Academic literature on the topic 'Protein-Arginine N-Methyltransferases'
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Journal articles on the topic "Protein-Arginine N-Methyltransferases"
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Yan, Dongsheng, Yong Zhang, Lifang Niu, Yi Yuan, and Xiaofeng Cao. "Identification and characterization of two closely related histone H4 arginine 3 methyltransferases in Arabidopsis thaliana." Biochemical Journal 408, no. 1 (October 29, 2007): 113–21. http://dx.doi.org/10.1042/bj20070786.
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Arginine methylation of histone H3 and H4 plays important roles in transcriptional regulation in eukaryotes such as yeasts, fruitflies, nematode worms, fish and mammals; however, less is known in plants. In the present paper, we report the identification and characterization of two Arabidopsis thaliana protein arginine N-methyltransferases, AtPRMT1a and AtPRMT1b, which exhibit high homology with human PRMT1. Both AtPRMT1a and AtPRMT1b methylated histone H4, H2A, and myelin basic protein in vitro. Site-directed mutagenesis of the third arginine (R3) on the N-terminus of histone H4 to lysine (H4R3N) completely abolished the methylation of histone H4. When fused to GFP (green fluorescent protein), both methyltransferases localized to the cytoplasm as well as to the nucleus. Consistent with their subcellular distribution, GST (glutathione transferase) pull-down assays revealed an interaction between the two methyltransferases, suggesting that both proteins may act together in a functional unit. In addition, we demonstrated that AtFib2 (Arabidopsis thaliana fibrillarin 2), an RNA methyltransferase, is a potential substrate for AtPRMT1a and AtPRMT1b, and, furthermore, uncovered a direct interaction between the protein methyltransferase and the RNA methyltransferase. Taken together, our findings implicate AtPRMT1a and AtPRMT1b as H4-R3 protein arginine N-methyltransferases in Arabidopsis and may be involved in diverse biological processes inside and outside the nucleus.
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Lakowski, Ted M., Peter ’t Hart, Christopher A. Ahern, Nathaniel I. Martin, and Adam Frankel. "Nη-Substituted Arginyl Peptide Inhibitors of Protein Arginine N-Methyltransferases." ACS Chemical Biology 5, no. 11 (August 26, 2010): 1053–63. http://dx.doi.org/10.1021/cb100161u.
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Lakowski, Ted M., Cecilia Zurita-Lopez, Steven G. Clarke, and Adam Frankel. "Approaches to measuring the activities of protein arginine N-methyltransferases." Analytical Biochemistry 397, no. 1 (February 2010): 1–11. http://dx.doi.org/10.1016/j.ab.2009.09.021.
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Murakami, Hironobu, Takehiro Suzuki, Kiyoto Tsuchiya, Hiroyuki Gatanaga, Manabu Taura, Eriko Kudo, Seiji Okada, et al. "Protein Arginine N-methyltransferases 5 and 7 Promote HIV-1 Production." Viruses 12, no. 3 (March 23, 2020): 355. http://dx.doi.org/10.3390/v12030355.
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Current therapies for human immunodeficiency virus type 1 (HIV-1) do not completely eliminate viral reservoirs in cells, such as macrophages. The HIV-1 accessory protein viral protein R (Vpr) promotes virus production in macrophages, and the maintenance of Vpr is essential for HIV-1 replication in these reservoir cells. We identified two novel Vpr-binding proteins, i.e., protein arginine N-methyltransferases (PRMTs) 5 and 7, using human monocyte-derived macrophages (MDMs). Both proteins found to be important for prevention of Vpr degradation by the proteasome; in the context of PRMT5 and PRMT7 knockdowns, degradation of Vpr could be prevented using a proteasome inhibitor. In MDMs infected with a wild-type strain, knockdown of PRMT5/PRMT7 and low expression of PRMT5 resulted in inefficient virus production like Vpr-deficient strain infections. Thus, our findings suggest that PRMT5 and PRMT7 support HIV-1 replication via maintenance of Vpr protein stability.
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't Hart, Peter, Ted M. Lakowski, Dylan Thomas, Adam Frankel, and Nathaniel I. Martin. "Peptidic Partial Bisubstrates as Inhibitors of the Protein Arginine N-Methyltransferases." ChemBioChem 12, no. 9 (May 10, 2011): 1427–32. http://dx.doi.org/10.1002/cbic.201100074.
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Rawal, Nenoo, Ramesh Rajpurohit, Michael A. Lischwe, Kenneth R. Williams, Woon Ki Paik, and Sangduk Kim. "Structural specificity of substrate for S-adenosylmethionine protein arginine N-methyltransferases." Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1248, no. 1 (April 1995): 11–18. http://dx.doi.org/10.1016/0167-4838(94)00213-z.
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Dacwag, Caroline S., Mark T. Bedford, Saïd Sif, and Anthony N. Imbalzano. "Distinct Protein Arginine Methyltransferases Promote ATP-Dependent Chromatin Remodeling Function at Different Stages of Skeletal Muscle Differentiation." Molecular and Cellular Biology 29, no. 7 (February 2, 2009): 1909–21. http://dx.doi.org/10.1128/mcb.00742-08.
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ABSTRACT Temporal regulation of gene expression is a hallmark of cellular differentiation pathways, yet the mechanisms controlling the timing of expression for different classes of differentiation-specific genes are not well understood. We previously demonstrated that the class II arginine methyltransferase Prmt5 was required for skeletal muscle differentiation at the early stages of myogenesis (C. S. Dacwag, Y. Ohkawa, S. Pal, S. Sif, and A. N. Imbalzano, Mol. Cell. Biol. 27:384-394, 2007). Specifically, when Prmt5 levels were reduced, the ATP-dependent SWI/SNF chromatin-remodeling enzymes could not interact with or remodel the promoter of myogenin, an essential early gene. Here we investigated the requirement for Prmt5 and the class I arginine methyltransferase Carm1/Prmt4 in the temporal control of myogenesis. Both arginine methyltransferases could bind to and modify histones at late-gene regulatory sequences. However, the two enzymes showed sequential requirements for gene expression. Prmt5 was required for early-gene expression but dispensable for late-gene expression. Carm1/Prmt4 was required for late- but not for early-gene expression. The reason for the requirement for Carm1/Prmt4 at late genes was to facilitate SWI/SNF chromatin-remodeling enzyme interaction and remodeling at late-gene loci. Thus, distinct arginine methyltransferases are employed at different times of skeletal muscle differentiation for the purpose of facilitating ATP-dependent chromatin-remodeling enzyme interaction and function at myogenic genes.
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SWIERCZ, Rafal, Maria D. PERSON, and Mark T. BEDFORD. "Ribosomal protein S2 is a substrate for mammalian PRMT3 (protein arginine methyltransferase 3)." Biochemical Journal 386, no. 1 (February 8, 2005): 85–91. http://dx.doi.org/10.1042/bj20041466.
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PRMT3 (protein arginine methyltransferase 3) is one of four type I arginine methyltransferases that catalyse the formation of asymmetric dimethylarginine. PRMT3 is unique in that its N-terminus harbours a C2H2 zinc-finger domain that is proposed to confer substrate specificity. In addition, PRMT3 is the only type I enzyme that is restricted to the cytoplasm. Known in vitro substrates for PRMT3 include GST–GAR (a glutathione S-transferase fusion protein containing the glycine- and arginine-rich N-terminal region of fibrillarin), Sam68 (Src-associated substrate during mitosis 68 kDa) and PABP-N1 [poly(A)-binding protein-N1; PABP2]. Here we report the identification of an in vivo substrate for mammalian PRMT3. We found that FLAG-tagged PRMT3 can ‘pull down’ a protein with a molecular mass of 30 kDa from HeLa cell extracts. MS identified this PRMT3-interacting protein as rpS2 (ribosomal protein S2). In vitro studies showed that the zinc-finger domain of PRMT3 is necessary and sufficient for binding to rpS2. In addition, rpS2 is methylated by PRMT3 in vitro and is also methylated in cell lines. Deletion analysis of the rpS2 amino acid sequence identified a N-terminal Arg-Gly repeat as the methylation site. Furthermore, both PRMT3 and rpS2 co-sediment with free ribosomal subunits. These studies implicate PRMT3 in ribosomal function and in the regulation of protein synthesis.
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Vhuiyan, Mynol, Dylan Thomas, Farhad Hossen, and Adam Frankel. "Targeting protein arginine N-methyltransferases with peptide-based inhibitors: opportunities and challenges." Future Medicinal Chemistry 5, no. 18 (December 2013): 2199–206. http://dx.doi.org/10.4155/fmc.13.184.
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Debler, Erik W., Kanishk Jain, Rebeccah A. Warmack, You Feng, Steven G. Clarke, Günter Blobel, and Pete Stavropoulos. "A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase." Proceedings of the National Academy of Sciences 113, no. 8 (February 8, 2016): 2068–73. http://dx.doi.org/10.1073/pnas.1525783113.
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Trypanosoma brucei PRMT7 (TbPRMT7) is a protein arginine methyltransferase (PRMT) that strictly monomethylates various substrates, thus classifying it as a type III PRMT. However, the molecular basis of its unique product specificity has remained elusive. Here, we present the structure of TbPRMT7 in complex with its cofactor product S-adenosyl-l-homocysteine (AdoHcy) at 2.8 Å resolution and identify a glutamate residue critical for its monomethylation behavior. TbPRMT7 comprises the conserved methyltransferase and β-barrel domains, an N-terminal extension, and a dimerization arm. The active site at the interface of the N-terminal extension, methyltransferase, and β-barrel domains is stabilized by the dimerization arm of the neighboring protomer, providing a structural basis for dimerization as a prerequisite for catalytic activity. Mutagenesis of active-site residues highlights the importance of Glu181, the second of the two invariant glutamate residues of the double E loop that coordinate the target arginine in substrate peptides/proteins and that increase its nucleophilicity. Strikingly, mutation of Glu181 to aspartate converts TbPRMT7 into a type I PRMT, producing asymmetric dimethylarginine (ADMA). Isothermal titration calorimetry (ITC) using a histone H4 peptide showed that the Glu181Asp mutant has markedly increased affinity for monomethylated peptide with respect to the WT, suggesting that the enlarged active site can favorably accommodate monomethylated peptide and provide sufficient space for ADMA formation. In conclusion, these findings yield valuable insights into the product specificity and the catalytic mechanism of protein arginine methyltransferases and have important implications for the rational (re)design of PRMTs.
Dissertations / Theses on the topic "Protein-Arginine N-Methyltransferases"
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Anthony, Shelagh. "Analysis of mammalian protein arginine N-methyltransferases in the vasculature." Thesis, University College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424909.
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Thomas, Dylan. "Oligomerization dependent enzyme kinetics and mechanistic characterization of type I protein arginine N-methyltransferases." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44623.
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Hu, Yu-Jie. "Roles of Protein Arginine Methyltransferase 7 and Jumonji Domain-Containing Protein 6 in Adipocyte Differentiation: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/797.
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Regulation of gene expression comprises a wide range of mechanisms that control the abundance of gene products in response to environmental and developmental changes. These biological processes can be modulated by posttranslational modifications including arginine methylation. Among the enzymes that catalyze the methylation, protein arginine methyltransferase 7 (PRMT7) is known to modify histones to repress gene expression. Jumonji domain-containing protein 6 (JMJD6) is a putative arginine demethylase that potentially antagonize PRMT7. However, the biological significance of these enzymes is not well understood. This thesis summarizes the investigation of both PRMT7 and JMJD6 in cell culture models for adipocyte differentiation. The results suggest that PRMT7 is not required for the differentiation, whereas JMJD6 is necessary for the differentiation by promoting the expression of the lineage determining transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancerbinding proteins (C/EBPs). The underlying mechanisms by which JMJD6 regulate differentiation involve transcriptional and post-transcriptional control of gene expression. Unexpectedly, the adipogenic function of JMJD6 is independent of its enzymatic activity. Collectively, the present research reveals a novel role of JMJD6 in gene regulation during the differentiation of adipocytes.
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Hu, Yu-Jie. "Roles of Protein Arginine Methyltransferase 7 and Jumonji Domain-Containing Protein 6 in Adipocyte Differentiation: A Dissertation." eScholarship@UMMS, 2010. http://escholarship.umassmed.edu/gsbs_diss/797.
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Regulation of gene expression comprises a wide range of mechanisms that control the abundance of gene products in response to environmental and developmental changes. These biological processes can be modulated by posttranslational modifications including arginine methylation. Among the enzymes that catalyze the methylation, protein arginine methyltransferase 7 (PRMT7) is known to modify histones to repress gene expression. Jumonji domain-containing protein 6 (JMJD6) is a putative arginine demethylase that potentially antagonize PRMT7. However, the biological significance of these enzymes is not well understood. This thesis summarizes the investigation of both PRMT7 and JMJD6 in cell culture models for adipocyte differentiation. The results suggest that PRMT7 is not required for the differentiation, whereas JMJD6 is necessary for the differentiation by promoting the expression of the lineage determining transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancerbinding proteins (C/EBPs). The underlying mechanisms by which JMJD6 regulate differentiation involve transcriptional and post-transcriptional control of gene expression. Unexpectedly, the adipogenic function of JMJD6 is independent of its enzymatic activity. Collectively, the present research reveals a novel role of JMJD6 in gene regulation during the differentiation of adipocytes.
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Suh-Lailam, Brenda Bienka. "Development of Novel Methods and their Utilization in the Analysis of the Effect of the N-terminus of Human Protein Arginine Methyltransferase 1 Variant 1 on Enzymatic Activity, Protein-protein Interactions, and Substrate Specificity." DigitalCommons@USU, 2010. https://digitalcommons.usu.edu/etd/863.
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Protein arginine methyltransferases (PRMTs) are enzymes that catalyze the methylation of protein arginine residues, resulting in the formation of monomethylarginine, and/or asymmetric or symmetric dimethylarginines. Although understanding of the PRMTs has grown rapidly over the last few years, several challenges still remain in the PRMT field. Here, we describe the development of two techniques that will be very useful in investigating PRMT regulation, small molecule inhibition, oligomerization, protein-protein interaction, and substrate specificity, which will ultimately lead to the advancement of the PRMT field. Studies have shown that having an N-terminal tag can influence enzyme activity and substrate specificity. The first protocol tackles this problem by developing a way to obtain active untagged recombinant PRMT proteins. The second protocol describes a fast and efficient method for quantitative measurement of AdoMet-dependent methyltranseferase activity with protein substrates. In addition to being very sensitive, this method decreases the processing time for the analysis of PRMT activity to a few minutes compared to weeks by traditional methods, and generates 3000-fold less radioactive waste. We then used these methods to investigate the effect of truncating the NT of human PRMT1 variant 1 (hPRMT1-V1) on enzyme activity, protein-protein interactions, and substrate specificity. Our studies show that the NT of hPRMT1-V1 influences enzymatic activity and protein-protein interactions. In particular, methylation of a variety of protein substrates was more efficient when the first 10 amino acids of hPRMT1v1 were removed, suggesting an autoinhibitory role for this small section of the N-terminus. Likewise, as portions of the NT were removed, the altered hPRMT1v1 constructs were able to interact with more proteins. Overall, my studies suggest the the sequence and length of the NT of hPRMT1v1 is capable of enforcing specific protein interactions.
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Zamiri, Maryam. "Synthesis of protein arginine N-methyltransferase 6 inhibitors." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43808.
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Protein arginine N-methyltransferases (PRMTs) are pertinent targets for drug discovery as their dysfunction is associated with a number of diseases such as cancers, cardiovascular diseases and viral pathogenesis. The precise role of PRMTs in the initiation, development, or progression of diseases is not known yet.
Due to association of PRMT1 and 4 with transcriptional activation, the main focus of inhibitor discovery has been on these two enzymes. On the other hand, the goal of this study is to find a PRMT6 specific inhibitor. PRMT6 methylates DNA polymerase β, histones H3 and H4 and HIV proteins: Rev and Tat.
PRMT6 uses S-adenosyl-L-methionine (AdoMet) as the “methyl group” source. AdoMet fits into a distinct conserved binding site in the enzyme, which is located adjacent to the protein substrate/catalytic site such that its S⁺-Me motif is correctly positioned with respect to the substrate arginine nitrogen atom that undergoes methylation.
Based on crystallography data for PRMT1, the purine C8 center in AdoMet is in close proximity to the methionine sulfur atom (M166 in PRMT6). As shown by Frankel et al. (Faculty of Pharmaceutical Sciences, UBC), the M166C PRMT6 mutant displays activity. Based upon this observation, we hypothesize that Ado-Met analogues with reactive substituents (e.g., CHO) at C8 position of adenine ring will form a covalent bond with the proximal Cys SH group in M166C PRMT6. This validates our further hypothesize that in appropriately designed analogues, it will be possible to subsequently detach the sugar and amino acid components of Ado-Met to leave the adenine ring component alone bound to the enzyme. This provides a unique opportunity to explore the “fragment based approach in drug discovery” to design PRMT6 specific inhibitors.
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Pak, Laam. "Insights into a heteromeric protein arginine N-methyltransferase complex." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42123.
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Protein arginine N-methyltransferases (PRMTs) act in signaling pathways and gene
expression by methylating arginine residues within target proteins. PRMT1 is responsible for
most cellular arginine methylation activity and can work independently or in collaboration with
other PRMTs. In this Ph.D. thesis I demonstrated an interaction between PRMT1 and -2 using
co-immunoprecipitation and bimolecular fluorescence complementation (BiFC). As a result of
this interaction, PRMT2 stimulated PRMT1 methyltransferase activity, affecting its apparent
Vmax and Km values in vitro, and increasing the production of methylarginines in cells. Active
site mutations and regional deletions on PRMT1 and -2 were also investigated, which
demonstrated that complex formation required full-length, active PRMT1. However, the
interaction between PRMT1 and -2 proved insensitive to methylation inhibition in the absence of
the PRMT2 Src homology 3 (SH3) domain, which suggests that the PRMT2 SH3 domain may
mediate this interaction between PRMT1 and -2 in a methylation-dependent fashion.
The role of the PRMT2 SH3 domain was investigated through screening for its associated
proteins using GST-pull down assays followed by LC-MS/MS proteomic analysis. The result of
this study revealed associations of the PRMT2 SH3 domain with at least 29 splicing-related
proteins, suggesting a potential role of PRMT2 in regulating pre-mRNA processing and splicing.
The interaction between PRMT2 and the Src substrate associated in mitosis of 68 kDa (Sam68)
possibly through the PRMT2 SH3 domain was demonstrated using co-immunoprecipitation.
Additionally, immunofluorescence results present herein imply that the PRMT2 SH3 domain
could affect Sam68 sub-cellular localization in hypomethylated HeLa cells. The biological functions of PRMT2 and the PRMT1/2 heteromeric complex were explored
by pursuing the identity of associated proteins common to both PRMT1 and -2 using mass
spectrometry proteomics. Approximately 50% of the identified protein hits have reported roles
in controlling gene expression, while other hits are involved in diverse cellular processes such as
protein folding, degradation, and metabolism. Importantly, three novel PRMT2 binders, p53,
promyelocytic leukemia protein (PML), and extra eleven nineteen (EEN) were uncovered,
suggesting that PRMT2 could participate in regulation of transcription and apoptosis through
PRMT2-protein interactions.
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Marechal, Nils. "Étude structurale des protéine arginine méthyltransférases : reconnaissance des substrats et conception rationnelle de modulateurs." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ048.
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Les protéine arginine méthyltransférases (PRMT) sont impliquées dans de nombreux processus cellulaires, incluant la régulation de l’expression des gènes, le contrôle de l’épissage, le maintien de l’intégrité du génome et la transduction du signal. De nombreuses études montrent que la dérégulation de l’activité des PRMT est associée au développement de pathologies, et en particulier de cancers. Les PRMT constituent ainsi une des nouvelles cibles potentielles en chimiothérapie. Les travaux présentés dans ce manuscrit portent sur trois cibles : PRMT2, PRMT3 et PRMT4/CARM1. Combinant des approches biochimiques, biophysiques et structurales (cristallographie et cryo- microscopie électronique), ces travaux comportent deux aspects : (I) comprendre au niveau atomique la régulation de la réaction de méthylation des protéines (reconnaissance protéines-protéines et interactions entre modifications post-traductionnelles) ; (II) découvrir des inhibiteurs spécifiques et puissants de plusieurs PRMT ciblesProtein arginine methyltransferases (PRMT) are involved in many cellular processes, including gene expression regulation, splicing control, maintenance of genome integrity and signal transduction.Since deregulation of those biological processes appears to be implicated in the pathogenesis of different diseases, PRMTs have emerged as potential new targets for the development of novel therapeutic modulators. Despite the large amount of biological and structural data on PRMTs, two challenges remain to be solved by structural biology ; (I) understanding how PRMTs recognize and bind their full-length substrates ; (II) revealing how PRMTs achieve specific arginine methylation on different target sites. The works presented here focused on 3 targets: PRMT2, PRMT3 and PRMT4/ CARM1. We used biochemical, biophysical and structural methods (bio-crystallography and cryo- electron microscopy) to decipher structural clues that drive PRMT-substrate recognition. We developed new chemical probes that can be used in early drug discovery for the conception of PRMT inhibitors
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Dacwag, Caroline S. "Analysis of Protein Arginine Methyltransferase Function during Myogenic Gene Transcription: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/402.
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Skeletal muscle differentiation requires synergy between tissue-specific transcription factors, chromatin remodeling enzymes and the general transcription machinery. Here we demonstrate that two distinct protein arginine methyltransferases are required to complete the differentiation program. Prmt5 is a type II methyltransferase, symmetrically dimethylates histones H3 and H4 and has been shown to play a role in transcriptional repression. An additional member of the Prmt family, Carm1 is a type I methyltransferase, and asymmetrically methylates histone H3 and its substrate proteins. MyoD regulates the activation of the early class of skeletal muscle genes, which includes myogenin. Prmt5 was bound to and dimethylates H3R8 at the myogenin promoter in a differentiation-dependent fashion. When proteins levels of Prmt5 were reduced by antisense, disappearance of H3R8 dimethylation and Prmt5 binding was observed. Furthermore, binding of Brg1 to regulatory sequences of the myogenin promoter was abolished. All subsequent events relying on Brg1 function, such as chromatin remodeling and stable binding by muscle specific transcription factors such as MyoD, were eliminated. Robust association of Prmt5 and dimethylation of H3R8 at myogenin promoter sequences was observed in mouse satellite cells, the precursors of mature myofibers. Prmt5 binding and histone modification were observed to a lesser degree in mature myofibers. Therefore, these results indicate that Prmt5 is required for dimethylating histone at the myogenin locus during skeletal muscle differentiation in order to facilitate the binding of Brg1, the ATPase subunit of the chromatin remodeling complex SWI/SNF.
Further exploration of the role of Prmt5 during the activation of the late class of muscle genes revealed that though Prmt5 is associated with and dimethylates histones at the regulatory elements of late muscle genes in tissue and in culture, it was dispensable for late gene activation. Previous reports had indicated that Carm1 was involved during late gene activation. We observed that Carm1 was bound to and responsible for dimethylating histones at late muscle gene promoters in tissue and in culture. In contrast to Prmt5, a complete knockout of Carm1 resulted in abrogation of late muscle gene activation. Furthermore, loss of Carm1 binding and dimethylated histones resulted in a disappearance of Brg1 binding and chromatin remodeling at late muscle gene loci. Time course chromatin immunoprecipitations revealed that Carm1 binding and histone dimethylation occurred concurrently with the onset of late gene activation. In vitro binding assays revealed that an interaction between Carm1, myogenin and Mef2D exists. These results demonstrate that Carm1 is recruited to the regulatory sequences of late muscle genes via its interaction with either myogenin or Mef2D and is responsible for dimethylates histones in order to facilitate the binding of Brg1. Therefore, these results indicate that during skeletal muscle differentiation, distinct roles exist for these Prmts such that Prmt5 is required for activation of early genes while Carm1 is essential for late gene induction.
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Chénard, Carol Anne. "Ribonucleoprotein complexes and protein arginine methylation : a role in diseases of the central nervous sytem." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115894.
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For the past 45 years, QKI has been studied for its role in the processes of development and central nervous system myelination using the qkv mouse. The presence of a single KH domain and the recent identification of a high-affinity binding site in mRNAs, suggests that it can bind to and regulate mRNAs through processes such as stability, splicing and transport. As a member of the STAR RNA binding family of proteins the QKI isoforms may also be involved in cell signaling pathways.QKI's involvement in all of these processes, lead us to examine both the protein partners and the mRNA targets of the QKI complex in order to identify potentially new pathways regulated by QKI. In doing so, we identified a novel direct protein-protein interaction with PABP and for the first time described the relocalization of QKI to cytoplasmic granules following oxidative stress. In addition, in vivo mRNA interaction studies were performed and allowed the identification of approximately 100 new mRNA targets in human glioblastoma cells. One of the targets identified was VEGF mRNA.
Another QKI target mRNA is MBP, a major protein component of the myelin sheath and the candidate auto-antigen in multiple sclerosis (MS). In vivo MBP is symmetrically dimethylated on a single arginine residue. To further establish the role of the methylation of MBP in myelination, a methyl-specific antibody and an adenovirus expressing a recombinant protein arginine methyltransferase 5 (PRMT5) was generated. We show that methylated MBP is found in areas of mature myelin and that overexpression of the PRTM5 blocked the differentiation of oligodendrocytes.
Taken together these datas implicate QKI for the first time in the process of human cancer angiogenesis and could explain the vascularization defects observed in some of the qkI mutant mice. In addition, arginine methylation of MBP may prove to have an important role in the process of myelination and in the pathogenesis of demyelination and the autoimmune reaction in diseases such as MS.
Book chapters on the topic "Protein-Arginine N-Methyltransferases"
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Schomburg, Dietmar, and Dörte Stephan. "Protein-arginine N-methyltransferase." In Enzyme Handbook 11, 101–5. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-61030-1_23.
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