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1
Crombie, Catriona Ann. "Histone hairpin binding protein, an RNA binding protein, essential for development". Thesis, University of Aberdeen, 2003. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU602058.
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Histones are proteins found in the nuclei of eukaryotic cells where they are complexed to DNA in chromatin. Rephcation-dependent histones are expressed only during S-phase. Regulation of expression of replication-dependent histone genes requires a highly conserved hairpin RNA element in the 3' untranslated region of histone mRNAs. Replication-dependent histone mRNAs are not polyadenylated; their 3' end is formed by an endonucleolytic cleavage event, 3' of a hairpin element, which is recognised by the Hairpin Binding Protein, HBP (also known as Stem-Loop Binding Protein, SLBP). This protein-RNA interaction is important for the endonucleolytic cleavage that generates the mature mRNA 3' end. The 3' hairpin, and presumably HBP, are also required for nucleocytoplasmic transport, translation and stability of histone mRNAs. It is therefore important to understand this interaction. The hairpin is highly conserved and I have demonstrated that residues in the hairpin loop are important for binding the HBP. This complimented structural studies that showed that the same residues are involved in stacking interactions in the RNA loop. In cell culture, expression of replication-dependent histone genes is S phase specific as is the expresion of HBP. Here I demonstrated that in Caenorhabditis elegans the HBP promoter is active in dividing cells during embryonic and postembryonic development. Depletion of HBP by RNAi leads to an embryonic lethal phenotype associated with defects in chromosome condensation. Postembryonic depletion of HBP results in defects in cell fate during late larval development, specifically in vulval development. A similar phenotype was obtained when histone H3 and H2A were depleted by RNAi suggesting that the phenotype of the hbp (RNAi) worms was due to a lack of histone proteins. I have confirmed this by showing that histone proteins are indeed reduced in hbp (RNAi) worms. I have also shown that depletion of HBP leads to a change in expression of a number of other proteins and specifically an up-regulation of a histone H3 like protein with an apparent molecular mass of 34 kDa. I have evidence that suggests that this protein is the centromer specific protein, CENP-A. As this protein was up-regulated when RNAi was used to deplete histones proteins, this suggests that there could be a compensatory mechanism that helps the animal to deal with the shortage of histone proteins.
2
Zhong, Jun. "A double-stranded RNA binding protein that is important for murine spermatogenesis and growth /". Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/10301.
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3
Kok, Kin-hang. "Roles of human double-stranded RNA binding proteins TRBP and PACT in RNA interference". Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B38523218.
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4
Kok, Kin-hang y 郭健恆. "Roles of human double-stranded RNA binding proteins TRBP and PACT in RNA interference". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38523218.
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5
Prichard, Lisa. "The role of the IQ motif, a protein kinase C and calmodulin regulatory domain, in neuroplasticity, RNA processing, and RNA metabolism /". Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/6302.
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6
Loushin, Newman Carrie Lee. "Characterization of QKI RNA binding function /". Full text (PDF) from UMI/Dissertation Abstracts International, 2000. http://wwwlib.umi.com/cr/utexas/fullcit?p3004323.
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7
Davies, Holly Gibs. "MSY4, a sequence-specific RNA binding protein expressed during mouse spermatogenesis /". Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/10307.
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8
Wolf, Joshua Jaeger. "Post-transcriptional coordination by an RNA-binding protein". Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/57893.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2010.Cataloged from PDF version of thesis.
Includes bibliographical references.
RNA-binding proteins can regulate the stability, localization, and translation of their target mRNAs. Post-transcriptional regulation can orchestrate dynamic changes in gene expression, and can coordinate multiple cellular processes in response to various stimuli. Filamentous growth in Saccharomyces cerevisiae is a morphogenetic switch that occurs in response to nitrogen starvation and requires alterations in cell growth, cell cycle, and cell wall functions. Tyl element retrotransposition is also induced under conditions of nitrogen starvation. I describe a role for the RNA-binding protein Khdl in regulating these two responses to environmental stress through its mRNA targets. I identified the RNA targets of Khdl using in vivo crosslinking and immunoprecipitation (CLIP), combined with deep sequencing. This produced a high-resolution map of Khdl binding sites across the transcriptome, and provided unprecedented insight into its biological functions. Khdl regulates multiple post-transcriptional regulatory loops to coordinate the components of filamentous growth and Tyl retrotransposition. Although similar mechanisms were known to transcriptionally regulate these processes, the posttranscriptional coordination is a novel discovery. The feed-forward regulation that Khdl confers on FLO11, which encodes a protein required for filamentous growth, enables asymmetric expression between mother and daughter cells to switch between filamentous and yeast form growth. In this thesis, I describe regulation of gene expression by RNA-binding proteins, methods to identify their target transcripts and recognition sequences, the KH domain, known functions of Khdl, and the phenotypes it coordinates. My work represents the first application of CLIP to budding yeast, and the growing understanding of RNA-binding proteins in this organism facilitated the placement of Khdl into its posttranscriptional regulatory network. While many questions remain regarding the role Khdl plays in regulating cellular activities, this thesis addresses its direct role in key processes.
by Joshua Jaeger Wolf.
Ph.D.
9
Zinnall, Ulrike. "Functional characterization of the RNA-binding protein HDLBP". Doctoral thesis, Humboldt-Universität zu Berlin, 2021. http://dx.doi.org/10.18452/23301.
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Der Sekretionsweg ist essenziell für die Funktion von Zellen und beginnt, wenn mRNAs, die für Membran- und Sekretionsproteine codieren, an das endoplasmatische Retikulum (ER) gebracht werden. Allerdings ist wenig darüber bekannt, inwiefern RNA-bindende Proteine zur Erkennung und Translation von ER lokalisierten mRNAs beitragen.
In dieser Arbeit haben wir das humane RNA-bindende Protein HDLBP charakterisiert. Wir haben durch PAR-CLIP-, Zellfraktionierungs- und RNA-Seqeuenzierexperimente festgestellt, dass HDLBP an mehr als 80% aller ER lokalisierten mRNAs bindet. Analysen zu HDLBPs Bindungsmotiv haben gezeigt, dass HDLBP vorwiegend an ein CU-haltiges Motiv in der codierenden Sequenz (CDS) hauptsächlich von ER lokalisierten mRNAs bindet. Im Gegensatz dazu enthalten zytosolische HDLBP gebundene mRNAs weniger Bindungsstellen und diese treten sowohl in der CDS als auch in 3‘ untranslatierten Regionen auf. Dies zeigt, dass sich ER lokalisierte mRNAs von Zytosol lokalisierten mRNAs in ihrer Sequenzzusammensetzung hinsichtlich der HDLBP Bindungsstellen unterscheiden.
Weitere Analysen des PAR-CLIP-Experiments ergaben, dass HDLBP mit RNA-Komponenten des Signalerkennungspartikels (SRP) und der 40S ribosomalen Untereinheit interagiert. Durch BioID-Experimente haben wir Proteine in unmittelbarer Nähe zu HDLBP bestimmt und konnten damit die Assoziation von HDLBP mit Komponenten des Translationsapparates und des SRPs bestätigen.
Funktionelle Studien, bei denen wir CRISPR-Cas9 erzeugte HDLBP Knockout (KO) Zelllinien in Kombination mit Ribosomen-Profiling verwendet haben, haben gezeigt, dass HDLBP die Translation von mRNAs fördert, die an HDLBP gebunden und am ER lokalisiert sind.
Letztlich haben in vivo Experimente mit Nacktmäusen ergeben, dass HDLBP KO eine Abnahme der Lungentumorbildung verursacht, was die Relevanz von HDLBP für die Tumorprogression hervorhebt. Insgesamt zeigt unsere Arbeit eine generelle Funktion von HDLBP bei der Translation von ER lokalisierten mRNAs.The secretory pathway is essential for proper cell functioning and starts when mRNAs encoding membrane and secretory proteins are targeted to the endoplasmic reticulum (ER). However, little is known about the contribution of RNA-binding proteins to the recognition, localization and translation of ER-localized mRNAs. In this work, we characterized the human RNA-binding protein HDLBP. We identified that HDLBP binds to more than 80% of all ER-localized mRNAs by PAR-CLIP, cell fractionation and RNA-sequencing experiments. Analysis of the HDLBP binding motif showed that it predominantly binds to a CU-containing motif and forms high affinity multivalent interactions primarily in the coding sequence (CDS) of ER-localized mRNAs. In contrast, we identified that cytosolic HDLBP mRNA targets show less HDLBP binding sites randomly distributed between the CDS or 3’ untranslated regions. This indicates that ER-localized mRNAs per se differ from cytosol-localized mRNAs in their sequence composition with regard to HDLBP binding sites. Further PAR-CLIP analysis revealed that HDLBP interacts with RNA components of the signal recognition particle (SRP) and the 40S ribosomal subunit. We identified by BioID experiments proteins in close proximity to HDLBP and confirmed the association of HDLBP with components of the translational apparatus and the SRP. Functional studies using CRISPR-Cas9 HDLBP knockout (KO) cell lines in combination with ribosome profiling demonstrated that HDLBP promotes the translation of its ER-localized target mRNAs. We validated this finding by pSILAC experiments and detected the corresponding decrease in protein synthesis of proteins encoded by mRNAs that are bound by HDLBP and ER-localized. Lastly, in vivo experiments with nude mice showed that HDLBP KO resulted in a decrease of lung tumor formation highlighting the relevance of HDLBP for tumor progression. Overall, these results demonstrate a general function for HDLBP in the translation of ER-localized mRNAs.
10
Moro, Alberto Maria. "Functional characterization of the RNA binding protein RALY". Doctoral thesis, University of Trento, 2013. http://eprints-phd.biblio.unitn.it/1086/1/Albertomaria_Moro_thesis_Final_version.pdf.
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Of 25000 genes encoded from genome, more than 90% are subject to alternative splicing or other post-transcriptional modifications. All these events produce a high number of different proteins that form the basis for the high variety of cells. The RNAbinding proteins (RBPs) play crucial roles in this variability by regulating many steps of biological processes regarding RNA metabolism. The heterogeneous nuclear ribonucleoproteins (hnRNPs) belong to big family of RBPs involved in many aspects of RNA metabolism including RNA stability, intracellular transport and translation. More recently, RALY, a RNA-binding protein associated with the lethal yellow mutation in mouse, has been identified as new member of the hnRNP family even if, its biological function remains still elusive.
My PhD project aimed to characterize human RALY and to assess its function in mammalian cells. Initially I dentified the expression pattern of this protein into the cell and I characterized the functional nuclear localization sequence that localizes RALY protein into the nuclear compartment. In order to better understand the role of RALY in the cells, I identified the proteins component of RALY-containing complexes using a new assay named iBioPQ (in vivo-Biotinylation-Pulldown-Quant assay). I also performed polyribosome profiling assay to check the resence of RALY in translating mRNAs. Moreover, a microarray assay was performed in order to identify potential mRNAs whose metabolism appears dependent on RALY expression. Taken together, the results that I obtained suggest that RALY is involved in mRNA metabolism. Unfortunately more studies remain to do before shedding some light on the biological
role of RALY in mammals
11
Nashchekin, Dmitri. "A Y-box protein/RNA helicase complex links mRNP assembly on the gene to mRNA translation /". Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-811-8/.
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12
Cass, Danielle Marie. "Role of two RNA binding properties in pre-mRNA splicing /". view abstract or download file of text, 2007. http://proquest.umi.com/pqdweb?did=1400950811&sid=2&Fmt=2&clientId=11238&RQT=309&VName=PQD.
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Thesis (Ph. D.)--University of Oregon, 2007.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 67-80). Also available for download via the World Wide Web; free to University of Oregon users.
13
Giorgini, Flaviano. "Functional analysis of the murine sequence-specific RNA binding protein MSY4 /". Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/10293.
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14
Sidiqi, Mahjooba. "The structure and RNA-binding of poly (C) protein 1". University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0077.
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[Truncated abstract] Regulation of mRNA stability is an important posttranscriptional mechanism involved in the control of gene expression. The rate of mRNA decay can differ greatly from one mRNA to another and may be regulated by RNA-protein interactions. A key determinant of mRNA decay are sequence instability (cis) elements often located in the 3' untranslated region (UTR) of many mRNAs. For example, the AU rich elements (AREs), are such well characterized elements, and most commonly involved in promoting mRNA degradation, and specific binding of proteins to these elements leading to the stabilization of some mRNAs. Other cis-elements have been described for mRNA in which mRNA stability is a critical component of gene regulation. This includes the androgen receptor (AR) UC-rich cis element in its 3'UTR. The AR is a key target for therapeutics in human prostate cancer and thus understanding the mechanism involved in regulating its expression is an important goal. The [alpha]CP1 protein, a KH-domain containing RNA-binding protein has been found to bind this UC-rich region of the AR and is thought to play an important role in regulating AR mRNA expression. [alpha]CP1 protein is a triple KH (hnRNP K homology) domain protein with specificity for Crich tracts of RNA and ssDNA (single stranded DNA). Relatively little is known about the structural interaction of [alpha]CP1 with target RNA cis elements, thus the present study aimed to better understand the nature of interaction between 30 nt 3'UTR UC-rich AR mRNA and [alpha]CP1 protein using various biophysical techniques, in an attempt to determine which [alpha]CP1 domain or combination of domains is involved in RNA-binding. These studies could ultimately provide novel targets for drugs aimed to regulate AR mRNA expression in prostate cancer cells. At the commencement of this study little was known about the structure of the [alpha]CP1- KH domains and their basis for poly (C) binding specificity. ... Additional studies addressed the significance of the four core recognition nucleotides (TCCC) using a series of cytosine to thymine mutants. The findings verified some of the results predicted from structural studies, especially the need for maximum KH binding to a core tetranucleotide recognition sequence. Our mutational studies of the four core bases confirmed the importance of cytosine in positions two and three as no binding was observed, while some binding was observed when the fourth base was mutated. In summary, the work presented in this thesis provides new detailed insight into the molecular interactions between the [alpha]CP1-KH domain and AR mRNA. Furthermore, these studies shed light on the nature of protein/mRNA interactions in general, as well as the specific complex that forms on AR mRNA. These studies have provided new understanding into the mode of [alpha]CP1 binding at a target oligonucleotide binding site and, provide a foundation for future studies to define structure of multiprotein/oligonucleotide complexes involved in AR mRNA gene regulation. Understanding the detailed interaction between the AR mRNA and [alpha]CP1 could provide possible targets for drug development at reducing AR expression in prostate cancer cells by interfering with the interaction of [alpha]CP1 and AR-mRNA.
15
Garrey, Stephen M. "Characterization of the specificity and affinity of the splicing factor BBP/SF1 /". view abstract or download file of text, 2007. http://proquest.umi.com/pqdweb?did=1324375731&sid=2&Fmt=2&clientId=11238&RQT=309&VName=PQD.
Texto completoResumen
Thesis (Ph. D.)--University of Oregon, 2007.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 81-88). Also available for download via the World Wide Web; free to University of Oregon users.
16
Kylberg, Karin. "Transcription and transport of a messenger RNP particle : novel regulatory mechanisms /". Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-318-4/.
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17
Whittington, Christi Leigh. "Molecular Dynamics of the RNA Binding Cavity of Influenza A Non-structural Protein 1 (NS1) RNA Binding Domain". Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4256.
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Molecular dynamics simulations were performed on the influenza A non-structural protein 1 (NS1) RNA binding domain (RBD), a homodimer. Fourteen simulations were performed at 298K, nine ionized with 0.1M KCl and five with no ions. Several analysis techniques were employed to study RBD residue flexibility. The focus of the study was the RNA binding cavity formed by side chains of helix 2 (chain A) and helix 2’ (chain B) and cavity intermonomeric salt bridges. Opening of the salt bridges D29–R46’ and D29’–R46 was observed in several of the trajectories. The RNA binding cavity has large flexibility, where the dimension and shape change during the dynamics. One pair of residues surrounding the cavity and necessary for RNA binding, residues R38 and R38’, have motions during the simulations which cover the top of the cavity. There is correlation between the salt bridge breaking, flexibility of R38 and R38’, and the cavity size and shape changes. Possible RBD small molecule drug targets are these two salt bridges and the pair R38 and R38’. Disrupting the events that occur around these areas could possibly inactivate RNA binding function of the domain. These results could have implications in searching for potential molecules that effectively treat influenza A.
18
Choudury, Sarah G. Choudury. "Identification and characterization of proteins required for RNA-directed DNA Methylation, including the RNA binding protein ALY1". The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1543508792612526.
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19
Huang, Ching-jung. "The role of HnRNP proteins, PSF and nonO/p54[superscript nrb], in pre-mRNA binding and splicing /". Full text (PDF) from UMI/Dissertation Abstracts International, 2000. http://wwwlib.umi.com/cr/utexas/fullcit?p3004292.
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20
Maitra, Sushmit. "The AU-rich element mRNA decay-promoting activity of BRF1 is regulated by mitogen-activated protein kinase activated protein kinase 2". Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008r/maitra.pdf.
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21
Park, Youngwoo. "Selective translation of influenza viral messenger RNAs mediated by trans-acting factor(s) through an interaction with the sequence element in the 5'-untranslated region /". Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/11496.
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22
Henscheid, Kristy L. "Functional conservation and RNA binding of the pre-mRNA splicing factor U2AF65 /". view abstract or download file of text, 2007. http://proquest.umi.com/pqdweb?did=1400950821&sid=5&Fmt=2&clientId=11238&RQT=309&VName=PQD.
Texto completoResumen
Thesis (Ph. D.)--University of Oregon, 2007.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 129-141). Also available for download via the World Wide Web; free to University of Oregon users.
23
Öhrmalm, Christina. "Functional characterization of the cellular protein p32 : a protein regulating adenovirus transcription and splicing through targeting of phosphorylation /". Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6794.
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24
Durie, Danielle. "RNA Binding Protein HuR Regulates the Expression of Bcl-xL". Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23206.
Texto completoResumen
The RNA-binding protein HuR controls key cellular processes by binding target
mRNAs and regulating them at
various
post-transcriptional levels. HuR
can function as
an
Internal
Ribosome
Entry
Site (IRES)
trans-acting factor
that
regulates the IRES-mediated
translation of XIAP.
Since
XIAP and Bcl-xL
expression was reported to be co-regulated, we
investigated whether
HuR
is also a
regulat
or of Bcl-xL expression. We found that HuR binds
the 3’end of the Bcl-xL 5’UTR
in-vitro. In U2OS cells, we showed that loss of HuR by
siRNA significantly increased Bcl-xL protein expression
while
Bcl-2 and Mcl-1 levels
remained unchanged. We found that
the HuR-dependent
Bcl-xL
increase was
through
translation,
shown by polysome
profiling.
Possible transcriptional, stability
and splicing
changes were eliminated.
At the physiological level HuR levels did not impact cell survival
but altered mitochondrial morphology,
partially through Bcl-xL.
Thus, HuR may be involved
in maintaining proper mitochondrial
function
by controlling Bcl-xL expression.
25
Spellman, Rachel Claudine Helen. "Investigation of polypyrimidine tract binding protein function by RNA interference". Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614210.
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26
Zinnall, Ulrike [Verfasser]. "Functional characterization of the RNA-binding protein HDLBP / Ulrike Zinnall". Berlin : Humboldt-Universität zu Berlin, 2021. http://d-nb.info/1241116946/34.
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27
Bourdeau-Julien, Isabelle. "ALS-associated RNA-binding protein FUS and mRNA translation regulation". Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/68742.
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Des mutations dans plusieurs gènes ont été liés à la sclérose latérale amyotrophique (SLA),en particulier dans celui codant pour la protéine Fused in Sarcoma (FUS). Les mutations sont retrouvées dans la partie codant pour le signal de localisation nucléaire, rendant la protéine anormalement abondante dans le cytoplasme. Combiné à d’autres observations, ça suggère qu’un gain de fonction toxique de FUS dans le cytoplasme serait à l’origine de la neurodégénérescence. La SLA est une maladie neurodégénérative qui affecte les neurones moteurs et cause une paralysie progressive. Les mécanismes moléculaires causant la maladies ont toujours inconnus. Une des pistes serait la perturbation de la traduction locale desARNm, qui permet aux synapses de répondre rapidement et indépendamment du corps cellulaire. Une traduction locale insuffisante pour soutenir l’activité synaptique à long terme mènerait à la perte des synapses et à la neurodégénérescence. Mon objectif est donc de déterminer le rôle de FUS dans régulation de la traduction des ARNm en caractérisant son interaction avec les composantes traductionnelles et d’évaluer sa fonction dans une condition reproduisant les caractéristiques de la SLA. J’ai montré que FUS s’associe aux polyribosomes inactifs, ce qui suggère que FUS jouerait un rôle dans la régulation de la traduction des ARNm en interagissant avec le cœur de la traduction. Il est également possible d’observer une augmentation de la présence de FUS dans le cytoplasme et de son interaction avec les polyribosomes suite à une inhibition de la traduction par mTOR, suggérant son rôle de régulateur négatif. De plus, les mutations liées à la SLA amplifient la fonction inhibitrice de FUS en rendant FUS cytoplasmique et en réduisant la synthèse des protéines. Mes résultats montrent que la protéine FUS aurait un rôle d’inhibiteur de la traduction quand celle-ci est cytoplasmique. Par conséquent, l’augmentation de la présence de FUS dans le cytoplasme dans la SLA entrainerait une inhibition de la traduction importante, à un niveau insuffisant pour soutenir l’activité synaptique.Mutations in several genes have been linked to amyotrophic lateral sclerosis (ALS),particularly in the gene coding for the Fused in Sarcoma protein (FUS). Those mutations are found in the part encoding for the nuclear localization signal, making the protein abnormallyabundant in the cytoplasm. Combined with other observations, it suggests that a toxic gainof function of FUS in the cytoplasm would be the cause of the neurodegeneration. ALS is a neurodegenerative disease that affects motor neurons and causes progressive paralysis. The molecular mechanisms causing the disease are still unknown. One of the hypotheses is the disruption of local translation of mRNAs, which allows synapses to respond quickly and independently from the cell body. Insufficient local translation to support long-term synapticactivity would lead to synaptic loss and neurodegeneration. Thereby, the objective of mystudy is to determine the role of FUS in the regulation of mRNA translation by characterizing its interaction with translational components and evaluate its function in an ALS-linked condition. I have shown that FUS is associated with stalled polyribosomes, which suggests that it plays a role in regulating mRNA translation by interacting with the core of translation.There is also an increase in the presence of FUS in the cytoplasm and in its interaction with polyribosomes following inhibition of translation through mTOR, suggesting its role as anegative regulator. In addition, ALS-related mutations amplify FUS inhibitory function bymaking FUS cytoplasmic and reducing protein synthesis. My results show that the FUSprotein would have a role as a translation inhibitor when it is cytoplasmic. There fore, increasing the presence of FUS in the cytoplasm in ALS would result in significant translation inhibition, at a level insufficient to support synaptic activity.
28
Lal, Preet. "Characterization of Small Molecules Inhibiting the RNA Binding Protein HuR". Doctoral thesis, Università degli studi di Trento, 2017. https://hdl.handle.net/11572/368442.
Texto completoResumen
HuR, the ubiquitously expressed member of the ELAV (embryonic lethal abnormal vision) family of RNA binding proteins, selectively binds to AREs (AU-rich elements) and mainly stabilizes ARE-containing mRNAs, e.g. TNFα, VEGF, c-FOS, favoring specific protein translation. TNFα mRNA is one of the most important target mRNA of HuR since the protein encoded by this gene mediates the inflammatory response and its overexpression is correlated with autoimmune diseases and cancer-related inflammation. Specific drugs are already available that can inhibit TNFα protein but cause important side-effects, as insurgence of tumoral pathologies, due to high immunodepression. Therefore, inhibition of TNFα mRNA translation by specific inhibitors targeting HuR, only in those cells undergoing pathological anomalies, is an alternative, intriguing novel therapeutic approach that deserves investigation. By REMSA and AlphaScreen assays we identified a family of low molecular weight inhibitors, called Tanshinones, among which DHTS-I (Dihydrotanshinone – I) was the most potent. Tanshinones are well known in the traditional Chinese Medicine Practice, and these anti-inflammatory agents possess the ability to prevent HuR-RNA complex formation in vitro. We further identified structural determinants of HuR and DHTS interaction using RRM1&RRM2 tandem domains. EMSA and AlphaScreen experiments, with truncated ΔRRM1 and mutants revealed that DHTS is a competitive binder of HuR with respect of target RNA. To ameliorate the solubility of DHTS, we synthesized a number of DHTS analogs, of which the most potent and soluble compound was named MFM49. We evaluated the anti-inflammatory potential of DHTS and DHTS analogs and the HuR-dependent mechanism of action, revealing that, at least in part, DHTS and DHTS analogs rely on HuR to exert their mechanism of action. Influence on NF-kB activation by DHTS and MFM49 upon LPS co-stimulation was not seen in immunofluorescence studies. So here, we disclose a previously unrecognized molecular mechanism of action exerted by DHTS, and anti-inflammatory potential of DHTS analogs opening new perspectives to therapeutically target the HuR mediated, post-transcriptional control in inflammation and cancer like anomalies.
29
Lal, Preet. "Characterization of Small Molecules Inhibiting the RNA Binding Protein HuR". Doctoral thesis, University of Trento, 2017. http://eprints-phd.biblio.unitn.it/2717/1/PhD_thesis_Lal_Preet.pdf.
Texto completoResumen
HuR, the ubiquitously expressed member of the ELAV (embryonic lethal abnormal vision) family of RNA binding proteins, selectively binds to AREs (AU-rich elements) and mainly stabilizes ARE-containing mRNAs, e.g. TNFα, VEGF, c-FOS, favoring specific protein translation. TNFα mRNA is one of the most important target mRNA of HuR since the protein encoded by this gene mediates the inflammatory response and its overexpression is correlated with autoimmune diseases and cancer-related inflammation. Specific drugs are already available that can inhibit TNFα protein but cause important side-effects, as insurgence of tumoral pathologies, due to high immunodepression. Therefore, inhibition of TNFα mRNA translation by specific inhibitors targeting HuR, only in those cells undergoing pathological anomalies, is an alternative, intriguing novel therapeutic approach that deserves investigation. By REMSA and AlphaScreen assays we identified a family of low molecular weight inhibitors, called Tanshinones, among which DHTS-I (Dihydrotanshinone – I) was the most potent. Tanshinones are well known in the traditional Chinese Medicine Practice, and these anti-inflammatory agents possess the ability to prevent HuR-RNA complex formation in vitro. We further identified structural determinants of HuR and DHTS interaction using RRM1&RRM2 tandem domains. EMSA and AlphaScreen experiments, with truncated ΔRRM1 and mutants revealed that DHTS is a competitive binder of HuR with respect of target RNA. To ameliorate the solubility of DHTS, we synthesized a number of DHTS analogs, of which the most potent and soluble compound was named MFM49. We evaluated the anti-inflammatory potential of DHTS and DHTS analogs and the HuR-dependent mechanism of action, revealing that, at least in part, DHTS and DHTS analogs rely on HuR to exert their mechanism of action. Influence on NF-kB activation by DHTS and MFM49 upon LPS co-stimulation was not seen in immunofluorescence studies. So here, we disclose a previously unrecognized molecular mechanism of action exerted by DHTS, and anti-inflammatory potential of DHTS analogs opening new perspectives to therapeutically target the HuR mediated, post-transcriptional control in inflammation and cancer like anomalies.
30
SALADINO, Patrizia. "ROLE OF RNA BINDING PROTEIN IN THE NERVE CELL DIFFERENTIATION". Doctoral thesis, Università degli Studi di Palermo, 2014. http://hdl.handle.net/10447/91214.
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Synthesis of H1˚ and H3.3 histone proteins, in the developing rat brain, seems to be regulated mainly at the post-transcriptional level. Since regulation of RNA metabolism depends on a series of RNA-binding proteins (RBPs), we have been searching for RBPs involved in the post-transcriptional regulation of the H1˚ and H3.3 genes. Previously, we reported isolation, from a cDNA expression library, of an insert encoding a novel protein, the C-terminal half of which is identical to that of PEP-19, a brain-specific protein involved in calcium metabolism. The novel protein was called long PEP-19 isoform (LPI). We showed that LPI, as well as PEP-19, can bind H1˚ RNA. Since PEP19 and LPI contain a calmodulin binding domain, we also investigated whether their ability to bind RNA is affected by calmodulin. Our results show that calmodulin interferes with binding of H1˚ RNA to both PEP-19 and LPI, while it is not able to bind RNA on its own. Pep-19/calmodulin high affinity binding has been demonstrated by Biolayer interferometry (BLI). This finding suggests that calcium/calmodulin may have a role in controlling H1˚ mRNA metabolism in the developing brain. Moreover, in order to improve production of functional LPI/PEP-19, we modified the protocol normally adopted for preparing histidine tagged-proteins from bacteria, by adding an additional purification step.
Furthermore, we found that both LPI and PEP-19 can compete for H1˚ RNA binding with PIPPin (also known as CSD-C2), another RBP previously discovered in our laboratory. PIPPin/CSD-C2 binds with high specificity to the mRNAs encoding H1° and H3.3 histone variants, undergoes thyroid hormone-dependent SUMOylation, and has been recently demonstrated to interact with other RBPs. PIPPin belongs to the CSD-containing class of RBPs, also called Y-box proteins, that play a key role in controlling the recruitment of mRNAs to the translational machinery, in response to environmental cues, both in development and in differentiated cells.
Another aspect of this study was to confirm histone mRNAs-PIPPin interactions and to describe binding properties through streptavidin-biotin conjugation method, by BLI.
We report the data obtained in the case of H3.3 and H1° mRNA-PIPPin interactions, and the specific affinity constant for these bindings. In order to identify RNA portions involved in binding, we used different RNA probes for H3.3 and H1°. In summary, we were able to confirm that PIPPin binds H3.3 and H1° mRNA with very high affinity.
Searching for other RBPs, we used in vitro transcribed, biotinylated H1° RNA as bait to isolate, by a chromatographic approach, proteins which interact with this mRNA, in the nuclei of brain cells. Abundant RBPs, such as heterogeneous nuclear ribonucleoprotein (hnRNP) K and hnRNP A1, and molecular chaperones (heat shock cognate 70, Hsc70) were identified by mass spectrometry. Western blot analysis also revealed the presence of CSD-C2. Co-immunoprecipitation assays were performed to investigate the possibility that identified proteins interact with each other and with other nuclear proteins. We found that hnRNP K interacts with both hnRNP A1 and Hsc70, whereas there is no interaction between hnRNP A1 and Hsc70. Moreover, CSD-C2 interacts with hnRNP A1, Y box-binding protein 1 (YB-1), and hnRNP K. We also have indications that CSD-C2 interacts with Hsc70.
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Dwyer, Holly. "Characterization of putative Porphyromonas gingivalis RNA-binding proteins". VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3550.
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Porphyromonas gingivalis (P. gingivalis) is a gram-negative, anaerobic bacterium recognized as a major player in progression of periodontal disease. P. gingivalis survives in the oral cavity while being exposed to dynamic environmental conditions such as pH, temperature, nutrient availability and host immune responses such as oxygen tension and nitrosative stress. Survival and pathogenesis of P. gingivalis in the oral cavity require mechanisms to regulate gene expression in response to the extracellular signals. Little is known about the regulatory mechanisms of P. gingivalis in the oral cavity, so it is important to investigate and characterize these regulatory mechanisms. Adaptation to environmental cues using riboregulation is a significant mechanism for post-transcriptional regulation in bacteria. Using bioinformatics, we have identified a putative RNA-binding protein in P. gingivalis: RBP. Bioinformatic studies have led to the selection of HUβ and HUα nucleoid associated proteins as controls for RNA binding. I hypothesize that the candidate proteins RBP, HUβ and HUα bind RNA in P. gingivalis. The first aim is to show that RBP, HUβ and HUα bind RNA. Using electrophoretic mobility shift assays with IRE RNA and synthesized RNA motifs, I have confirmed that the proteins do bind RNA. The second aim is to isolate and sequence the P. gingivalis RNA that bind to RBP, HUβ and HUα. I have isolated the RNAs that bound the proteins and determined identity of the RNA using high throughput sequencing. Finally, I have identified an antibody that specifically binds RBP to use for in vivo immunoprecipitation of RNA-protein complexes from P. gingivalis. In conclusion RBP, HUβ and HUα are novel RNA binding proteins in P. gingivalis, and further investigation of these proteins is necessary to understand the mechanisms of gene regulation in P. gingivalis.
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Howe, Peter W. A. "NMR studies of the RNA binding domain of U1A protein and its complexes with RNA". Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313879.
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Lee, Sang C., Jack Zhang, Josh Strom, Danzhou Yang, Thai Nho Dinh, Kyle Kappeler y Qin M. Chen. "G-Quadruplex in the NRF2 mRNA 5′ Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress". AMER SOC MICROBIOLOGY, 2017. http://hdl.handle.net/10150/622753.
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Inhibition of protein synthesis serves as a general measure of cellular consequences of chemical stress. A few proteins are translated selectively and influence cell fate. How these proteins can bypass the general control of translation remains unknown. We found that low to mild doses of oxidants induce de novo translation of the NRF2 protein. Here we demonstrate the presence of a G-quadruplex structure in the 5' untranslated region (UTR) of NRF2 mRNA, as measured by circular dichroism, nuclear magnetic resonance, and dimethylsulfate footprinting analyses. Such a structure is important for 5'-UTR activity, since its removal by sequence mutation eliminated H2O2-induced activation of the NRF2 5' UTR. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics revealed elongation factor 1 alpha (EF1a) as a protein binding to the G-quadruplex sequence. Cells responded to H2O2 treatment by increasing the EF1a protein association with NRF2 mRNA, as measured by RNA-protein interaction assays. The EF1a interaction with small and large subunits of ribosomes did not appear to change due to H2O2 treatment, nor did post translational modifications, as measured by two-dimensional (2-D) Western blot analysis. Since NRF2 encodes a transcription factor essential for protection against tissue injury, our data have revealed a novel mechanism of cellular defense involving de novo NRF2 protein translation governed by the EF1a interaction with the G-quadruplex in the NRF2 5' UTR during oxidative stress.
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Iwaoka, Ryo. "Structural basis for translational regulation by RNA-binding protein Musashi-1". Kyoto University, 2017. http://hdl.handle.net/2433/227652.
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Valeiras, Brenda. "Probing RNA binding specificities of AID/APOBEC proteins by iCLIP". Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288562.
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The AID/APOBEC protein family comprises a group of cytosine deaminases found in vertebrates that are capable of modifying cytosine to uracil in the context of RNA or singlestranded DNA. They exert diverse valuable physiological functions including antibody diversification and restriction of viral infection. However, off-target mutations have also been shown to contribute to cancer development, making it crucial to better understand the interactions and mechanisms that regulate AID/APOBEC activity and editing site fidelity. In this regard, a new focus on RNA as a putative regulator of AID/APOBECs has recently emerged. Regardless of whether it is used or not as a substrate for deamination, most members of the family have been shown to retain the ability to bind RNA, emphasizing a potential regulatory role for this interaction. However, little is known about AID/APOBECs RNA binding specificity. A promiscuous binding has been suggested in some cases while in vitro evidence for other members of the family indicate a certain level of specificity. Therefore, to thoroughly unravel the AID/APOBECs RNA binding specificity, in my doctoral research I applied cross-linking and immunoprecipitation (iCLIP), an unbiased technique that allows identification of protein-bound RNAs with nucleotide resolution in living cells. As a first approach, I adapted the technique for its use in yeast and probed the RNA binding of AID and APOBEC3G, revealing different degrees of preference for small structured RNAs and recognition of particular sites within them. I then expanded the analysis to mammalian cells (HEK293T) and evaluated an extended set of APOBECs finding that, even in the presence of a broader and more complex pool of RNAs, small RNAs were still significantly bound by some members of the family. Furthermore, the comparative analysis of AID, APOBEC1, APOBEC3G, APOBEC3A and APOBEC3B iCLIP data obtained in my research, revealed shared and individual preferences for certain RNAs, suggesting a degree of binding specificity among APOBECs. In summary, my thesis outlines for the first time a comprehensive analysis of the RNA binding specificity of different AID/APOBECs in vivo, including the description of novel interactions with nucleotide resolution. The results obtained are of great value and open the field for further investigation of the specific meaning and validation of each preferential binding, providing new insights into understanding the role of AID/APOBEC interaction with RNA.
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Ó, Catnaigh Pól. "An investigation into the RNA-binding protein UNR and its interactors". Thesis, University of Warwick, 2016. http://wrap.warwick.ac.uk/91504/.
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Recent work linked the RNA-binding protein UNR to a number of human pathologies although little is currently known about how UNR functions in human cells. This thesis aims to elucidate how UNR functions by, among other things, discovering novel UNR-interacting proteins and transcripts and proteins that are differentially expressed in the presence or absence of UNR. It is shown that UNR levels decrease with increasing cell confluency in cultured HeLa cells but that they increase with increasing confluency in the wild type TP53-containing U2OS cell line. UNR is shown to colocalise to stress granules with TP53 in arsenite-stressed HeLa cells. A number of novel UNR-interacting proteins were discovered in three cell lines (HeLa, U2OS and SaOS-2), including HUWE1, NARR, SQSTM1 and LDB1. GO-term overrepresentation analysis confirmed that UNR is an RNA-binding protein as ‘RNA binding’ and ‘poly(A) RNA binding’ were the top two overrepresented molecular function GO terms by p-value across each of the cell types. Less expected overrepresented GO terms pertained to selenium metabolism and the extracellular exosome. There was no evidence for conservation of UNR-interacting transcripts across the cell types but there were some similar significantly overrepresented GO terms among the respective UNR-interacting transcripts. These included terms pertaining to RNA and the nucleus. The most significant UNR-interacting transcript in HeLa cells was PABPC1 and that the PABP protein was also significantly upregulated following UNR knockdown in HeLa cells. ‘Poly (A) RNA binding’ was a significantly overrepresented GO term among proteins differentially regulated following UNR knockdown in HeLa and U2OS cells. ‘Adherens junction’ was another significantly overrepresented GO term using proteins that were higher in abundance in siUNR-treated HeLa cells and either higher or lower in abundance in either arsenite-stressed or unstressed U2OS cells. UNR was observed at cell-cell junctions in HeLa and U2OS cells by immunofluorescence microscopy.
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Git, Anna. "Studies of the expression and function of Vg1 RNA binding protein". Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620990.
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Culley, Rachel Louise. "The role of the RNA binding protein FUS in androgen signalling". Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/14613.
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The multi-functional RNA binding protein FUS was identified as an androgen down-regulated target in a 2D proteomic screen in the LNCaP cell line. This screen was designed to identify novel markers and therapeutic targets for prostate cancer. Cell cycle analysis and growth assays revealed that increased FUS levels in LNCaP cells resulted in inhibition of the androgen-dependent G1-S cell cycle transition and induced apoptosis. This is brought about, in part, via the FUS-dependent modulation of the expression of G1- S check-point regulatory proteins, including decreased expression of Cyclin D1. Therefore, we have identified FUS as a key link between androgen signalling and cell cycle regulation. FUS also modulates androgen signalling by repressing Androgen Receptor (AR) activity. FUS is known to interact with the DNA binding domain of some nuclear receptors, and a mammalian 2-hybrid interaction assay revealed a ligand-dependent interaction between FUS and the AR that required the FUS RNA recognition motif. Transcription assays demonstrated that FUS is a novel co-repressor of AR activity, and quantitative real time PCR showed that increasing FUS levels down-regulated androgen-regulated gene expression in LNCaP cells, whilst reducing FUS levels resulted in an increase of the androgen-regulated gene TMPRSS2. Investigation into the mechanism(s) by which FUS represses AR activity revealed that FUS contains an NH2-terminal activation domain (amino acids 1-366) that is consistent with the AR transcriptional repression domain. Furthermore, the FUS NH2- terminal interacts with co-activators, including SRC-1, suggesting FUS may repress AR activity by competition with co-activator activity. Recent studies in Dr Charlotte Bevan’s laboratory demonstrated an inverse correlation between FUS expression and Gleason grade in human prostate tumours. This, combined with these findings that FUS is an inhibitor of androgen-dependent growth which is, in part, via repression of the AR, suggests that FUS is a key regulator in AR signalling and prostate cancer progression, and may be a novel tumour suppressor.
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Livi, Carmen Maria. "Protein-dependent prediction of messenger RNA binding using Support Vector Machines". Doctoral thesis, Università degli studi di Trento, 2013. https://hdl.handle.net/11572/369261.
Texto completoResumen
RNA-binding proteins interact specifically with RNA strands to regulate important cellular processes. Knowing the binding partners of a protein is a crucial issue in biology and it is essential to understand the protein function and its involvement in diseases. The identification of the interactions is currently resolvable only through in vivo and in vitro experiments which may not detect all binding partners. Computational methods which capture the protein-dependent nature of the binding phenomena could help to predict, in silico, the binding and could be resistant against experimental biases.
This thesis addresses the creation of models based on support vector machines and trained on experimental data. The goal is the identification of RNAs which bind specifically to a regulatory protein. Starting from a case study, done with protein CELF1, we extend our approach and propose three methods to predict whether an RNA strand can be bound by a particular RNA-binding protein. The methods use support vector machines and different features based on the sequence (method Oli), the motif score (method OliMo) and the secondary structure (method OliMoSS). We apply them to different experimentally-derived datasets and compare the predictions with two methods: RNAcontext and RPISeq. Oli outperforms OliMoSS and RPISeq affirming our protein specific prediction and suggesting that oligo frequencies are good discriminative features. Oli and RNAcontext are the most competitive methods in terms of AUC. A Precision-Recall analysis reveals a better performance for Oli. On a second experimental dataset, where negative binding information is available, Oli outperforms RNAcontext with
a precision of 0.73 vs. 0.59. Our experiments show that features based on primary sequence information are highly discriminative to predict the binding between protein and RNA. Sequence motifs can improve the prediction only for some RNA-binding proteins. Finally, we can conclude that experimental data on RNA-binding can be effectively used to train protein-specific models for in silico predictions.
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Livi, Carmen Maria. "Protein-dependent prediction of messenger RNA binding using Support Vector Machines". Doctoral thesis, University of Trento, 2013. http://eprints-phd.biblio.unitn.it/995/1/phd-thesisLivi.pdf.
Texto completoResumen
RNA-binding proteins interact specifically with RNA strands to regulate important cellular processes. Knowing the binding partners of a protein is a crucial issue in biology and it is essential to understand the protein function and its involvement in diseases. The identification of the interactions is currently resolvable only through in vivo and in vitro experiments which may not detect all binding partners. Computational methods which capture the protein-dependent nature of the binding phenomena could help to predict, in silico, the binding and could be resistant against experimental biases.
This thesis addresses the creation of models based on support vector machines and trained on experimental data. The goal is the identification of RNAs which bind specifically to a regulatory protein. Starting from a case study, done with protein CELF1, we extend our approach and propose three methods to predict whether an RNA strand can be bound by a particular RNA-binding protein. The methods use support vector machines and different features based on the sequence (method Oli), the motif score (method OliMo) and the secondary structure (method OliMoSS). We apply them to different experimentally-derived datasets and compare the predictions with two methods: RNAcontext and RPISeq. Oli outperforms OliMoSS and RPISeq affirming our protein specific prediction and suggesting that oligo frequencies are good discriminative features. Oli and RNAcontext are the most competitive methods in terms of AUC. A Precision-Recall analysis reveals a better performance for Oli. On a second experimental dataset, where negative binding information is available, Oli outperforms RNAcontext with
a precision of 0.73 vs. 0.59. Our experiments show that features based on primary sequence information are highly discriminative to predict the binding between protein and RNA. Sequence motifs can improve the prediction only for some RNA-binding proteins. Finally, we can conclude that experimental data on RNA-binding can be effectively used to train protein-specific models for in silico predictions.
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Audano, M. "THE RNA BINDING PROTEIN ZC3H10 COUPLES MITOCHONDRIAL FUNCTION AND IRON METABOLISM". Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/481986.
Texto completoResumen
Mitochondria play a crucial role in energy metabolism. Mitochondria have their own genome (mtDNA), whose replication and transcription are mainly regulated by the mitochondrial transcription factor A (Tfam). Recent researches demonstrate how mitochondria participate to a large number of cellular processes like cell cycle and differentiation. Our goal is to identify new mitochondrial regulators to light up the molecular mechanisms underlying mitochondrial function biology.
We used a high throughput screening in 293 cells in order to identify positive mitochondrial regulators. By these means, we identified Zinc Finger CCCH-type containing 10 (Zc3h10) as the best hit. Following experiments demonstrated that Zc3h10 knockdown decreased mitochondrial function and differentiation in myotubes. RNA immunoprecipitation assay indicates that Zc3h10 is able to bind 410 transcripts. Several target genes are involved in energy metabolism and iron balance. Notably, Zc3h10 downregulation in C2C12 leads to iron overload while its overexpression restores ferric ion content to control levels.
Collectively, our findings annotate Zc3h10 as a new mitochondrial regulator in skeletal muscle.
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Yatherajam, Gayatri. "Regulation of transcription by factors interacting with the TATA binding protein". Access citation, abstract and download form; downloadable file 7.32 Mb, 2004. http://wwwlib.umi.com/dissertations/fullcit/3131704.
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Wang, Weizhong. "Nuclear galectins and their role in pre-mRNA splicing". Diss., Connect to online resource - MSU authorized users, 2006.
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Thesis (Ph. D.)--Michigan State University. Dept. of Microbiology and Molecular Genetics, 2006.Title from PDF t.p. (viewed on Nov. 20, 2008) Includes bibliographical references. Also issued in print.
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Whitman, Samantha. "Fragile X Related Protein-1 (FXR1) Regulates RNA Metabolism in Striated Muscle". Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/195153.
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Cardiac muscle function necessitates the meticulous assembly and interactions of several cytoskeletal and regulatory proteins into specialized structures that orchestrate contraction and transmission forces. Despite extensive studies identifying the protein components responsible for these important aspects of heart development, putative RNA based mechanisms remain poorly understood, even with their demonstrated importance in other tissues. Evidence suggests that post-transcriptional regulation is critical for muscle function, but the molecular players involved (RNA binding proteins and mRNA targets) have remained elusive. We investigated the molecular mechanisms and targets of the muscle-specific Fragile X Related protein-1 (FXR1), an RNA binding protein whose absence leads to perinatal lethality in mice. Loss of FXR1 results in global protein level alterations. Morphological and biochemical analyses of Fxr1^(-/-) mice revealed severe disruption of intercalated disc and costamere architecture and composition. We identified several candidate mRNAs specifically enriched in the FXR1 protein complex. Two targets that likely contribute to the architectural defects are desmoplakin (dsp) and talin2 (tln2). In vitro assays indicate that FXR1 binds to these mRNA targets directly and represses their translation. Additionally, we provide preliminary evidence that the Fxr1^(-/-) mice mimic a hypothyroid state of cardiac gene expression, with alterations in myosin heavy chain and troponin I isoforms. Our findings reveal the first mRNA targets of FXR1 in muscle and support translational repression as a novel mechanism for cardiac muscle development and function.
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James, Marion Clare. "The role of the La antigen and associated RNAs in the regulation of protein synthesis". Thesis, St George's, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243864.
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Tollervey, James Robert. "Understanding misregulation of alternative splicing in the human TDP-43 proteinopathies". Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609056.
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Sun, Xueguang. "Characterization of E. coli HFQ structure and its RNA binding properties". Available online, Georgia Institute of Technology, 2006, 2006. http://etd.gatech.edu/theses/available/etd-12052005-145342/.
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Thesis (Ph. D.)--Biology, Georgia Institute of Technology, 2006.Wartell Roger, Committee Chair ; Chernoff Yury, Committee Member ; Harvey Stephen, Committee Member ; Spiro Stephen, Committee Member ; Williams Loren, Committee Member.
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Behrmann, Jason. "Determining the role of the RNA-binding protein, RasGAP- SH3 domain-binding protein, in the mammalian cellular response to ultraviolet radiation". Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18459.
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The RasGAP—SH3-domain Binding Protein (G3BP1) is an endoribonuclease that links Ras-signalling pathways and mRNA stability. Though implicated in many cellular roles, a well defined function for G3BP1 has yet to be determined. The aim of the following dissertation is to further implicate G3BP1 in mammalian cellular responses to environmental stress, most notably that of Ultraviolet Radiation. We observe G3BP1 transverse from the cytoplasm to the nucleus upon treatment of HeLa cells with apoptotic levels of UVC. Interestingly, forcing its nuclear accumulation in the absence of stress is sufficient to induce apoptotic characteristics. Preliminary observations suggest that plasma membrane signalling and the resultant activation of stress activated protein kinases, JNK and p38 MAPK, and CASPases might play a role in this process. Thus, we further elaborate G3BP1's role in cellular responses to stress and suggest a new function for the protein, that being the promotion of apoptosis."RasGAP—SH3-domain Binding Protein (G3BP)" est un endoribonucléase qui associe la voie de signalisation de Ras et la stabilité d'ARN messager. On ne connaît pas une fonction bien défini pour cette protéine, même si c'est impliquée dans plusieurs rôles cellulaire. Le but de cette dissertation est d'appuyer l'implication du G3BP1 aux réponses cellulaire mammalien au stress environmental, particulièrement à la radiation ultraviolet. On observe le G3BP1 transverse du cytoplasm au noyau au traitement des cellules HeLa avec des doses UV apoptotique. La chose fascinante est quand on introduit s'accumulation du noyau en l'absence du stress est suffisant de provoquer les charactéristiques apoptotique. Les observations au premier degré suggèrent que les signalisations d'origine de membrane plasmique et l'activation resultant du JNK, p38 MAPK, et CASPases peuvent jouer un rôle en ce processus. Ainsi, on a élaboré le rôle du G3BP1 en réponse cellulaire au stress et suggère une nouvelle fonction pour la protéine : la promotion de l'apoptose.
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Bertossi, Arianna. "Role of the RNA-binding protein Roquin in immune homeostasis and autoimmunity". Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-137761.
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Blais-Crépeau, Marie-Laure. "The Double-stranded RNA-binding Protein Staufen1 Negatively Regulates Skeletal Muscle Differentiation". Thesis, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/19766.
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Staufen1 is a double-stranded RNA-binding protein known to be involved in the transport, localization, decay and increased translation of some mRNAs. The goal of the present study is to determine the role of Staufen1 during myogenic differentiation by characterizing the effects of Staufen1 over-expression in C2C12 cells. Immunofluorescence experiments revealed that Staufen1 over-expression causes a decrease in the fusion and differentiation indices and leads to the formation of myotubes with significantly fewer nuclei. We show, by western blot and qRT-PCR, that the protein expression of MyoD, myogenin and MyHC and the mRNA expression of MyoD, myogenin, Mef2A, Mef2C and p35 are significantly decreased during differentiation when Staufen1 is over-expressed. We then found that c-myc protein expression was increased during proliferation but that its mRNA expression remained unchanged. In this study we propose that Staufen1 negatively regulates skeletal muscle differentiation through the posttranscriptional regulation of c-myc, Mef2A, Mef2C and p35 transcripts.