcSgn1, which contains one RNA recognition motif (RRM). TcSgn1 is a close ortholog of yeast Saccharomyces cerevisiae protein ScSgn1, which plays a role in translational regulation in the cytoplasm. We found that TcSgn1 in Trypanosoma cruzi is localized in the nucleus in exponentially growing epimastigotes. By performing immunoprecipitation assays of TcSgn1, we identified hundreds of mRNAs associated with the protein, a significant fraction of them coding for nucleic acids binding, transcription, and endocytosis proteins. In addition, we show that TcSgn1 is capable of interacting directly with the poly(A) tail of the mRNAs. The study of parasites under nutritional stress showed that TcSgn1 was localized in cytoplasmic granules in addition to localizing in the nucleus. Similar to ScSgn1, we observed that TcSgn1 also interacts with the PABP1 protein, suggesting that this protein may play a role in regulating gene expression in T. cruzi. Taken together, our results show that RNA-binding protein TcSgn1 is part of ribonucleoprotein complexes associated with nuclear functions, stress response, and RNA metabolism.

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32

Rowlett, Robert M., Carol A. Chrestensen, Melanie J. Schroeder, Mary G. Harp, Jared W. Pelo, Jeffery Shabanowitz, Robert DeRose, Donald F. Hunt, Thomas W. Sturgill e Mark T. Worthington. "Inhibition of tristetraprolin deadenylation by poly(A) binding protein". American Journal of Physiology-Gastrointestinal and Liver Physiology 295, n. 3 (settembre 2008): G421—G430. http://dx.doi.org/10.1152/ajpgi.00508.2007.

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Abstract (sommario):

Tristetraprolin (TTP) is the prototype for a family of RNA binding proteins that bind the tumor necrosis factor (TNF) messenger RNA AU-rich element (ARE), causing deadenylation of the TNF poly(A) tail, RNA decay, and silencing of TNF protein production. Using mass spectrometry sequencing we identified poly(A) binding proteins-1 and -4 (PABP1 and PABP4) in high abundance and good protein coverage from TTP immunoprecipitates. PABP1 significantly enhanced TNF ARE binding by RNA EMSA and prevented TTP-initiated deadenylation in an in vitro macrophage assay of TNF poly(A) stability. Neomycin inhibited TTP-promoted deadenylation at concentrations shown to inhibit the deadenylases poly(A) ribonuclease and CCR4. Stably transfected RAW264.7 macrophages overexpressing PABP1 do not oversecrete TNF; instead they upregulate TTP protein without increasing TNF protein production. The PABP1 inhibition of deadenylation initiated by TTP does not require the poly(A) binding regions in RRM1 and RRM2, suggesting a more complicated interaction than simple masking of the poly(A) tail from a 3′-exonuclease. Like TTP, PABP1 is a substrate for p38 MAP kinase. Finally, PABP1 stabilizes cotransfected TTP in 293T cells and prevents the decrease in TTP levels seen with p38 MAP kinase inhibition. These findings suggest several levels of functional antagonism between TTP and PABP1 that have implications for regulation of unstable mRNAs like TNF.

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Robert, Claude, Marie-France Palin, Frederick G. Silversides, Robert M. Mckay e Ghislain Pelletier. "Messenger RNA levels of growth factors, ligands, receptors, and proteins affecting lipid metabolism in pigs". Canadian Journal of Animal Science 80, n. 4 (1 dicembre 2000): 559–67. http://dx.doi.org/10.4141/a00-029.

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Abstract (sommario):

The Northern blot technique was used for mRNA phenotyping of 19 growth factors, ligands, receptors, and proteins involved in lipid metabolism in two populations of pigs with different fat deposition capabilities. The mRNA levels were measured in backfat, liver, and muscle tissue at different slaughter weights, taking backfat thickness, gender and breed of the animals into consideration. Of all the RNA patterns measured in the Landrace population, only the mRNA transcript level of low density lipoprotein receptor-related protein (also called alpha 2-macroglobulin receptor) was associated with the pig's backfat thickness phenotype in muscle and backfat tissues. In the population composed of purebred Yorkshire and Hampshire, epidermal growth factor receptor, malic enzyme, platelet derived growth factor β and insulin-like growth factor binding protein 3 show different mRNA patterns associated with backfat thickness phenotypes. When analyzing the data using the gender or the breed as the main effect, the insulin receptor and insulin-like growth factor binding protein 1 were different between genders whereas insulin-like growth factor binding protein 3, malic enzyme, epidermal growth factor receptor and low density lipoprotein receptor-related protein were different between breeds. Analysis of this type should be helpful in understanding the regulation of fat deposition. Key words: mRNA levels, marker genes, backfat, pig

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Gao, Jie, Désirée Schatton, Paola Martinelli, Henriette Hansen, David Pla-Martin, Esther Barth, Christian Becker et al. "CLUH regulates mitochondrial biogenesis by binding mRNAs of nuclear-encoded mitochondrial proteins". Journal of Cell Biology 207, n. 2 (27 ottobre 2014): 213–23. http://dx.doi.org/10.1083/jcb.201403129.

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Abstract (sommario):

Mitochondrial function requires coordination of two genomes for protein biogenesis, efficient quality control mechanisms, and appropriate distribution of the organelles within the cell. How these mechanisms are integrated is currently not understood. Loss of the Clu1/CluA homologue (CLUH) gene led to clustering of the mitochondrial network by an unknown mechanism. We find that CLUH is coregulated both with genes encoding mitochondrial proteins and with genes involved in ribosomal biogenesis and translation. Our functional analysis identifies CLUH as a cytosolic messenger ribonucleic acid (RNA; mRNA)–binding protein. RNA immunoprecipitation experiments followed by next-generation sequencing demonstrated that CLUH specifically binds a subset of mRNAs encoding mitochondrial proteins. CLUH depletion decreased the levels of proteins translated by target transcripts and caused mitochondrial clustering. A fraction of CLUH colocalizes with tyrosinated tubulin and can be detected close to mitochondria, suggesting a role in regulating transport or translation of target transcripts close to mitochondria. Our data unravel a novel mechanism linking mitochondrial biogenesis and distribution.

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35

Jacobsen, Julian O. B., Mark D. Allen, Stefan M. V. Freund e Mark Bycroft. "High-resolution NMR structures of the domains ofSaccharomyces cerevisiaeTho1". Acta Crystallographica Section F Structural Biology Communications 72, n. 6 (23 maggio 2016): 500–506. http://dx.doi.org/10.1107/s2053230x16007597.

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Abstract (sommario):

THO is a multi-protein complex involved in the formation of messenger ribonuclear particles (mRNPs) by coupling transcription with mRNA processing and export. THO is thought to be formed from five subunits, Tho2p, Hpr1p, Tex1p, Mft1p and Thp2p, and recent work has determined a low-resolution structure of the complex [Poulsenet al.(2014),PLoS One,9, e103470]. A number of additional proteins are thought to be involved in the formation of mRNP in yeast, including Tho1, which has been shown to bind RNAin vitroand is recruited to actively transcribed chromatinin vivoin a THO-complex and RNA-dependent manner. Tho1 is known to contain a SAP domain at the N-terminus, but the ability to suppress the expression defects of thehpr1Δ mutant of THO was shown to reside in the RNA-binding C-terminal region. In this study, high-resolution structures of both the N-terminal DNA-binding SAP domain and C-terminal RNA-binding domain have been determined.

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36

Shao, Ming, Tong Lu, Chong Zhang, Yi-Zhuang Zhang, Shu-Hui Kong e De-Li Shi. "Rbm24 controls poly(A) tail length and translation efficiency of crystallin mRNAs in the lens via cytoplasmic polyadenylation". Proceedings of the National Academy of Sciences 117, n. 13 (13 marzo 2020): 7245–54. http://dx.doi.org/10.1073/pnas.1917922117.

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Abstract (sommario):

Lens transparency is established by abundant accumulation of crystallin proteins and loss of organelles in the fiber cells. It requires an efficient translation of lens messenger RNAs (mRNAs) to overcome the progressively reduced transcriptional activity that results from denucleation. Inappropriate regulation of this process impairs lens differentiation and causes cataract formation. However, the regulatory mechanism promoting protein synthesis from lens-expressed mRNAs remains unclear. Here we show that in zebrafish, the RNA-binding protein Rbm24 is critically required for the accumulation of crystallin proteins and terminal differentiation of lens fiber cells. In the developing lens, Rbm24 binds to a wide spectrum of lens-specific mRNAs through the RNA recognition motif and interacts with cytoplasmic polyadenylation element-binding protein (Cpeb1b) and cytoplasmic poly(A)-binding protein (Pabpc1l) through the C-terminal region. Loss of Rbm24 reduces the stability of a subset of lens mRNAs encoding heat shock proteins and shortens the poly(A) tail length of crystallin mRNAs encoding lens structural components, thereby preventing their translation into functional proteins. This severely impairs lens transparency and results in blindness. Consistent with its highly conserved expression in differentiating lens fiber cells, the findings suggest that vertebrate Rbm24 represents a key regulator of cytoplasmic polyadenylation and plays an essential role in the posttranscriptional control of lens development.

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37

Bembich, Sara, Jeremias S. Herzog, Laura De Conti, Cristiana Stuani, S. Eréndira Avendaño-Vázquez, Emanuele Buratti, Marco Baralle e Francisco E. Baralle. "Predominance of spliceosomal complex formation over polyadenylation site selection in TDP-43 autoregulation". Nucleic Acids Research 42, n. 5 (24 dicembre 2013): 3362–71. http://dx.doi.org/10.1093/nar/gkt1343.

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Abstract (sommario):

AbstractTDP-43 is a nuclear protein involved in many aspects of RNA metabolism. To ensure cellular viability, its expression levels within cells must be tightly regulated. We have previously demonstrated that TDP-43 autoregulation occurs through the activation of a normally silent intron in its 3′-UTR sequence that results in the use of alternative polyadenylation sites. In this work, we analyse which is the dominant event in autoregulation: the recognition of the splice sites of 3′-UTR intron 7 or the intrinsic quality of the alternative polyadenylation sites. A panel of minigene constructs was tested for autoregulation functionality, protein production and subcellular messenger RNA localization. Our data clearly indicate that constitutive spliceosome complex formation across intron 7 does not lead to high protein production but, on the contrary, to lower TDP-43 messenger RNA and protein levels. This is due to altered nucleocytoplasmic distribution of the RNA that is mostly retained in the nucleus and degraded. This study provides a novel in-depth characterization of how RNA binding proteins can autoregulate their own levels within cells, an essential regulatory process in maintaining cellular viability.

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Dinur, Maya, Rachel Kilav, Alin Sela-Brown, Helene Jacquemin-Sablon e Tally Naveh-Many. "In Vitro Evidence that Upstream of N-ras Participates in the Regulation of Parathyroid Hormone Messenger Ribonucleic Acid Stability". Molecular Endocrinology 20, n. 7 (1 luglio 2006): 1652–60. http://dx.doi.org/10.1210/me.2005-0333.

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Abstract (sommario):

Abstract Calcium and phosphate regulate PTH gene expression posttranscriptionally through the binding of trans-acting factors to a defined cis-acting instability element in the PTH mRNA 3′-untranslated region (UTR). We have previously defined AU-rich binding factor 1 as a PTH mRNA binding and stabilizing protein. We have now identified, by affinity chromatography, Upstream of N-ras (Unr) as another PTH mRNA 3′-UTR binding protein. Recombinant Unr bound the PTH 3′-UTR transcript, and supershift experiments with antibodies to Unr showed that Unr is part of the parathyroid RNA binding complex. Finally, because there is no parathyroid cell line, the functionality of Unr in regulating PTH mRNA levels was demonstrated in cotransfection experiments in heterologous human embryonic kidney 293 cells. Depletion of Unr by small interfering RNA decreased simian virus 40-driven PTH gene expression in human embryonic kidney 293 cells transiently cotransfected with the human PTH gene. Overexpression of Unr increased the rat full-length PTH mRNA levels but not a PTH mRNA lacking the terminal 60-nucleotide cis-acting protein binding region. Unr also stabilized a chimeric GH reporter mRNA that contained the rat PTH 63-nucleotide cis-acting element but not a truncated PTH element. Therefore, Unr binds to the PTH cis element and increases PTH mRNA levels, as does AU-rich binding factor 1. Our results suggest that Unr, together with the other proteins in the RNA binding complex, determines PTH mRNA stability.

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Oyejobi, Greater Kayode, Xiaodan Yan, Piotr Sliz e Longfei Wang. "Regulating Protein–RNA Interactions: Advances in Targeting the LIN28/Let-7 Pathway". International Journal of Molecular Sciences 25, n. 7 (22 marzo 2024): 3585. http://dx.doi.org/10.3390/ijms25073585.

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Abstract (sommario):

Originally discovered in C. elegans, LIN28 is an evolutionarily conserved zinc finger RNA-binding protein (RBP) that post-transcriptionally regulates genes involved in developmental timing, stem cell programming, and oncogenesis. LIN28 acts via two distinct mechanisms. It blocks the biogenesis of the lethal-7 (let-7) microRNA (miRNA) family, and also directly binds messenger RNA (mRNA) targets, such as IGF-2 mRNA, and alters downstream splicing and translation events. This review focuses on the molecular mechanism of LIN28 repression of let-7 and current strategies to overcome this blockade for the purpose of cancer therapy. We highlight the value of the LIN28/let-7 pathway as a drug target, as multiple oncogenic proteins that the pathway regulates are considered undruggable due to their inaccessible cellular location and lack of cavities for small molecule binding.

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Katoh, Y., I. Komuro, F. Takaku, H. Yamaguchi e Y. Yazaki. "Messenger RNA levels of guanine nucleotide-binding proteins are reduced in the ventricle of cardiomyopathic hamsters." Circulation Research 67, n. 1 (luglio 1990): 235–39. http://dx.doi.org/10.1161/01.res.67.1.235.

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41

Singh, Gatikrushna, Sarah E. Fritz, Bradley Seufzer e Kathleen Boris-Lawrie. "The mRNA encoding the JUND tumor suppressor detains nuclear RNA-binding proteins to assemble polysomes that are unaffected by mTOR". Journal of Biological Chemistry 295, n. 22 (20 aprile 2020): 7763–73. http://dx.doi.org/10.1074/jbc.ra119.012005.

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Abstract (sommario):

One long-standing knowledge gap is the role of nuclear proteins in mRNA translation. Nuclear RNA helicase A (DHX9/RHA) is necessary for the translation of the mRNAs of JUND (JunD proto-oncogene AP-1 transcription factor subunit) and HIV-1 genes, and nuclear cap-binding protein 1 (NCBP1)/CBP80 is a component of HIV-1 polysomes. The protein kinase mTOR activates canonical messenger ribonucleoproteins by post-translationally down-regulating the eIF4E inhibitory protein 4E-BP1. We posited here that NCBP1 and DHX9/RHA (RHA) support a translation pathway of JUND RNA that is independent of mTOR. We present evidence from reciprocal immunoprecipitation experiments indicating that NCBP1 and RHA both are components of messenger ribonucleoproteins in several cell types. Moreover, tandem affinity and RT–quantitative PCR results revealed that JUND mRNA is a component of a previously unknown ribonucleoprotein complex. Results from the tandem IP indicated that another component of the JUND-containing ribonucleoprotein complex is NCBP3, a recently identified ortholog of NCBP2/CBP20. We also found that NCBP1, NCBP3, and RHA, but not NCBP2, are components of JUND-containing polysomes. Mutational analysis uncovered two dsRNA-binding domains of RHA that are necessary to tether JUND–NCBP1/NCBP3 to polysomes. We also found that JUND translation is unaffected by inhibition of mTOR, unless RHA was down-regulated by siRNA. These findings uncover a noncanonical cap-binding complex consisting of NCBP1/NCBP3 and RHA substitutes for the eukaryotic translation initiation factors 4E and 4G and activates mTOR-independent translation of the mRNA encoding the tumor suppressor JUND.

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42

Jin, Suk-Won, Nancy Arno, Adam Cohen, Amy Shah, Qijin Xu, Nadine Chen e Ronald E. Ellis. "In Caenorhabditis elegans, the RNA-Binding Domains of the Cytoplasmic Polyadenylation Element Binding Protein FOG-1 Are Needed to Regulate Germ Cell Fates". Genetics 159, n. 4 (1 dicembre 2001): 1617–30. http://dx.doi.org/10.1093/genetics/159.4.1617.

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Abstract (sommario):

Abstract FOG-1 controls germ cell fates in the nematode Caenorhabditis elegans. Sequence analyses revealed that FOG-1 is a cytoplasmic polyadenylation element binding (CPEB) protein; similar proteins from other species have been shown to bind messenger RNAs and regulate their translation. Our analyses of fog-1 mutations indicate that each of the three RNA-binding domains of FOG-1 is essential for activity. In addition, biochemical tests show that FOG-1 is capable of binding RNA sequences in the 3′-untranslated region of its own message. Finally, genetic assays reveal that fog-1 functions zygotically, that the small fog-1 transcript has no detectable function, and that missense mutations in fog-1 cause a dominant negative phenotype. This last observation suggests that FOG-1 acts in a complex, or as a multimer, to regulate translation. On the basis of these data, we propose that FOG-1 binds RNA to regulate germ cell fates and that it does so by controlling the translation of its targets. One of these targets might be the fog-1 transcript itself.

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Ravel-Chapuis, Aymeric, Guy Bélanger, Ramesh S. Yadava, Mani S. Mahadevan, Luc DesGroseillers, Jocelyn Côté e Bernard J. Jasmin. "The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing". Journal of Cell Biology 196, n. 6 (19 marzo 2012): 699–712. http://dx.doi.org/10.1083/jcb.201108113.

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Abstract (sommario):

In myotonic dystrophy type 1 (DM1), dystrophia myotonica protein kinase messenger ribonucleic acids (RNAs; mRNAs) with expanded CUG repeats (CUGexp) aggregate in the nucleus and become toxic to cells by sequestering and/or misregulating RNA-binding proteins, resulting in aberrant alternative splicing. In this paper, we find that the RNA-binding protein Staufen1 is markedly and specifically increased in skeletal muscle from DM1 mouse models and patients. We show that Staufen1 interacts with mutant CUGexp mRNAs and promotes their nuclear export and translation. This effect is critically dependent on the third double-stranded RNA–binding domain of Staufen1 and shuttling of Staufen1 into the nucleus via its nuclear localization signal. Moreover, we uncover a new role of Staufen1 in splicing regulation. Overexpression of Staufen1 rescues alternative splicing of two key pre-mRNAs known to be aberrantly spliced in DM1, suggesting its increased expression represents an adaptive response to the pathology. Altogether, our results unravel a novel function for Staufen1 in splicing regulation and indicate that it may positively modulate the complex DM1 phenotype, thereby revealing its potential as a therapeutic target.

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Pascual, Rosa, Judit Martín, Fernando Salvador, Oscar Reina, Veronica Chanes, Alba Millanes-Romero, Clara Suñer et al. "The RNA binding protein CPEB2 regulates hormone sensing in mammary gland development and luminal breast cancer". Science Advances 6, n. 20 (maggio 2020): eaax3868. http://dx.doi.org/10.1126/sciadv.aax3868.

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Abstract (sommario):

Organogenesis is directed by coordinated cell proliferation and differentiation programs. The hierarchical networks of transcription factors driving mammary gland development and function have been widely studied. However, the contribution of posttranscriptional gene expression reprogramming remains largely unexplored. The 3′ untranslated regions of messenger RNAs (mRNAs) contain combinatorial ensembles of cis-regulatory elements that define transcript-specific regulation of protein synthesis through their cognate RNA binding proteins. We analyze the contribution of the RNA binding cytoplasmic polyadenylation element–binding (CPEB) protein family, which collectively regulate mRNA translation for about 30% of the genome. We find that CPEB2 is required for the integration of hormonal signaling by controlling the protein expression from a subset of ER/PR- regulated transcripts. Furthermore, CPEB2 is critical for the development of ER-positive breast tumors. This work uncovers a previously unknown gene expression regulation level in breast morphogenesis and tumorigenesis, coordinating sequential transcriptional and posttranscriptional layers of gene expression regulation.

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Rybak-Wolf, Agnieszka, e Mireya Plass. "RNA Dynamics in Alzheimer’s Disease". Molecules 26, n. 17 (24 agosto 2021): 5113. http://dx.doi.org/10.3390/molecules26175113.

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Abstract (sommario):

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There is a significant requirement to understand the still unknown molecular mechanisms underlying AD. Current evidence shows that two of the major features of AD are transcriptome dysregulation and altered function of RNA binding proteins (RBPs), both of which lead to changes in the expression of different RNA species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs). In this review, we will conduct a comprehensive overview of how RNA dynamics are altered in AD and how this leads to the differential expression of both short and long RNA species. We will describe how RBP expression and function are altered in AD and how this impacts the expression of different RNA species. Furthermore, we will also show how changes in the abundance of specific RNA species are linked to the pathology of AD.

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46

Rosen, Grace A., Inwha Baek, Larry J. Friedman, Yoo Jin Joo, Stephen Buratowski e Jeff Gelles. "Dynamics of RNA polymerase II and elongation factor Spt4/5 recruitment during activator-dependent transcription". Proceedings of the National Academy of Sciences 117, n. 51 (8 dicembre 2020): 32348–57. http://dx.doi.org/10.1073/pnas.2011224117.

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Abstract (sommario):

In eukaryotes, RNA polymerase II (RNApII) transcribes messenger RNA from template DNA. Decades of experiments have identified the proteins needed for transcription activation, initiation complex assembly, and productive elongation. However, the dynamics of recruitment of these proteins to transcription complexes, and of the transitions between these steps, are poorly understood. We used multiwavelength single-molecule fluorescence microscopy to directly image and quantitate these dynamics in a budding yeast nuclear extract that reconstitutes activator-dependent transcription in vitro. A strong activator (Gal4-VP16) greatly stimulated reversible binding of individual RNApII molecules to template DNA. Binding of labeled elongation factor Spt4/5 to DNA typically followed RNApII binding, was NTP dependent, and was correlated with association of mRNA binding protein Hek2, demonstrating specificity of Spt4/5 binding to elongation complexes. Quantitative kinetic modeling shows that only a fraction of RNApII binding events are productive and implies a rate-limiting step, probably associated with recruitment of general transcription factors, needed to assemble a transcription-competent preinitiation complex at the promoter. Spt4/5 association with transcription complexes was slowly reversible, with DNA-bound RNApII molecules sometimes binding and releasing Spt4/5 multiple times. The average Spt4/5 residence time was of similar magnitude to the time required to transcribe an average length yeast gene. These dynamics suggest that a single Spt4/5 molecule remains associated during a typical transcription event, yet can dissociate from RNApII to allow disassembly of abnormally long-lived (i.e., stalled) elongation complexes.

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Flygaard, Rasmus, Rune Kidmose, Maja Nielsen e Lasse Jenner. "Regulation of the ribosome and protein synthesis by RNAi". Acta Crystallographica Section A Foundations and Advances 70, a1 (5 agosto 2014): C1400. http://dx.doi.org/10.1107/s2053273314085994.

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Abstract (sommario):

In many biological processes, e.g. the development of multicellular organisms, a tight regulation of the protein synthesis is a necessity. Among numerous mechanisms for translational control, RNA interference (RNAi) based mechanisms have been shown to regulate the translation of messenger RNA (mRNA) and hence regulate the synthesis of proteins. The key proteins in all RNAi mechanisms are the argonaute proteins. The only catalytically active argonaute protein is denoted argonaute2 (Ago2) in humans. This single chain protein is comprised of four globular domains arranged in a crescent shape tertiary structure [1]. The guide RNA binding specificity lies within the Mid and PAZ domain while the active site resides in the PIWI domain. In 2011 it was reported that the receptor for activated C-kinase (RACK1), an integral protein of the ribosomal 40S subunit, directly binds the microRNA induced silencing complex (miRISC) [2] and thereby contributes to gene repression through RNAi mediated knockdown. This interaction of RACK1 with miRISC was furthermore shown to be a specific interaction between Ago2 and RACK1. Structural investigation of this interaction will be of great interest to elucidate how Ago2 is positioned in relation to ribosome bound mRNA and if this positioning of Ago2 on the ribosome facilitates mRNA binding to the guide RNA bound in Ago2. In our studies we will co-crystallize recombinantly expressed Ago2 with 80S ribosome from S. cerevisiae [3] and solve the structure by x-ray crystallography. Recent project progress will be presented on the conference poster.

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48

-, Abhya Bhardwaj, Neelmani - e Charanjit Kaur -. "Recent Advances on Bioactive Molecules Acting on RNA and RNA Binding Proteins". International Journal For Multidisciplinary Research 6, n. 3 (24 maggio 2024). http://dx.doi.org/10.36948/ijfmr.2024.v06i03.21115.

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Abstract (sommario):

This review discusses the binding of biologically active molecules to RNA, a crucial component in understanding the molecular basis of life. RNA is replicated from DNA by RNA polymerase and is essential for protein formation. Three types of cellular RNA are messenger RNA (mRNA), ribosomal RNA (rRNA), and soluble RNA (sRNA). The impact of altered RNA binding proteins on human diseases is also discussed. The article also discusses the function of human Pol III in transcription of noncoding RNAs with immuno stimulatory effects, which can promote antiviral immunity. The intricacies of RNA and RNA binding proteins (RBPs) have captivated researchers across various disciplines, owing to their pivotal roles in fundamental cellular processes and their emerging significance in disease mechanisms and therapeutics. RNA molecules, once considered mere messengers in the flow of genetic information, are now recognized as versatile regulators of gene expression, participating in transcriptional and translational control, RNA processing, and epigenetic modifications. In cancer cells, off-target signalling can be harmful, and a new mouse monoclonal antibody (6E4) targets 8-oxoA. RepRNA platforms have been found to lower bacterial lung burden and induce a spectrum of humoral and cellular immune responses. RNA-protein interactions can be inhibited and are potential therapeutic targets for various diseases. RNA-protein interactions can be inhibited and have both protective and pathogenic roles in some diseases. This review aims to provide a comprehensive overview of the recent advances in bioactive molecules binding on RNA and RBPs, encompassing key findings, technological breakthroughs, and therapeutic implications. By synthesizing current knowledge and identifying future directions, this review seeks to elucidate the multifaceted landscape of RNA biology and its implications for drug discovery and precision medicine.

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Wheeler, Joshua R., Oscar N. Whitney, Thomas O. Vogler, Eric D. Nguyen, Bradley Pawlikowski, Evan Lester, Alicia Cutler et al. "RNA-binding proteins direct myogenic cell fate decisions". eLife 11 (13 giugno 2022). http://dx.doi.org/10.7554/elife.75844.

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Abstract (sommario):

RNA-binding proteins (RBPs), essential for skeletal muscle regeneration, cause muscle degeneration and neuromuscular disease when mutated. Why mutations in these ubiquitously expressed RBPs orchestrate complex tissue regeneration and direct cell fate decisions in skeletal muscle remains poorly understood. Single-cell RNA-sequencing of regenerating Mus musculus skeletal muscle reveals that RBP expression, including the expression of many neuromuscular disease-associated RBPs, is temporally regulated in skeletal muscle stem cells and correlates with specific stages of myogenic differentiation. By combining machine learning with RBP engagement scoring, we discovered that the neuromuscular disease-associated RBP Hnrnpa2b1 is a differentiation-specifying regulator of myogenesis that controls myogenic cell fate transitions during terminal differentiation in mice. The timing of RBP expression specifies cell fate transitions by providing post-transcriptional regulation of messenger RNAs that coordinate stem cell fate decisions during tissue regeneration.

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Dallastella, Marianna, Willian Klassen de Oliveira, Marcio L. Rodrigues, Samuel Goldenberg e Lysangela R. Alves. "The characterization of RNA-binding proteins and RNA metabolism-related proteins in fungal extracellular vesicles". Frontiers in Cellular and Infection Microbiology 13 (14 settembre 2023). http://dx.doi.org/10.3389/fcimb.2023.1247329.

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RNA-binding proteins (RBPs) are essential for regulating RNA metabolism, stability, and translation within cells. Recent studies have shown that RBPs are not restricted to intracellular functions and can be found in extracellular vesicles (EVs) in different mammalian cells. EVs released by fungi contain a variety of proteins involved in RNA metabolism. These include RNA helicases, which play essential roles in RNA synthesis, folding, and degradation. Aminoacyl-tRNA synthetases, responsible for acetylating tRNA molecules, are also enriched in EVs, suggesting a possible link between these enzymes and tRNA fragments detected in EVs. Proteins with canonical RNA-binding domains interact with proteins and RNA, such as the RNA Recognition Motif (RRM), Zinc finger, and hnRNP K-homology (KH) domains. Polyadenylate-binding protein (PABP) plays a critical role in the regulation of gene expression by binding the poly(A) tail of messenger RNA (mRNA) and facilitating its translation, stability, and localization, making it a key factor in post-transcriptional control of gene expression. The presence of proteins related to the RNA life cycle in EVs from different fungal species suggests a conserved mechanism of EV cargo packing. Various models have been proposed for selecting RNA molecules for release into EVs. Still, the actual loading processes are unknown, and further molecular characterization of these proteins may provide insight into the mechanism of RNA sorting into EVs. This work reviews the current knowledge of RBPs and proteins related to RNA metabolism in EVs derived from distinct fungi species, and presents an analysis of proteomic datasets through GO term and orthology analysis, Our investigation identified orthologous proteins in fungal EVs on different fungal species.

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