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  • Protein arginine methyltransferase 5 (PRMT5) signaling suppresses protein kinase Cδ- and p38δ-dependent signaling and keratinocyte differentiation. 22199349

    PKCδ is a key regulator of keratinocyte differentiation that activates p38δ phosphorylation leading to increased differentiation as measured by an increased expression of the structural protein involucrin. Our previous studies suggest that p38δ exists in association with protein partners. A major goal is to identify these partners and understand their role in regulating keratinocyte differentiation. In this study we use affinity purification and mass spectrometry to identify protein arginine methyltransferase 5 (PRMT5) as part of the p38δ signaling complex. PRMT5 is an arginine methyltransferase that symmetrically dimethylates arginine residues on target proteins to alter target protein function. We show that PRMT5 knockdown is associated with increased p38δ phosphorylation, suggesting that PRMT5 impacts the p38δ signaling complex. At a functional level we show that PRMT5 inhibits the PKCδ- or 12-O-tetradecanoylphorbol-13-acetate-dependent increase in human involucrin expression, and PRMT5 dimethylates proteins in the p38δ complex. Moreover, PKCδ expression reduces the PRMT5 level, suggesting that PKCδ activates differentiation in part by reducing PRMT5 level. These studies indicate antagonism between the PKCδ and PRMT5 signaling in control of keratinocyte differentiation.
    Document Type:
    Reference
    Product Catalog Number:
    07-412
    Product Catalog Name:
    Anti-dimethyl-Arginine Antibody, symmetric (SYM10)

  • Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene. 26487724

    Histone lysine methylation is important in early zebrafish development; however, the role of histone arginine methylation in this process remains unclear. H3R2me2a, generated by protein arginine methyltransferase 6 (Prmt6), is a repressive mark. To explore the role of Prmt6 and H3R2me2a during zebrafish embryogenesis, we identified the maternal characteristic of prmt6 and designed two prmt6-specific morpholino-oligos (MOs) to study its importance in early development, application of which led to early epiboly defects and significantly reduced the level of H3R2me2a marks. prmt6 mRNA could rescue the epiboly defects and the H3R2me2a reduction in the prmt6 morphants. Functionally, microarray data demonstrated that growth arrest and DNA damage-inducible, α, a (gadd45αa) was a significantly up-regulated gene in MO-treated embryos, the activity of which was linked to the activation of the p38/JNK pathway and apoptosis. Importantly, gadd45αa MO and p38/JNK inhibitors could partially rescue the defect of prmt6 morphants, the downstream targets of Prmt6, and the apoptosis ratios of the prmt6 morphants. Moreover, the results of ChIP quantitative real time PCR and luciferase reporter assay indicated that gadd45αa is a repressive target of Prmt6. Taken together, these results suggest that maternal Prmt6 is essential to early zebrafish development by directly repressing gadd45αa.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™

  • Protein arginine methyltransferase 7 regulates cellular response to DNA damage by methylating promoter histones H2A and H4 of the polymerase δ catalytic subunit gene, POL ... 22761421

    Covalent modification of histones by protein arginine methyltransferases (PRMTs) impacts genome organization and gene expression. In this report, we show that PRMT7 interacts with the BRG1-based hSWI/SNF chromatin remodeling complex and specifically methylates histone H2A Arg-3 (H2AR3) and histone H4 Arg-3 (H4R3). To elucidate the biological function of PRMT7, we knocked down its expression in NIH 3T3 cells and analyzed global gene expression. Our findings show that PRMT7 negatively regulates expression of genes involved in DNA repair, including ALKBH5, APEX2, POLD1, and POLD2. Chromatin immunoprecipitation (ChIP) revealed that PRMT7 and dimethylated H2AR3 and H4R3 are enriched at target DNA repair genes in parental cells, whereas PRMT7 knockdown caused a significant decrease in PRMT7 recruitment and H2AR3/H4R3 methylation. Decreased PRMT7 expression also resulted in derepression of target DNA repair genes and enhanced cell resistance to DNA-damaging agents. Furthermore, we show that BRG1 co-localizes with PRMT7 on target promoters and that expression of a catalytically inactive form of BRG1 results in derepression of PRMT7 target DNA repair genes. Remarkably, reducing expression of individual PRMT7 target DNA repair genes showed that only the catalytic subunit of DNA polymerase, POLD1, was able to resensitize PRMT7 knock-down cells to DNA-damaging agents. These results provide evidence for the important role played by PRMT7 in epigenetic regulation of DNA repair genes and cellular response to DNA damage.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • The arginine methyltransferase PRMT6 regulates cell proliferation and senescence through transcriptional repression of tumor suppressor genes. 22904088

    The protein arginine methyltransferase 6 (PRMT6) is a coregulator of gene expression and executes its repressing as well as activating function by asymmetric dimethylation of histone H3 at R2 (H3 R2me2a). Given that elevated expression levels of PRMT6 have been reported in various cancer types, we explore here its role in cell proliferation and senescence. We find that knockdown of PRMT6 results in proliferation defects of transformed as well as non-transformed cells, causes G1-phase arrest and induces senescence. This phenotype is accompanied by transcriptional upregulation of important cell cycle regulators, most prominently the cyclin-dependent kinase (CDK) inhibitor gene p21 (p21(CIP1/WAF1), CDKN1A) and p16 (p16(INK4A), CDKN2A). Chromatin immuno-precipitation analysis reveals that the p21 gene is a direct target of PRMT6 and the corresponding histone mark H3 R2me2a. Using a cell model of oncogene-induced senescence (OIS), in which p21 is an essential activator of the senescent phenotype, we show that PRMT6 expression declines upon induction of senescence and conversely p21 gene expression increases. Moreover, overexpression of PRMT6 leads to reduced levels of OIS. These findings indicate that the transcriptional repressor activity of PRMT6 facilitates cell proliferation and blocks senescence by regulation of tumor suppressor genes and that this might contribute to the oncogenic capacity of PRMT6.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Protein arginine methyltransferase Prmt5-Mep50 methylates histones H2A and H4 and the histone chaperone nucleoplasmin in Xenopus laevis eggs. 22009756

    Histone proteins carry information contained in post-translational modifications. Eukaryotic cells utilize this histone code to regulate the usage of the underlying DNA. In the maturing oocytes and eggs of the frog Xenopus laevis, histones are synthesized in bulk in preparation for deposition during the rapid early developmental cell cycles. During this key developmental time frame, embryonic pluripotent chromatin is established. In the egg, non-chromatin-bound histones are complexed with storage chaperone proteins, including nucleoplasmin. Here we describe the identification and characterization of a complex of the protein arginine methyltransferase 5 (Prmt5) and the methylosome protein 50 (Mep50) isolated from Xenopus eggs that specifically methylates predeposition histones H2A/H2A.X-F and H4 and the histone chaperone nucleoplasmin on a conserved motif (GRGXK). We demonstrate that nucleoplasmin (Npm), an exceedingly abundant maternally deposited protein, is a potent substrate for Prmt5-Mep50 and is monomethylated and symmetrically dimethylated at Arg-187. Furthermore, Npm modulates Prmt5-Mep50 activity directed toward histones, consistent with a regulatory role for Npm in vivo. We show that H2A and nucleoplasmin methylation appears late in oogenesis and is most abundant in the laid egg. We hypothesize that these very abundant arginine methylations are constrained to pre-mid blastula transition events in the embryo and therefore may be involved in the global transcriptional repression found in this developmental time frame.
    Document Type:
    Reference
    Product Catalog Number:
    07-405
    Product Catalog Name:
    Anti-PRMT5 Antibody

  • Arginine and asymmetric dimethylarginine in puromycin aminonucleoside-induced chronic kidney disease in the rat. 22179117

    Reduced renal L-arginine (L-Arg) synthesis/transport, induction of arginases and increased endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA) will inhibit NO production. This study investigated pathways of L-Arg synthesis/uptake/utilization, ADMA degradation and oxidant/antioxidants in puromycin aminonucleoside (PAN) chronic kidney disease (CKD).Rats were given low- (LD) or high-dose (HD) PAN and followed for 11 weeks for proteinuria. BP was measured and blood and tissues were harvested and analyzed for abundance of argininosuccinate synthase (ASS) and lyase (ASL), arginase, cationic amino acid transporter (CAT1) and dimethylargininedimethylaminohydrolase (DDAH) in kidney, cortex, aorta and liver. Arginase and DDAH activity, plasma L-Arg and ADMA, renal pathology and creatinine clearances were also measured.PAN caused dose-dependent kidney damage and hypertension and creatinine clearance fell in HD-PAN. Renal ASS fell in HD-PAN, renal cortex and aortic ASL and membrane CAT1 fell in both PAN groups. There was no activation of renal arginase, but aortic arginase increased in LD-PAN. Renal DDAH activity fell moderately in LD-PAN and markedly in HD-PAN where hepatic DDAH activity also fell. Plasma L-Arg was unchanged while ADMA rose moderately and dose-dependently with PAN. There were several indices of oxidative stress which was most prominent in HD-PAN.Reduction in renal ASS/ASL and loss of renal cortex CAT1 compromises renal L-Arg synthesis and release. Loss of aortic CAT1 impairs L-Arg uptake. Increased plasma ADMA was associated with progressive loss of renal DDAH activity. However, loss of renal clearance and falls in hepatic DDAH activity in HD-PAN did not have additive effects on plasma ADMA.
    Document Type:
    Reference
    Product Catalog Number:
    05-233
    Product Catalog Name:
    Anti-Nitrotyrosine Antibody, clone 1A6

  • Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation. 24507716

    Tudor domain-containing protein 3 (TDRD3) is a major methylarginine effector molecule that reads methyl-histone marks and facilitates gene transcription. However, the underlying mechanism by which TDRD3 functions as a transcriptional coactivator is unknown. We identified topoisomerase IIIB (TOP3B) as a component of the TDRD3 complex. TDRD3 serves as a molecular bridge between TOP3B and arginine-methylated histones. The TDRD3-TOP3B complex is recruited to the c-MYC gene promoter primarily by the H4R3me2a mark, and the complex promotes c-MYC gene expression. TOP3B relaxes negative supercoiled DNA and reduces transcription-generated R loops in vitro. TDRD3 knockdown in cells increases R loop formation at the c-MYC locus, and Tdrd3 null mice exhibit elevated R loop formation at this locus in B cells. Tdrd3 null mice show significantly increased c-Myc/Igh translocation, a process driven by R loop structures. By reducing negative supercoiling and resolving R loops, TOP3B promotes transcription, protects against DNA damage, and reduces the frequency of chromosomal translocations.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Arginine methylation of a mitochondrial guide RNA binding protein from Trypanosoma brucei. 11704273

    RBP16 is a mitochondrial Y-box protein from the parasitic protozoan Trypanosoma brucei that binds guide RNAs and ribosomal RNAs. It is comprised of an N-terminal cold-shock domain and a C-terminal domain rich in glycine and arginine residues, resembling the RGG RNA-binding motif. Arginine residues found within RGG domains are frequently asymmetrically dimethylated by a class of enzymes termed protein arginine methyltransferases (PRMTs). As Arg-93 of RBP16 exists in the context of a preferred sequence for asymmetric arginine dimethylation (G/FGGRGGG/F), we investigated whether modified arginines are present in native RBP16 by MALDI-TOF and post-source decay analyses. These analyses confirmed that Arg-93 is dimethylated. In addition, Arg-78 exists as an unmodified or as a monomethylated derivative, and Arg-85 is present in forms corresponding to the unmodified, di-, and tri-methylated state. While Arg-93 is apparently constitutively dimethylated, the methylation of Arg-78 and Arg-85 is mutually exclusive. Furthermore, whole cell extracts from procyclic form T. brucei are able to methylate bacterially expressed RBP16 (rRBP16), as well as endogenous proteins, in the presence of S-adenosyl-L-[methyl-3H]methionine. While assays of mitochondrial extracts suggest a small amount of PRMT may also be present in this subcellular compartment, the majority of trypanosome PRMT activity is extramitochondrial. We show that rRBP16 is methylated in trypanosome extracts through the action of a type I methyltransferase as well as serving as a substrate for heterologous mammalian type I PRMTs. In addition, we demonstrate the presence of type II PRMT activity in trypanosome cell extracts. These results suggest that protein arginine methylation is a common posttranslational modification in trypanosomes, and that it may regulate the function of RBP16.
    Document Type:
    Reference
    Product Catalog Number:
    AB3349
    Product Catalog Name:
    Anti-PRMT5 Antibody, CT

  • Arginine Methyltransferases Are Regulated by Epstein-Barr Virus in B Cells and Are Differentially Expressed in Hodgkin's Lymphoma. 25436604

    Although there is increasing evidence that aberrant expression of those enzymes which control protein arginine methylation contribute to carcinogenesis, their de-regulation by oncogenic viruses in primary cells has yet to be reported. We first show that the protein arginine methyltransferases, CARM1, PRMT1 and PRMT5 are strongly expressed in Hodgkin Reed-Sternberg (HRS) cells, and up-regulated in Hodgkin's lymphoma (HL) cell lines. Given that Epstein-Barr virus (EBV) can be detected in approximately 50% of primary HL, we next examined how EBV infection of germinal centre (GC) B cells, the presumptive precursors of HRS cells, modulated the expression of these proteins. EBV infection of GC B cells was followed by the up-regulation of CARM1, PRMT1 and PRMT5, and by the down-regulation of the arginine deiminase, PADI4. Latent membrane protein 1 (LMP1), the major EBV transforming gene was shown to induce PRMT1 in GC B cells and in a stably transfected B cell line. The recent development of compounds which inhibit PRMT-mediated reactions provides a compelling case for continuing to dissect the contribution of virus induced changes in these proteins to lymphomagenesis.
    Document Type:
    Reference
    Product Catalog Number:
    07-405
    Product Catalog Name:
    Anti-PRMT5 Antibody

  • Arginine methylation of translocated in liposarcoma (TLS) inhibits its binding to long noncoding RNA, abrogating TLS-mediated repression of CBP/p300 activity. 29784880

    Translocated in liposarcoma (TLS) is an RNA-binding protein and a transcription-regulatory sensor of DNA damage. TLS binds promoter-associated noncoding RNA (pncRNA) and inhibits histone acetyltransferase (HAT) activity of CREB-binding protein (CBP)/E1A-binding protein P300 (p300) on the cyclin D1 (CCND1) gene. Although post-translational modifications of TLS, such as arginine methylation, are known to regulate TLS's nucleocytoplasmic shuttling and assembly in stress granules, its interactions with RNAs remain poorly characterized. Herein, using various biochemical assays, we confirmed the earlier observations that TLS is methylated by protein arginine methyltransferase 1 (PRMT1) in vitro The arginine methylation of TLS disrupted binding to pncRNA and also prevented binding of TLS to and inhibition of CBP/p300. This result indicated that arginine methylation of TLS abrogates both binding to pncRNA and TLS-mediated inhibition of CBP/p300 HAT activities. We also report that an arginine residue within the Arg-Gly-Gly domain of TLS, Arg-476, serves as the major determinant for binding to pncRNA. Either methylation or mutation of Arg-476 of TLS significantly decreased pncRNA binding and thereby prevented a pncRNA-induced allosteric alteration in TLS that is required for its interaction with CBP/p300. Moreover, unlike WT TLS, an R476A TLS mutant did not inhibit CCND1 promoter activity in luciferase reporter assays. Taken together, we propose the hypothesis that arginine methylation of TLS regulates both TLS-nucleic acid and TLS-protein interactions and thereby participates in transcriptional regulation.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple