Symmetric arginine dimethylation is selectively required for mRNA splicing and the initiation of type I and type III interferon signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA594283 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10611205_1.fastq.gz | Fastqsanger.gz | |||
| SRR10611205_2.fastq.gz | Fastqsanger.gz | |||
| SRR10611206_1.fastq.gz | Fastqsanger.gz | |||
| SRR10611206_2.fastq.gz | Fastqsanger.gz | |||
| SRR10611207_1.fastq.gz | Fastqsanger.gz |
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Project description:The goal of this study was to assess the extent of symmetric arginine dimethylation-dependent splicing and its associated signaling outcomes by using human T lymphocyte activation as a model system with a high rate of de novo transcription. Naïve human T lymphocytes were activated and treated with a selective inhibitor of PRMT5, PF-06829927, and investigated for changes in gene expression, alternative splicing, and chromatin accessibility.
2020-02-11 | GSE141645 | GEO
Project description:Post-translational arginine methylation is responsible for regulation of a variety of biological processes. The protein arginine methyltransferase 5 (PRMT5) is the major enzyme responsible for generating monomethyl- and symmetric dimethyl arginine (MMA and SDMA, respectively) in proteins. PRMT5 is essential for viability and normal development, and overexpressed in a wide variety of cancer types. In the present study, we found that the levels of PRMT5 and symmetric dimethylation in proteins from colorectal cancer (CRC) tissues are more highly maintained relative to adjacent normal tissues from patients. Using immunoaffinity enrichment of methylated peptides combined with high resolution mass spectrometry, a total of 147 SDMA sites from 94 proteins were identified. Most abundant methylated proteins identified from normal and CRC tissues are RNA processing proteins, transcriptional and translational regulators. Furthermore, when quantitative analysis of the two tissue types of samples was carried out, 77 SDMA sites exhibited statistically significant changes (>2.0-fold, p-value <0.05) between normal and CRC tissues. We confirmed KSRP, G3BP2 and TRIP6 which are more highly maintained in cancer tissues relative to adjacent normal tissues from same patients as well as the expression levels of the proteins. This study is the first comprehensive analysis of symmetric arginine dimethylation using clinical samples and suggests that the modification can be used in clinical application.
2020-06-01 | PXD015653 | Pride
Project description:Protein Arginine Methyltransferase (PRMT) 5 is the major type 2 methyltransferase catalyzing symmetric dimethylation (SDM) of arginine. PRMT5 inhibition or deletion in CD4 Th cells reduces TcR engagement-induced IL-2 production and Th cell expansion and confers protection against experimental autoimmune encephalomyelitis (EAE), the animal model of Multiple Sclerosis. However, the mechanisms by which PRMT5 modulates T helper (Th) cell proliferation are still not completely understood and neither are the methylation targets in T cells. In this manuscript, we uncover the role of PRMT5 on alternative splicing (AS) in activated T cells and identify several targets of PRMT5 SDM involved in splicing. In addition, we find a possible link between PRMT5 mediated AS of Trpm4 (Transient Receptor Potential Cation Channel Subfamily M Member 4) and TcR/NFAT signaling/IL-2 production. This understanding may guide development of drugs targeting these processes to benefit patients with T cell-mediated diseases.
2021-10-01 | GSE181931 | GEO
Project description:The C-terminal domain (CTD) of the RNA polymerase II (RNAPII) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodeling. Here, we show that a CTD arginine residue (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires Protein Arginine Methyltransferase 5 (PRMT5) and recruits the Tudor domain of the Survival of Motor Neuron (SMN) protein, which is mutated in spinal muscular atrophy (SMA). SMN interacts with Senataxin, which is sometimes mutated in Ataxia Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis (ALS4). Because R1810me2s and SMN, like Senataxin, are required for resolving RNA-DNA hybrids, created by RNA polymerase II, that form â??R-loopsâ?? in transcription termination regions, we propose that R1810me2s, SMN, and Senataxin are components of a pathway for R-loop resolution in which defects can influence transcription termination and may contribute to neurodegenerative disorders. ChIP of RNAPII in Raji cells expressing shRNG against SMN or GFP; ChIP against RNAPII in Raji cells where endogenous RNAPII has been replaced with wt or R1810A mutant amanitin-resistant protein; and ChIP of SMN in HEK293 cells.
2015-12-31 | E-GEOD-73379 | biostudies-arrayexpress
Project description:We report that a protein arginine methyltransferase Prmt and symmetric dimethylation at histone H arginine (HRsme) directly associates with chromatin of Bmp to suppress its transcription. Inactivation of Prmt in the lung epithelium results in halted branching morphogenesis, altered P-D airway patterning and neonatal lethality.
2019-01-30 | GSE108934 | GEO
Project description:The C-terminal domain (CTD) of the RNA polymerase II (RNAPII) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodeling. Here, we show that a CTD arginine residue (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires Protein Arginine Methyltransferase 5 (PRMT5) and recruits the Tudor domain of the Survival of Motor Neuron (SMN) protein, which is mutated in spinal muscular atrophy (SMA). SMN interacts with Senataxin, which is sometimes mutated in Ataxia Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis (ALS4). Because R1810me2s and SMN, like Senataxin, are required for resolving RNA-DNA hybrids, created by RNA polymerase II, that form ‘R-loops’ in transcription termination regions, we propose that R1810me2s, SMN, and Senataxin are components of a pathway for R-loop resolution in which defects can influence transcription termination and may contribute to neurodegenerative disorders.
2015-12-31 | GSE73379 | GEO
Project description:Arginine methylation is essential for both cellular viability and development and is also dysregulated in cancer. PRMTs catalyze the post translational monomethylation (Rme1/MMA, catalyzed by Type I-III), asymmetric (Rme2a/ADMA, Type I enzymes)-, or symmetric (Rme2s/SDMA, Type II enzymes) dimethylation of arginine. Despite many studies, a thorough integration of PRMT enzyme substrate determination and proteomic and transcriptomic consequences of inhibiting Type I and II PRMTs is lacking. To characterize cellular substrates for Type I (Rme2a) and Type II (Rme2s) PRMTs, human A549 lung adenocarcinoma cells were treated with either Type I (MS023) or Type II (GSK591) inhibitors. Using total proteome hydrolysis, we developed a new mass spectrometry approach to analyze total arginine and lysine content. We showed that Rme1 was a minor population (~0.1% of total arginine), Rme2a was highly abundant (~1.1%), and Rme2s was intermediate (~0.4%). While Rme2s was mostly eliminated by GSK591 treatment, total Rme1 and Rme2a were more resistant to perturbation. To quantitatively characterize substrate preferences of the major enzymes PRMT1, PRMT4(CARM1), and PRMT5, we used oriented peptide array libraries (OPAL) in methyltransferase assays. We demonstrated that while PRMT5 tolerates aspartic acid residues in the substrate, PRMT1 does not. Importantly, PRMT4 methylated previously uncharacterized hydrophobic motifs. To integrate our studies, we performed PTMScan on PRMT-inhibited A549 cells and enriched for methylated arginine containing tryptic peptides. For detection of highly charged peptides, a method to analyze the samples using electron transfer dissociation was developed. Proteomic analysis revealed distinct methylated species enriched in nuclear function, RNA-binding, intrinsically disordered domains, and liquid-liquid phase separation. Parallel studies with proteomics and RNA-Seq revealed distinct, but ontologically overlapping, consequences to PRMT inhibition. Overall, we demonstrate a wider PRMT substrate diversity and methylarginine functional consequence than previously shown.
2021-08-01 | GSE158625 | GEO
Project description:Symmetric and asymmetric dimethylation of arginine are isomeric protein posttranslational modifications with distinct biological effects, evidenced by the methylation of arginine 3 of histone H4 (H4R3): symmetric dimethylation of H4R3 leads to repression of gene expression, while asymmetric dimethylation of H4R3 is associated with gene activation. The enzymes catalyzing these modifications share identifiable sequence similarities, but the relationship between their catalytic mechanisms is unknown. Here we analyzed the structure of a prototypic symmetric arginine dimethylase, PRMT5, and discovered that a conserved phenylalanine in the active site is critical for specifying symmetric addition of methyl groups. Changing it to a methionine significantly elevates the overall methylase activity, but also converts PRMT5 to an enzyme that catalyzes both symmetric and asymmetric dimethylation of arginine. Our results demonstrate a common catalytic mechanism intrinsic to both symmetric and asymmetric arginine dimethylases, and show that steric constrains in the active sites play an essential role in determining the product specificity of arginine methylases. This discovery also implies a potentially regulatable outcome of arginine dimethylation that may provide versatile control of eukaryotic gene expression.
| S-EPMC3251124 | biostudies-literature
Project description:In the study, we identified protein arginine methyltransferase 5 (PRMT5) as a novel restriction factor of HBV replication. We have also demonstrated that PRMT5 can interact with the HBV core and methylate its arginine residues within arginine-rich domain. We identified two types of HBc post-translational modifications: arginine methylation and ubiquitination. While monomethylated HBc retains cytoplasmic localization, symmetric dimethylation is linked to serine phosphorylation and nuclear transport. Thus arginine methylation and ubiquitination are novel types of HBc post-translational modifications which add another level of complexity to the understanding of HBc function and regulation of HBV replication
2017-11-01 | PXD006828 | Pride
Project description:Protein arginine methyltransferase 5 (PRMT5) is the type II arginine methyltransferase that catalyzes the mono- and symmetrical dimethylation of protein substrates at the arginine residues. Emerging evidence reveals that PRMT5 is involved in the regulation of tumor cell proliferation and cancer development. However, the exact role of PRMT5 in human lung cancer cell proliferation and the underlying molecular mechanism remain largely elusive. Here, it is shown that PRMT5 promotes lung cancer cell proliferation through the Smad7-STAT3 axis. Depletion or inhibition of PRMT5 dramatically dampens STAT3 activation and thus suppresses the proliferation of human lung cancer cells. Furthermore, depletion of Smad7 blocks PRMT5-mediated STAT3 activation. Mechanistically, PRMT5 binds to and methylates Smad7 on Arg-57, enhances Smad7 binding to IL-6 co-receptor gp130, and consequently ensures robust STAT3 activation. The findings position PRMT5 as a critical regulator of STAT3 activation, and suggest it as a potential therapeutic target for the treatment of human lung cancer.
| S-EPMC8132155 | biostudies-literature