PRMT3 Is a Distinct Member of the Protein Arginine N-Methyltransferase Family

Frankel, Adam; Clarke, Steven

doi:10.1074/jbc.m006445200

Cited by 109 publications

(98 citation statements)

References 40 publications

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“…It has been proposed that the relatively short N terminus of mammalian PRMT1 and yeast Rmt1/Hmt1 may contribute to methyltransferase substrate specificity by interacting with regions of the substrate protein distinct from the sequence immediately surrounding the target arginine residue (29,30). In addition, deletion of the relatively long unique N terminus of PRMT3 altered its substrate specificity in vitro (33). However, mutants of CARM1 lacking the unique N-or C-terminal regions appeared to be unaffected in their ability to methylate histone H3 (Fig.…”

Section: Role Of the Unique N-and C-terminal Regions Of Carm1 In Its mentioning

confidence: 96%

“…However, CARM1 is the only member of the family to harbor unique domains at its N and C termini. The contribution of these additional domains to the function of the PRMTs is unknown, although some studies suggest that they may be involved in the specificity of protein substrate binding (29,30,33). Previous studies indicate that while the methyltransferase activity of CARM1 is required for coactivator function, other unspecified domains also contribute (25).…”

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Requirement for Multiple Domains of the Protein Arginine Methyltransferase CARM1 in Its Transcriptional Coactivator Function

Teyssier¹,

Chen²,

Stallcup

2002

Journal of Biological Chemistry

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The p160 coactivator complex plays a critical role in transcriptional activation by nuclear receptors and possibly other classes of DNA-binding transcriptional activators. The complex contains at least one of three p160 coactivators (SRC-1, GRIP1/TIF2, or pCIP/RAC3/ACTR/ AIB1/TRAM1), a histone acetyltransferase such as CBP or p300, and the histone methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1). Methylation of histone H3 and possibly other proteins in the transcription initiation complex by CARM1 occurs along with acetylation of histones and other proteins by CBP and p300 to help remodel chromatin structure and recruit RNA polymerase II. Here we show that other domains of CARM1 are required for the coactivator function of CARM1 in addition to the methyltransferase activity. The methyltransferase GRIP1, binding, and homo-oligomerization activities all reside in the central region of CARM1, which is highly conserved among the entire protein arginine methyltransferase family. In addition to this conserved domain, the unique N-and C-terminal regions of CARM1 were also required for enhancement of transcriptional activation by nuclear receptors. While the N-terminal region has no known activity at present, the C-terminal part of CARM1 contains an autonomous activation domain, suggesting that it interacts with other proteins that help to mediate CARM1 coactivator function.Activation of transcription by DNA-binding transcriptional activator proteins is mediated by coactivators, which locally remodel chromatin structure and recruit RNA polymerase II and its transcription initiation complex to the promoter. Members of the nuclear receptor (NR)

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Section: Role Of the Unique N-and C-terminal Regions Of Carm1 In Its mentioning

confidence: 96%

mentioning

confidence: 99%

Requirement for Multiple Domains of the Protein Arginine Methyltransferase CARM1 in Its Transcriptional Coactivator Function

Teyssier¹,

Chen²,

Stallcup

2002

Journal of Biological Chemistry

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“…Another unique property of PRMT3 is that it harbors a zinc finger domain at its N terminus. It has been proposed that this domain may play a role in the regulation of PRMT3 activity or in the recognition of PRMT3 substrates (6,10). Deletion analysis studies demonstrated that PRMT3 lacking the zinc finger domain is still active in vitro, however the zinc finger minus enzyme loses its ability to methylate substrates when presented with a complex mix of hypomethylated proteins isolated from RAT1 cells (10).…”

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confidence: 99%

Ribosomal Protein rpS2 Is Hypomethylated in PRMT3-deficient Mice

Swiercz

Cheng

Kim

et al. 2007

Journal of Biological Chemistry

124

100

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PRMT3 is a type I arginine methyltransferase that resides in the cytoplasm. A large proportion of this cystosolic PRMT3 is found associated with ribosomes. It is tethered to the ribosomes through its interaction with rpS2, which is also its substrate. Here we show that mouse embryos with a targeted disruption of PRMT3 are small in size but survive after birth and attain a normal size in adulthood, thus displaying Minute-like characteristics. The ribosome protein rpS2 is hypomethylated in the absence of PRMT3, demonstrating that it is a bona fide, in vivo PRMT3 substrate that cannot be modified by other PRMTs. Finally, the levels 40 S, 60 S, and 80 S monosomes and polyribosomes are unaffected by the loss of PRMT3, but there are additional as yet unidentified proteins that co-fractionate with ribosomes that are also dedicated PRMT3 substrates.Arginine methylation is a common posttranslational modification that occurs in both the nucleus and the cytoplasm (1). The methylation of arginine residues is catalyzed by at least two different classes of protein arginine methyltransferase (PRMT) 2 enzymes. The Type I enzymes catalyze the formation of asymmetric N G ,N G -dimethylarginine residues and the Type II enzyme catalyzes the formation of symmetric N G ,NЈ G -dimethylarginine residues. In mammals, there are five Type I enzymes (PRMT1,3,4, 6 and 8).Proteins that are substrates for the PRMTs usually contain glycine and arginine-rich patches, GAR motifs, that are the sites of methylation. The major pools of protein that are arginine methylated are the heterogeneous nuclear ribonucleoproteins, histones, and ribosomal proteins. Thirty years ago, HeLa cell ribosomal proteins were shown to be heavily lysine-and arginine-methylated (2), and further two-dimensional gel electrophoresis studies of purified ribosomes demonstrated that at least six prominent proteins are arginine methylated (3). PRMT3 is a ribosome-associated protein (4, 5) and may be responsible for much of the arginine methylation that occurs in this molecular machine.PRMT3 was identified as a PRMT1 binding protein in a yeast two-hybrid screen (6). However, gel filtration analysis of RAT1 cells demonstrated that PRMT3 occurs as a monomer and is not complexed in vivo with PRMT1 (6). PRMT3 also interacts with the tumor suppressor DAL-1 (7). This interaction inhibits PRMT3 enzymatic activity, both in in vitro reactions and in cell lines. At the organ level, PRMT3 is ubiquitously expressed (6), but in the brain it displays higher expression in neurons than in glial cells (8). PRMT3 is the only type 1 arginine methyltransferase that is localized exclusively to the cytoplasm (6, 9). Another unique property of PRMT3 is that it harbors a zinc finger domain at its N terminus. It has been proposed that this domain may play a role in the regulation of PRMT3 activity or in the recognition of PRMT3 substrates (6, 10). Deletion analysis studies demonstrated that PRMT3 lacking the zinc finger domain is still active in vitro, however the zinc finger minus enzyme loses its abil...

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“…Most RBPs contain GAR domains, which consist of a repetition of RGG or RXR (X is an aliphatic residue) (11,58) and are the canonical targets for type I PRMTs that catalyze the formation of asymmetric NG,NG-dimethylarginine residues (37,49). Type I enzymes PRMT1 and PRMT3 favor GAR domains as their substrates (18,25,66), and especially PRMT1 has a promiscuity to methylate arginine residues encompassed by GAR domains (65,66). On the other hand, another type I enzyme, CARM1, methylates a narrow spectrum of proteins, histone H3 (12,44), p300/CBP (69), PABP1, and TARPP (39), all of which lack GAR-like domains around the arginine residues.…”

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confidence: 99%

CARM1 Regulates Proliferation of PC12 Cells by Methylating HuD

Fujiwara¹,

Mori²,

Chu³

et al. 2006

Molecular and Cellular Biology

117

107

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HuD is an RNA-binding protein that has been shown to induce neuronal differentiation by stabilizing labile mRNAs carrying AU-rich instability elements. Here, we show a novel mechanism of arginine methylation of HuD by coactivator-associated arginine methyltransferase 1 (CARM1) that affected mRNA turnover of p21 cip1/waf1 mRNA in PC12 cells. CARM1 specifically methylated HuD in vitro and in vivo and colocalized with HuD in the cytoplasm. Inhibition of HuD methylation by CARM1 knockdown elongated the p21 cip1/waf1 mRNA half-life and resulted in a slow growth rate and robust neuritogenesis in response to nerve growth factor (NGF). Methylation-resistant HuD bound more p21 cip1/waf1 mRNA than did the wild type, and its overexpression upregulated p21 cip1/waf1 protein expression. These results suggested that CARM1-methylated HuD maintains PC12 cells in the proliferative state by committing p21 cip1/waf1 mRNA to its decay system. Since the methylated population of HuD was reduced in NGF-treated PC12 cells, downregulation of HuD methylation is a possible pathway through which NGF induces differentiation of PC12 cells.

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PRMT3 Is a Distinct Member of the Protein Arginine N-Methyltransferase Family

Cited by 109 publications

References 40 publications

Requirement for Multiple Domains of the Protein Arginine Methyltransferase CARM1 in Its Transcriptional Coactivator Function

Requirement for Multiple Domains of the Protein Arginine Methyltransferase CARM1 in Its Transcriptional Coactivator Function

Ribosomal Protein rpS2 Is Hypomethylated in PRMT3-deficient Mice

CARM1 Regulates Proliferation of PC12 Cells by Methylating HuD

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