PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation

Hyllus, Dawin; Stein, Cláudia; Schnabel, Kristin; Schiltz, Emile; Imhof, Axel; Dou, Yali; Hsieh, James J.; Bauer, Uta Maria

doi:10.1101/gad.447007

Cited by 263 publications

(334 citation statements)

References 51 publications

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“…1; Couture et al 2006;Han et al 2006;Ruthenburg et al 2006;Schuetz et al 2006). Indeed, recent studies revealed that methylation of H3R2 by the PRMT6 methyltransferase impedes both H3K4 trimethylation and recruitment of WDR5 (Guccione et al 2007;Hyllus et al 2007). R2 is also important for the recognition of methylated K4 by CHD1 (Flanagan et al 2005).…”

Section: Wd40 Repeat Protein Structurementioning

confidence: 99%

Diverse functions of WD40 repeat proteins in histone recognition: Figure 1.

Suganuma¹,

Pattenden²,

Workman³

2008

Genes Dev.

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WD40 repeat proteins have been shown to bind the histone H3 tail at the center of their ␤-propeller structure. In contrast, in this issue of Genes & Development, Song and colleagues (pp. 1313-1318) demonstrate that the WD40 repeat protein p55 binds a structured region of H4 through a novel binding pocket on the side of ␤-propeller, illustrating a diversity of histone recognition by WD40 repeat proteins.The association of WD40 repeat proteins with histones and nucleosomes is of increasing interest because of their functions in a variety of histone/chromatin-modifying complexes. In this issue of Genes & Development, Song et al. (2008) solve the crystal structure of p55, a Drosophila seven-WD40-repeat protein. Binding of p55 is shown to be incompatible with the histone fold of H4 and results in a change in H4 structure. The interaction of p55 with H4 is distinct from that of previously characterized WD40 repeat proteins and utilizes a novel binding pocket on the side of the ␤-propeller instead of the center of the propeller. This novel p55-H4 interaction extends the known contacts by which WD40 repeat proteins recognize histones and reveals diversity in the manner in which this important recognition domain functions. WD40 repeat proteins are important for a variety of cellular functionsWD40 repeats were first noted in the ␤-subunit of the heterotrimeric GTP-binding protein (G protein) (Fong et al. 1986). The G protein structure contained seven WD40 repeats. Each repeating unit formed one of seven ␤-propeller blades with four small anti-parallel ␤-sheets built into a toroidal structure with a tapered end and central canal (Wall et al. 1995;Neer and Smith 2000). The conserved core of repeating units contained 44-60 residues that ended with tryptophan (W) and aspartate (D). Since the initial identification of the WD40 repeats, >160 WD40 repeat proteins have been identified, with the majority found in higher eukaryotes (Smith et al. 1999). Each family member has between four and 10 copies of the WD40 repeats. In general, WD40 repeat proteins have been associated with a diverse range of cellular processes, including RNA processing, transcriptional regulation (Williams et al. 1991;Hoey et al. 1993), mitotic spindle formation (de Hostos et al. 1991;Vaisman et al. 1995), regulation of vesicle formation and vesicular trafficking (Pryer et al. 1993), and control of cell division (Feldman et al. 1997).Four WD40 repeat proteins-WDR5, RbBP5, RbAp48/ 46 (each with seven repeats)-and the Drosophila homolog of RbAp48/46, p55, are components of histone-modifying complexes (Fig. 1). WDR5 is associated with SET domain-containing methyltransferases, such as Set1, MLL, MLL2, and MLL3/4 (Wysocka et al. 2005;Dou et al. 2006;Mendjan et al. 2006;Cho et al. 2007). In addition to its role in histone methylation, WDR5 and WDS, the Drosophila homolog of WDR5, are associated with several histone acetyltransferase (HAT) complexes, including the MSL (male-specific lethal) complex (Mendjan et al. 2006); the ATAC (Ada Two A-containing) complex, whi...

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Section: Wd40 Repeat Protein Structurementioning

confidence: 99%

Diverse functions of WD40 repeat proteins in histone recognition: Figure 1.

Suganuma¹,

Pattenden²,

Workman³

2008

Genes Dev.

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“…1,2 PRMT6 is a nuclear-localized RMT capable of creating omega-N(G)-monomethylarginine and asymmetric omega-N(G),N(G)-dimethylarginine derivatives on histone and other protein substrates containing a GAR motif; 3 it is the only RMT known to methylate the H3R2 mark. 4,5 This mark can act in opposition to the activating H3K4me3 mark, effectively acting as a transcriptional repressor. 6 PRMT6 has been reported to play a role in a variety of cellular processes including maintenance of stem cell pluripotency, 7 regulation of cell cycle, 8 DNA repair, 9 regulation of nuclear receptor-mediated transcription, 10 and viral transactivation.…”

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Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound

Mitchell

Drew

Ribich

et al. 2015

ACS Med. Chem. Lett.

114

107

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A novel aryl pyrazole series of arginine methyltransferase inhibitors has been identified. Synthesis of analogues within this series yielded the first potent, selective, small molecule PRMT6 inhibitor tool compound, EPZ020411. PRMT6 overexpression has been reported in several cancer types suggesting that inhibition of PRMT6 activity may have therapeutic utility. Identification of EPZ020411 provides the field with the first small molecule tool compound for target validation studies. EPZ020411 shows good bioavailability following subcutaneous dosing in rats making it a suitable tool for in vivo studies. KEYWORDS: PRMT6, protein methyltransferase, oncology, tool compound PRMT6 is a member of the protein arginine methyltransferase (RMT) family, which comprises 45 enzymes, nine of which are known to catalyze protein arginine N-methylation reactions. These post-translational modifications are important regulators of RNA processing, transcriptional regulation, signal transduction, and other cellular processes. 1,2 PRMT6 is a nuclear-localized RMT capable of creating omega-N(G)-monomethylarginine and asymmetric omega-N(G),N(G)-dimethylarginine derivatives on histone and other protein substrates containing a GAR motif; 3 it is the only RMT known to methylate the H3R2 mark. 4,5 This mark can act in opposition to the activating H3K4me3 mark, effectively acting as a transcriptional repressor. 6 PRMT6 has been reported to play a role in a variety of cellular processes including maintenance of stem cell pluripotency, 7 regulation of cell cycle, 8 DNA repair, 9 regulation of nuclear receptor-mediated transcription, 10 and viral transactivation. 11 PRMT6 overexpression has been reported in several cancer types including melanoma 12 and bladder, lung, 13 and prostate 14 carcinoma, suggesting that inhibition of PRMT6 may have therapeutic utility and supporting development of small molecule inhibitors for use as tool compounds for in vitro and in vivo target validation studies.An aryl pyrazole bearing a diamine side-chain, 1, was found to have potent PRMT1, PRMT6, and PRMT8 inhibitory activity through screening of the Epizyme internal library.A 2.4 Å resolution crystal structure of a ternary complex of 1, SAH, and PRMT6 was obtained and is shown in Figure 1a,b (4Y2H). The diamine side-chain occupies the putative site of the substrate arginine side-chain. The terminal nitrogen atom is 3.4 Å away from the sulfur atom of SAH. The terminal NH 2 group makes multiple direct hydrogen bonds to the Glu155 side-chain and backbone carbonyl and water-mediated hydrogen bond interactions with the backbone carbonyl of Trp156

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“…The role PRMTs play in cancer epigenetics remains unexplored, and it is essential to unravel how histone arginine methylation influences cancer. Previous studies have shown that the expression of EZH2, the catalytic subunit of PRC2/3, is altered in cancer cells (19,32,40,41). Similarly, several reports have shown that the interplay and cross-talk between chromatin-modifying enzymes is necessary for the efficient regulation of gene expression, and that changes that affect the activity and/or targeting of chromatin remodelers can trigger cancer (13, 23).…”

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Protein Arginine Methyltransferase 5 Suppresses the Transcription of the RB Family of Tumor Suppressors in Leukemia and Lymphoma Cells

Wang

Pal

Sif

2008

Molecular and Cellular Biology

229

225

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The proper epigenetic modification of chromatin by protein arginine methyltransferases (PRMTs) is crucial for normal cell growth and health. The human SWI/SNF-associated PRMT5 is involved in the transcriptional repression of target genes by directly methylating H3R8 and H4R3. To further understand the impact of PRMT5-mediated histone methylation on cancer, we analyzed its expression in normal and transformed human B lymphocytes. Our findings reveal that PRMT5 protein levels are enhanced in various human lymphoid cancer cells, including transformed chronic lymphocytic leukemia (B-CLL) cell lines. PRMT5 overexpression is caused by the altered expression of the PRMT5-specific microRNAs 19a, 25, 32, 92, 92b, and 96 and results in the increased global symmetric methylation of H3R8 and H4R3. An evaluation of both epigenetic marks at PRMT5 target genes such as RB1 (p105), RBL1 (p107), and RBL2 (p130) showed that promoters H3R8 and H4R3 are hypermethylated, which in turn triggers pocket protein transcriptional repression. Furthermore, reducing PRMT5 expression in WaC3CD5 B-CLL cells abolishes H3R8 and H4R3 hypermethylation, restores RBL2 expression, and inhibits cancer cell proliferation. These results indicate that PRMT5 overexpression epigenetically alters the transcription of key tumor suppressor genes and suggest a causal role of the elevated symmetric methylation of H3R8 and H4R3 at the RBL2 promoter in transformed B-lymphocyte pathology.Enzymes that modify chromatin via arginine methylation have different effects on gene expression, depending on whether they catalyze either the symmetric or asymmetric dimethylation of histones (20,31). Recent work has clearly established a link between the aberrant expression of chromatinmodifying enzymes and cancer; however, the impact protein arginine methyltransferases (PRMTs) have on cell growth and proliferation has only begun to be appreciated. The role PRMTs play in cancer epigenetics remains unexplored, and it is essential to unravel how histone arginine methylation influences cancer. Previous studies have shown that the expression of EZH2, the catalytic subunit of PRC2/3, is altered in cancer cells (19,32,40,41). Similarly, several reports have shown that the interplay and cross-talk between chromatin-modifying enzymes is necessary for the efficient regulation of gene expression, and that changes that affect the activity and/or targeting of chromatin remodelers can trigger cancer (13, 23).Histone methylation has emerged as an important epigenetic modification in the control of chromatin structure and gene expression, and there is little doubt that different epigenetic marks act either synergistically or antagonistically to specify transcriptional performance in various chromatin regions (13). The methylation of histones can be found on both lysine and arginine residues, and both modifications are introduced by SET and PRMT enzymes, respectively. Just like SET proteins, which either can induce or repress transcription, PRMTs either can induce or inhibit transcription depen...

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PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation

Cited by 263 publications

References 51 publications

Diverse functions of WD40 repeat proteins in histone recognition: Figure 1.

Diverse functions of WD40 repeat proteins in histone recognition: Figure 1.

Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound

Protein Arginine Methyltransferase 5 Suppresses the Transcription of the RB Family of Tumor Suppressors in Leukemia and Lymphoma Cells

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