Protein Arginine Methyltransferase Expression Affects Ectomycorrhizal Symbiosis and the Regulation of Hormone Signaling Pathways

The genomes of all eukaryotic organisms, from small unicellular yeasts to humans, include members of the protein arginine methyltransferase (PRMT) family. These enzymes affect gene transcription, cellular signaling, and function through the posttranslational methylation of arginine residues. Mis-regulation of PRMTs results in serious developmental defects, disease, or death, illustrating the importance of these enzymes to cellular processes. Plant genomes encode almost the full complement of PRMTs found in other higher organisms, plus an additional PRMT found uniquely in plants, PRMT10. Here, we investigate the role of these highly conserved PRMTs in a process that is unique to perennial plants—the development of symbiosis with ectomycorrhizal fungi. We show that PRMT expression and arginine methylation is altered in the roots of the model tree Eucalyptus grandis by the presence of its ectomycorrhizal fungal symbiont Pisolithus albus. Further, using transgenic modifications, we demonstrate that E. grandis–encoded PRMT1 and PRMT10 have important but opposing effects in promoting this symbiosis. In particular, the plant-specific EgPRMT10 has a potential role in the expression of plant hormone pathways during the colonization process and its overexpression reduces fungal colonization success.

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Structure, Activity and Function of the Protein Arginine Methyltransferase 6

Life ◽

10.3390/life11090951 ◽

2021 ◽

Vol 11 (9) ◽

pp. 951

Author(s):

Somlee Gupta ◽

Rajashekar Varma Kadumuri ◽

Anjali Kumari Singh ◽

Sreenivas Chavali ◽

Arunkumar Dhayalan

Keyword(s):

Viral Infections ◽

Global Gene Expression ◽

Structural Features ◽

Arginine Methylation ◽

Type I ◽

Protein Arginine Methyltransferase ◽

Arginine Methyltransferase ◽

Wide Range ◽

Arginine Residues ◽

And Function

Members of the protein arginine methyltransferase (PRMT) family methylate the arginine residue(s) of several proteins and regulate a broad spectrum of cellular functions. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that asymmetrically dimethylates the arginine residues of numerous substrate proteins. PRMT6 introduces asymmetric dimethylation modification in the histone 3 at arginine 2 (H3R2me2a) and facilitates epigenetic regulation of global gene expression. In addition to histones, PRMT6 methylates a wide range of cellular proteins and regulates their functions. Here, we discuss (i) the biochemical aspects of enzyme kinetics, (ii) the structural features of PRMT6 and (iii) the diverse functional outcomes of PRMT6 mediated arginine methylation. Finally, we highlight how dysregulation of PRMT6 is implicated in various types of cancers and response to viral infections.

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Structure, Activity and Function of the PRMT2 Protein Arginine Methyltransferase

Life ◽

10.3390/life11111263 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1263

Author(s):

Vincent Cura ◽

Jean Cavarelli

Keyword(s):

Hormone Receptors ◽

Arginine Methylation ◽

Type I ◽

Cellular Functions ◽

Protein Arginine Methyltransferase ◽

Arginine Methyltransferase ◽

Cellular Processes ◽

Src Homology ◽

And Function

PRMT2 belongs to the protein arginine methyltransferase (PRMT) family, which catalyzes the arginine methylation of target proteins. As a type I enzyme, PRMT2 produces asymmetric dimethyl arginine and has been shown to have weak methyltransferase activity on histone substrates in vitro, suggesting that its authentic substrates have not yet been found. PRMT2 contains the canonical PRMT methylation core and a unique Src homology 3 domain. Studies have demonstrated its clear implication in many different cellular processes. PRMT2 acts as a coactivator of several nuclear hormone receptors and is known to interact with a multitude of splicing-related proteins. Furthermore, PRMT2 is aberrantly expressed in several cancer types, including breast cancer and glioblastoma. These reports highlight the crucial role played by PRMT2 and the need for a better characterization of its activity and cellular functions.

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The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms20153840 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3840 ◽

Cited By ~ 2

Author(s):

Sun ◽

Wang ◽

Yang ◽

Zhu ◽

Wu ◽

...

Keyword(s):

Binding Free Energy ◽

Arginine Methylation ◽

Free Energy Calculations ◽

Protein Arginine Methyltransferase ◽

Dynamic Simulations ◽

Arginine Methyltransferase ◽

Diverse Range ◽

Protein Arginine Methyltransferase 1 ◽

Canonical Wnt ◽

Tetrazole Derivatives

Protein arginine methyltransferase 1 (PRMT1) can catalyze protein arginine methylation by transferring the methyl group from S-adenosyl-L-methionine (SAM) to the guanidyl nitrogen atom of protein arginine, which influences a variety of biological processes. The dysregulation of PRMT1 is involved in a diverse range of diseases, including cancer. Therefore, there is an urgent need to develop novel and potent PRMT1 inhibitors. In the current manuscript, a series of 1-substituted 1H-tetrazole derivatives were designed and synthesized by targeting at the substrate arginine-binding site on PRMT1, and five compounds demonstrated significant inhibitory effects against PRMT1. The most potent PRMT1 inhibitor, compound 9a, displayed non-competitive pattern with respect to either SAM or substrate arginine, and showed the strong selectivity to PRMT1 compared to PRMT5, which belongs to the type II PRMT family. It was observed that the compound 9a inhibited the functions of PRMT1 and relative factors within this pathway, and down-regulated the canonical Wnt/β-catenin signaling pathway. The binding of compound 9a to PRMT1 was carefully analyzed by using molecular dynamic simulations and binding free energy calculations. These studies demonstrate that 9a was a potent PRMT1 inhibitor, which could be used as lead compound for further drug discovery.

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Lead induces the up-regulation of the protein arginine methyltransferase 5 possibly by its promoter demethylation

Biochemical Journal ◽

10.1042/bcj20180009 ◽

2018 ◽

Vol 475 (16) ◽

pp. 2653-2666 ◽

Cited By ~ 4

Author(s):

Krishna Ghosh ◽

Biji Chatterjee ◽

Santosh R. Kanade

Keyword(s):

Cpg Island ◽

Proximal Region ◽

Dependent Manner ◽

Protein Arginine Methyltransferase ◽

Arginine Methyltransferase ◽

Arginine Residues ◽

Pb Exposure ◽

Mcf 7 ◽

Protein Arginine Methyltransferase 5

The studies on lead (Pb) exposure linking to epigenetic modulations are caused by its differential actions on global DNA methylation and histone modifications. These epigenetic changes may result in increased accessibility of the transcription factors to promoter DNA-binding elements leading to activation and expression of the gene. The protein arginine methyltransferase 5 (PRMT5) and its partner methylosome protein 50 (MEP50) together catalyze the mono- and symmetric dimethylation of arginine residues in many histone and non-histone protein substrates. Moreover, it is overexpressed in many forms of cancer. In the present study, the effects of Pb on the PRMT5 and MEP50 expression and formation of the symmetrically dimethylated arginine (SDMA), the catalytic product of the PRMT5–MEP50 complex were analyzed in vitro after exposing the A549 and MCF-7 cells. The results show that exposure to 0.1 and 1 µM of Pb strongly enhanced the expression of both PRMT5 and MEP50 transcript and protein leading to increased SDMA levels globally with H4R3 being increasingly symmetrically dimethylated in a dose-dependent manner after 48 h of Pb exposure in both cell types. The methylation-specific PCR also revealed that the CpG island present on the PRMT5 promoter proximal region was increasingly demethylated as the dose of Pb increased in a 48-h exposure window in both cells, with MCF-7 being more responsive to Pb-mediated PRMT5 promoter demethylation. The bisulfite sequencing confirmed this effect. The findings therefore indicate that Pb exposure increasing the PRMT5 expression might be one of the contributing epigenetic factors in the lead-mediated disease processes as PRMT5 has a versatile role in cellular functions and oncogenesis.

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FBXO11/PRMT9, a new protein arginine methyltransferase, symmetrically dimethylates arginine residues

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2006.01.167 ◽

2006 ◽

Vol 342 (2) ◽

pp. 472-481 ◽

Cited By ~ 92

Author(s):

Jeffry R. Cook ◽

Jin-Hyung Lee ◽

Zhi-Hong Yang ◽

Christopher D. Krause ◽

Nicole Herth ◽

...

Keyword(s):

Protein Arginine Methyltransferase ◽

Arginine Methyltransferase ◽

Arginine Residues ◽

New Protein

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Downregulation of Protein Arginine Methyltransferase – 4 (PRMT4) Promotes MiR-223 Expression and Myeloid Differentiation.

Blood ◽

10.1182/blood.v116.21.3632.3632 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3632-3632

Author(s):

Ly P Vu ◽

Xinyang Zhao ◽

Fabiana Perna ◽

Stephen D Nimer

Keyword(s):

Transcription Factors ◽

Binding Site ◽

Rna Binding ◽

Myeloid Differentiation ◽

Type I ◽

Protein Arginine Methyltransferase ◽

Arginine Methyltransferase ◽

Cd34 Cells ◽

Wide Range ◽

Arginine Residues

Abstract Abstract 3632 Protein arginine methyltransferase 4 is a Type I member of PRMT family, that catalyses the addition of a methyl-group to arginine residues of a wide range of proteins, including histones, transcription factors, and RNA binding proteins. PRMT4 has been shown to regulate gene expression through its interaction with various transcription factors and via methylation of numerous substrates. Although PRMT4 has been reported to play an important role in T cell development, lung development and adipocyte differentiation in mouse models, the function of PRMT4 during hematopoiesis has not been studied. To investigate the function of PRMT4 in the hematopoietic system, we utilized human CD34+ haematopoietic stem/progenitor cells (HSPCs). We observed that PRMT4 protein level is markedly downregulated during the myeloid differentiation of CD34+ cells without a significant change in the mRNA level. We then utilized a loss of function approach, using short hairpin RNAs, and found that knockdown of PRMT4 leads to an acceleration of myeloid differentiation, with a concomitant loss of the clonogenic potential of the cells. Interestingly, knocking down PRMT4 results in upregulation of miR-223, a myeloid specific microRNA. We also found that, during the myeloid differentiation of CD34+ cells, miR-223 expression steadily increased. Using a microRNA target prediction program, we identified a binding site for miR-223 in the 3′-UTR region of PRMT4 and found that when we over-expressed miR-223 in CD34+ cells, PRMT4 protein expression decreased. To determine the importance of PRMT4 downregulation in myeloid differentiation, we expressed the PRMT4-ORF (that should not be regulated by microRNAs) in CD34+ cells. The forced expression of PRMT4, that lacks the 3′-UTR region, leads to a block in myeloid differentiation and the inability of cells to up-regulate miR-223 during differentiation. Taken together, these data indicate a regulatory loop between PRMT4 and miR-223 that controls the differentiation of CD34+ toward the myeloid lineage. To examine how PRMT4 regulates transcription of miR-223, we examined the miR-223 locus and found a RUNX1 binding site in the promoter of pri-miR-223. We discovered that PRMT4 interacts with RUNX1 and methylates RUNX1 at a specific arginine residue. This results in the recruitment of several novel interacting partners, which appear to control the expression of miR-223. Thus our results indicate that PRMT4 regulate the transcription of miR-223 transcription via its effects on RUNX1. Our study demonstrates a novel function of PRMT4 in myeloid differentiation, through regulation of RUNX1 function and miR-223 expression. Disclosures: No relevant conflicts of interest to declare.

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