Full text data of CARM1
CARM1
(PRMT4)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Histone-arginine methyltransferase CARM1; 2.1.1.-; 2.1.1.125 (Coactivator-associated arginine methyltransferase 1; Protein arginine N-methyltransferase 4)
Histone-arginine methyltransferase CARM1; 2.1.1.-; 2.1.1.125 (Coactivator-associated arginine methyltransferase 1; Protein arginine N-methyltransferase 4)
hRBCD
IPI00412880
IPI00412880 CoaCtivator-assoCiated arginine methyltransferase 1 S-adenosyl-L-methionine + histone-arginine = S-adenosyl-L-homocysteine + histone-N-methyl-arginine. soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Cytoplasmic and nuclear n/a expected molecular weight found in band found in band 98 kdDa
IPI00412880 CoaCtivator-assoCiated arginine methyltransferase 1 S-adenosyl-L-methionine + histone-arginine = S-adenosyl-L-homocysteine + histone-N-methyl-arginine. soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Cytoplasmic and nuclear n/a expected molecular weight found in band found in band 98 kdDa
UniProt
Q86X55
ID CARM1_HUMAN Reviewed; 608 AA.
AC Q86X55; A6NN38;
DT 04-JAN-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-OCT-2010, sequence version 3.
DT 22-JAN-2014, entry version 105.
DE RecName: Full=Histone-arginine methyltransferase CARM1;
DE EC=2.1.1.-;
DE EC=2.1.1.125;
DE AltName: Full=Coactivator-associated arginine methyltransferase 1;
DE AltName: Full=Protein arginine N-methyltransferase 4;
GN Name=CARM1; Synonyms=PRMT4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND NUCLEOTIDE SEQUENCE [MRNA]
RP OF 194-608 (ISOFORM 1).
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 43-608 (ISOFORM 2).
RC TISSUE=Amygdala;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP METHYLATION OF ELAVL1.
RX PubMed=12237300; DOI=10.1074/jbc.M206187200;
RA Li H., Park S., Kilburn B., Jelinek M.A., Henschen-Edman A.,
RA Aswad D.W., Stallcup M.R., Laird-Offringa I.A.;
RT "Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing
RT protein, by CARM1. Coactivator-associated arginine
RT methyltransferase.";
RL J. Biol. Chem. 277:44623-44630(2002).
RN [6]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=15221992; DOI=10.1002/cncr.20327;
RA Hong H., Kao C., Jeng M.-H., Eble J.N., Koch M.O., Gardner T.A.,
RA Zhang S., Li L., Pan C.-X., Hu Z., MacLennan G.T., Cheng L.;
RT "Aberrant expression of CARM1, a transcriptional coactivator of
RT androgen receptor, in the development of prostate carcinoma and
RT androgen-independent status.";
RL Cancer 101:83-89(2004).
RN [7]
RP INTERACTION WITH NR1H4.
RX PubMed=15471871; DOI=10.1074/jbc.M410021200;
RA Ananthanarayanan M., Li S., Balasubramaniyan N., Suchy F.J.,
RA Walsh M.J.;
RT "Ligand-dependent activation of the farnesoid X-receptor directs
RT arginine methylation of histone H3 by CARM1.";
RL J. Biol. Chem. 279:54348-54357(2004).
RN [8]
RP METHYLATION OF EP300.
RX PubMed=15731352; DOI=10.1073/pnas.0407159102;
RA Lee Y.-H., Coonrod S.A., Kraus W.L., Jelinek M.A., Stallcup M.R.;
RT "Regulation of coactivator complex assembly and function by protein
RT arginine methylation and demethylimination.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:3611-3616(2005).
RN [9]
RP INTERACTION WITH HTLV-1 TAX-1.
RX PubMed=17005681; DOI=10.1128/JVI.00186-06;
RA Jeong S.J., Lu H., Cho W.K., Park H.U., Pise-Masison C., Brady J.N.;
RT "Coactivator-associated arginine methyltransferase 1 enhances
RT transcriptional activity of the human T-cell lymphotropic virus type 1
RT long terminal repeat through direct interaction with Tax.";
RL J. Virol. 80:10036-10044(2006).
RN [10]
RP METHYLATION OF HISTONE H3, INTERACTION WITH RELA, AND FUNCTION.
RX PubMed=16497732; DOI=10.1210/me.2005-0365;
RA Miao F., Li S., Chavez V., Lanting L., Natarajan R.;
RT "Coactivator-associated arginine methyltransferase-1 enhances nuclear
RT factor-kappaB-mediated gene transcription through methylation of
RT histone H3 at arginine 17.";
RL Mol. Endocrinol. 20:1562-1573(2006).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=19405910; DOI=10.1042/BJ20090268;
RA Lakowski T.M., Frankel A.;
RT "Kinetic analysis of human protein arginine N-methyltransferase 2:
RT formation of monomethyl- and asymmetric dimethyl-arginine residues on
RT histone H4.";
RL Biochem. J. 421:253-261(2009).
RN [13]
RP PHOSPHORYLATION AT SER-216, SUBCELLULAR LOCATION, AND MASS
RP SPECTROMETRY.
RX PubMed=19843527; DOI=10.1074/jbc.M109.065524;
RA Feng Q., He B., Jung S.Y., Song Y., Qin J., Tsai S.Y., Tsai M.J.,
RA O'Malley B.W.;
RT "Biochemical control of CARM1 enzymatic activity by phosphorylation.";
RL J. Biol. Chem. 284:36167-36174(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 135-482 IN COMPLEX WITH SAM
RP ANALOG AND INHIBITORS, AND SAM BINDING SITES.
RX PubMed=21410432; DOI=10.1042/BJ20102161;
RA Sack J.S., Thieffine S., Bandiera T., Fasolini M., Duke G.J.,
RA Jayaraman L., Kish K.F., Klei H.E., Purandare A.V., Rosettani P.,
RA Troiani S., Xie D., Bertrand J.A.;
RT "Structural basis for CARM1 inhibition by indole and pyrazole
RT inhibitors.";
RL Biochem. J. 436:331-339(2011).
CC -!- FUNCTION: Methylates (mono- and asymmetric dimethylation) the
CC guanidino nitrogens of arginyl residues in several proteins
CC involved in DNA packaging, transcription regulation, pre-mRNA
CC splicing, and mRNA stability. Recruited to promoters upon gene
CC activation together with histone acetyltransferases from
CC EP300/P300 and p160 families, methylates histone H3 at 'Arg-17'
CC (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a),
CC leading to activate transcription via chromatin remodeling. During
CC nuclear hormone receptor activation and TCF7L2/TCF4 activation,
CC acts synergically with EP300/P300 and either one of the p160
CC histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR
CC or CTNNB1/beta-catenin to activate transcription. During myogenic
CC transcriptional activation, acts together with NCOA3/ACTR as a
CC coactivator for MEF2C. During monocyte inflammatory stimulation,
CC acts together with EP300/P300 as a coactivator for NF-kappa-B.
CC Acts as coactivator for PPARG, promotes adipocyte differentiation
CC and the accumulation of brown fat tissue. Plays a role in the
CC regulation of pre-mRNA alternative splicing by methylation of
CC splicing factors. Also seems to be involved in p53/TP53
CC transcriptional activation. Methylates EP300/P300, both at 'Arg-
CC 2142', which may loosen its interaction with NCOA2/GRIP1, and at
CC 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its
CC interaction with CREB and inhibits CREB-dependent transcriptional
CC activation. Also methylates arginine residues in RNA-binding
CC proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-
CC stabilizing properties and the half-life of their target mRNAs.
CC -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine + arginine-[histone] =
CC S-adenosyl-L-homocysteine + N(omega)-methyl-arginine-[histone].
CC -!- ENZYME REGULATION: Methylation of H3R17 (H3R17me) by CARM1 is
CC stimulated by preacetylation of H3 'Lys-18' (H3K18ac) H3 'Lys-23'
CC (H3K23ac) by EP300 and blocked by citrullination of H3 'Arg-17'
CC (H3R17ci) by PADI4 (By similarity).
CC -!- SUBUNIT: Homodimer (Probable). Interacts with the C-terminus of
CC NCOA2/GRIP1, NCO3/ACTR and NCOA1/SRC1. Part of a complex
CC consisting of CARM1, EP300/P300 and NCOA2/GRIP1. Interacts with
CC FLII, TP53, myogenic factor MEF2, EP300/P300, TRIM24, CREBBP and
CC CTNNB1. Identified in a complex containing CARM1, TRIM24 and
CC NCOA2/GRIP1. Interacts with NCOA3/SRC3. Interacts with SNRPC (By
CC similarity). Interacts with NR1H4. Interacts with RELA. Interacts
CC with HTLV-1 Tax-1.
CC -!- INTERACTION:
CC P17676:CEBPB; NbExp=2; IntAct=EBI-2339854, EBI-969696;
CC Q05826:CEBPB (xeno); NbExp=3; IntAct=EBI-2339854, EBI-7774198;
CC Q96EY1:DNAJA3; NbExp=2; IntAct=EBI-2339854, EBI-356767;
CC O43809:NUDT21; NbExp=2; IntAct=EBI-2339854, EBI-355720;
CC Q96PU8:QKI; NbExp=2; IntAct=EBI-2339854, EBI-945792;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Note=Mainly nuclear
CC during the G1, S and G2 phases of the cell cycle. Cytoplasmic
CC during mitosis, after breakup of the nuclear membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=3;
CC IsoId=Q86X55-3; Sequence=Displayed;
CC Name=1;
CC IsoId=Q86X55-1; Sequence=VSP_039876;
CC Name=2;
CC IsoId=Q86X55-2; Sequence=VSP_012506, VSP_012507;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Overexpressed in prostate adenocarcinomas and
CC high-grade prostatic intraepithelial neoplasia.
CC -!- PTM: Auto-methylated on Arg-550. Methylation enhances
CC transcription coactivator activity. Methylation is required for
CC its role in the regulation of pre-mRNA alternative splicing (By
CC similarity).
CC -!- PTM: Phosphorylation at Ser-216 interferes with S-adenosyl-L-
CC methionine binding and strongly reduces methyltransferase activity
CC (By similarity). Phosphorylation at Ser-216 is strongly increased
CC during mitosis, and decreases rapidly to a very low, basal level
CC after entry into the G1 phase of the cell cycle. Phosphorylation
CC at Ser-216 may promote location in the cytosol.
CC -!- SIMILARITY: Belongs to the class I-like SAM-binding
CC methyltransferase superfamily. Protein arginine N-
CC methyltransferase family.
CC -!- SIMILARITY: Contains 1 SAM-dependent MTase PRMT-type domain.
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DR EMBL; AC007565; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC011442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471106; EAW84156.1; -; Genomic_DNA.
DR EMBL; BC046240; AAH46240.1; -; mRNA.
DR EMBL; BC172490; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AL833242; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_954592.1; NM_199141.1.
DR RefSeq; XP_005259765.1; XM_005259708.1.
DR UniGene; Hs.323213; -.
DR PDB; 2Y1W; X-ray; 2.10 A; A/B/C/D=135-482.
DR PDB; 2Y1X; X-ray; 2.40 A; A/B/C/D=135-482.
DR PDB; 4IKP; X-ray; 2.00 A; A/B/C/D=140-480.
DR PDBsum; 2Y1W; -.
DR PDBsum; 2Y1X; -.
DR PDBsum; 4IKP; -.
DR ProteinModelPortal; Q86X55; -.
DR SMR; Q86X55; 27-130, 143-476.
DR IntAct; Q86X55; 20.
DR MINT; MINT-3379851; -.
DR STRING; 9606.ENSP00000325690; -.
DR BindingDB; Q86X55; -.
DR ChEMBL; CHEMBL5406; -.
DR PhosphoSite; Q86X55; -.
DR DMDM; 308153622; -.
DR PaxDb; Q86X55; -.
DR PRIDE; Q86X55; -.
DR DNASU; 10498; -.
DR Ensembl; ENST00000327064; ENSP00000325690; ENSG00000142453.
DR Ensembl; ENST00000344150; ENSP00000340934; ENSG00000142453.
DR GeneID; 10498; -.
DR KEGG; hsa:10498; -.
DR UCSC; uc002mpz.3; human.
DR CTD; 10498; -.
DR GeneCards; GC19P010982; -.
DR H-InvDB; HIX0014757; -.
DR HGNC; HGNC:23393; CARM1.
DR HPA; CAB032961; -.
DR MIM; 603934; gene.
DR neXtProt; NX_Q86X55; -.
DR PharmGKB; PA134959553; -.
DR eggNOG; COG0500; -.
DR HOGENOM; HOG000198522; -.
DR HOVERGEN; HBG050797; -.
DR KO; K05931; -.
DR OMA; HAKKYLR; -.
DR OrthoDB; EOG72NRPM; -.
DR PhylomeDB; Q86X55; -.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; CARM1; human.
DR GenomeRNAi; 10498; -.
DR NextBio; 39836; -.
DR PRO; PR:Q86X55; -.
DR ArrayExpress; Q86X55; -.
DR Bgee; Q86X55; -.
DR CleanEx; HS_CARM1; -.
DR Genevestigator; Q86X55; -.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0008013; F:beta-catenin binding; TAS:AgBase.
DR GO; GO:0070577; F:histone acetyl-lysine binding; ISS:UniProtKB.
DR GO; GO:0035642; F:histone methyltransferase activity (H3-R17 specific); ISS:UniProtKB.
DR GO; GO:0030374; F:ligand-dependent nuclear receptor transcription coactivator activity; ISS:UniProtKB.
DR GO; GO:0035242; F:protein-arginine omega-N asymmetric methyltransferase activity; ISS:UniProtKB.
DR GO; GO:0044212; F:transcription regulatory region DNA binding; ISS:UniProtKB.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0060350; P:endochondral bone morphogenesis; IEA:Ensembl.
DR GO; GO:0034970; P:histone H3-R2 methylation; IMP:UniProtKB.
DR GO; GO:0030520; P:intracellular estrogen receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0032091; P:negative regulation of protein binding; IEA:Ensembl.
DR GO; GO:0009405; P:pathogenesis; IEA:InterPro.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0003420; P:regulation of growth plate cartilage chondrocyte proliferation; IEA:Ensembl.
DR GO; GO:0033146; P:regulation of intracellular estrogen receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; ISS:UniProtKB.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR InterPro; IPR025799; Arg_MeTrfase.
DR InterPro; IPR020989; Histone-Arg_MeTrfase_N.
DR PANTHER; PTHR11006; PTHR11006; 1.
DR Pfam; PF11531; CARM1; 1.
DR Pfam; PF05185; PRMT5; 1.
DR PROSITE; PS51678; SAM_MT_PRMT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Chromatin regulator;
KW Complete proteome; Cytoplasm; Host-virus interaction; Methylation;
KW Methyltransferase; Nucleus; Phosphoprotein; Reference proteome;
KW S-adenosyl-L-methionine; Transcription; Transcription regulation;
KW Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 608 Histone-arginine methyltransferase CARM1.
FT /FTId=PRO_0000212338.
FT DOMAIN 146 453 SAM-dependent MTase PRMT-type.
FT REGION 499 608 Transactivation domain (By similarity).
FT BINDING 159 159 S-adenosyl-L-methionine.
FT BINDING 168 168 S-adenosyl-L-methionine.
FT BINDING 192 192 S-adenosyl-L-methionine; via carbonyl
FT oxygen.
FT BINDING 214 214 S-adenosyl-L-methionine.
FT BINDING 243 243 S-adenosyl-L-methionine.
FT BINDING 271 271 S-adenosyl-L-methionine.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 216 216 Phosphoserine.
FT MOD_RES 550 550 Dimethylated arginine (By similarity).
FT VAR_SEQ 369 384 RIEIPFKFHMLHSGLV -> SACLASPAATALCLPG (in
FT isoform 2).
FT /FTId=VSP_012506.
FT VAR_SEQ 385 608 Missing (in isoform 2).
FT /FTId=VSP_012507.
FT VAR_SEQ 539 561 Missing (in isoform 1).
FT /FTId=VSP_039876.
FT HELIX 136 140
FT HELIX 145 152
FT HELIX 156 163
FT HELIX 166 177
FT HELIX 178 182
FT TURN 183 185
FT STRAND 187 192
FT HELIX 197 204
FT STRAND 208 214
FT HELIX 218 228
FT TURN 232 234
FT STRAND 235 240
FT TURN 242 244
FT STRAND 251 256
FT TURN 264 266
FT HELIX 268 274
FT HELIX 275 278
FT STRAND 279 287
FT STRAND 289 297
FT HELIX 300 310
FT HELIX 311 314
FT HELIX 324 326
FT HELIX 327 335
FT STRAND 339 341
FT HELIX 345 347
FT STRAND 353 358
FT TURN 359 361
FT HELIX 364 368
FT STRAND 369 377
FT STRAND 382 396
FT STRAND 401 405
FT STRAND 417 428
FT STRAND 433 442
FT STRAND 446 456
FT TURN 457 459
FT STRAND 462 468
SQ SEQUENCE 608 AA; 65854 MW; 094AC60D4A70B263 CRC64;
MAAAAAAVGP GAGGAGSAVP GGAGPCATVS VFPGARLLTI GDANGEIQRH AEQQALRLEV
RAGPDSAGIA LYSHEDVCVF KCSVSRETEC SRVGKQSFII TLGCNSVLIQ FATPNDFCSF
YNILKTCRGH TLERSVFSER TEESSAVQYF QFYGYLSQQQ NMMQDYVRTG TYQRAILQNH
TDFKDKIVLD VGCGSGILSF FAAQAGARKI YAVEASTMAQ HAEVLVKSNN LTDRIVVIPG
KVEEVSLPEQ VDIIISEPMG YMLFNERMLE SYLHAKKYLK PSGNMFPTIG DVHLAPFTDE
QLYMEQFTKA NFWYQPSFHG VDLSALRGAA VDEYFRQPVV DTFDIRILMA KSVKYTVNFL
EAKEGDLHRI EIPFKFHMLH SGLVHGLAFW FDVAFIGSIM TVWLSTAPTE PLTHWYQVRC
LFQSPLFAKA GDTLSGTCLL IANKRQSYDI SIVAQVDQTG SKSSNLLDLK NPFFRYTGTT
PSPPPGSHYT SPSENMWNTG STYNLSSGMA VAGMPTAYDL SSVIASGSSV GHNNLIPLAN
TGIVNHTHSR MGSIMSTGIV QGSSGAQGSG GGSTSAHYAV NSQFTMGGPA ISMASPMSIP
TNTMHYGS
//
ID CARM1_HUMAN Reviewed; 608 AA.
AC Q86X55; A6NN38;
DT 04-JAN-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-OCT-2010, sequence version 3.
DT 22-JAN-2014, entry version 105.
DE RecName: Full=Histone-arginine methyltransferase CARM1;
DE EC=2.1.1.-;
DE EC=2.1.1.125;
DE AltName: Full=Coactivator-associated arginine methyltransferase 1;
DE AltName: Full=Protein arginine N-methyltransferase 4;
GN Name=CARM1; Synonyms=PRMT4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND NUCLEOTIDE SEQUENCE [MRNA]
RP OF 194-608 (ISOFORM 1).
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 43-608 (ISOFORM 2).
RC TISSUE=Amygdala;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP METHYLATION OF ELAVL1.
RX PubMed=12237300; DOI=10.1074/jbc.M206187200;
RA Li H., Park S., Kilburn B., Jelinek M.A., Henschen-Edman A.,
RA Aswad D.W., Stallcup M.R., Laird-Offringa I.A.;
RT "Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing
RT protein, by CARM1. Coactivator-associated arginine
RT methyltransferase.";
RL J. Biol. Chem. 277:44623-44630(2002).
RN [6]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=15221992; DOI=10.1002/cncr.20327;
RA Hong H., Kao C., Jeng M.-H., Eble J.N., Koch M.O., Gardner T.A.,
RA Zhang S., Li L., Pan C.-X., Hu Z., MacLennan G.T., Cheng L.;
RT "Aberrant expression of CARM1, a transcriptional coactivator of
RT androgen receptor, in the development of prostate carcinoma and
RT androgen-independent status.";
RL Cancer 101:83-89(2004).
RN [7]
RP INTERACTION WITH NR1H4.
RX PubMed=15471871; DOI=10.1074/jbc.M410021200;
RA Ananthanarayanan M., Li S., Balasubramaniyan N., Suchy F.J.,
RA Walsh M.J.;
RT "Ligand-dependent activation of the farnesoid X-receptor directs
RT arginine methylation of histone H3 by CARM1.";
RL J. Biol. Chem. 279:54348-54357(2004).
RN [8]
RP METHYLATION OF EP300.
RX PubMed=15731352; DOI=10.1073/pnas.0407159102;
RA Lee Y.-H., Coonrod S.A., Kraus W.L., Jelinek M.A., Stallcup M.R.;
RT "Regulation of coactivator complex assembly and function by protein
RT arginine methylation and demethylimination.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:3611-3616(2005).
RN [9]
RP INTERACTION WITH HTLV-1 TAX-1.
RX PubMed=17005681; DOI=10.1128/JVI.00186-06;
RA Jeong S.J., Lu H., Cho W.K., Park H.U., Pise-Masison C., Brady J.N.;
RT "Coactivator-associated arginine methyltransferase 1 enhances
RT transcriptional activity of the human T-cell lymphotropic virus type 1
RT long terminal repeat through direct interaction with Tax.";
RL J. Virol. 80:10036-10044(2006).
RN [10]
RP METHYLATION OF HISTONE H3, INTERACTION WITH RELA, AND FUNCTION.
RX PubMed=16497732; DOI=10.1210/me.2005-0365;
RA Miao F., Li S., Chavez V., Lanting L., Natarajan R.;
RT "Coactivator-associated arginine methyltransferase-1 enhances nuclear
RT factor-kappaB-mediated gene transcription through methylation of
RT histone H3 at arginine 17.";
RL Mol. Endocrinol. 20:1562-1573(2006).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=19405910; DOI=10.1042/BJ20090268;
RA Lakowski T.M., Frankel A.;
RT "Kinetic analysis of human protein arginine N-methyltransferase 2:
RT formation of monomethyl- and asymmetric dimethyl-arginine residues on
RT histone H4.";
RL Biochem. J. 421:253-261(2009).
RN [13]
RP PHOSPHORYLATION AT SER-216, SUBCELLULAR LOCATION, AND MASS
RP SPECTROMETRY.
RX PubMed=19843527; DOI=10.1074/jbc.M109.065524;
RA Feng Q., He B., Jung S.Y., Song Y., Qin J., Tsai S.Y., Tsai M.J.,
RA O'Malley B.W.;
RT "Biochemical control of CARM1 enzymatic activity by phosphorylation.";
RL J. Biol. Chem. 284:36167-36174(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 135-482 IN COMPLEX WITH SAM
RP ANALOG AND INHIBITORS, AND SAM BINDING SITES.
RX PubMed=21410432; DOI=10.1042/BJ20102161;
RA Sack J.S., Thieffine S., Bandiera T., Fasolini M., Duke G.J.,
RA Jayaraman L., Kish K.F., Klei H.E., Purandare A.V., Rosettani P.,
RA Troiani S., Xie D., Bertrand J.A.;
RT "Structural basis for CARM1 inhibition by indole and pyrazole
RT inhibitors.";
RL Biochem. J. 436:331-339(2011).
CC -!- FUNCTION: Methylates (mono- and asymmetric dimethylation) the
CC guanidino nitrogens of arginyl residues in several proteins
CC involved in DNA packaging, transcription regulation, pre-mRNA
CC splicing, and mRNA stability. Recruited to promoters upon gene
CC activation together with histone acetyltransferases from
CC EP300/P300 and p160 families, methylates histone H3 at 'Arg-17'
CC (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a),
CC leading to activate transcription via chromatin remodeling. During
CC nuclear hormone receptor activation and TCF7L2/TCF4 activation,
CC acts synergically with EP300/P300 and either one of the p160
CC histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR
CC or CTNNB1/beta-catenin to activate transcription. During myogenic
CC transcriptional activation, acts together with NCOA3/ACTR as a
CC coactivator for MEF2C. During monocyte inflammatory stimulation,
CC acts together with EP300/P300 as a coactivator for NF-kappa-B.
CC Acts as coactivator for PPARG, promotes adipocyte differentiation
CC and the accumulation of brown fat tissue. Plays a role in the
CC regulation of pre-mRNA alternative splicing by methylation of
CC splicing factors. Also seems to be involved in p53/TP53
CC transcriptional activation. Methylates EP300/P300, both at 'Arg-
CC 2142', which may loosen its interaction with NCOA2/GRIP1, and at
CC 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its
CC interaction with CREB and inhibits CREB-dependent transcriptional
CC activation. Also methylates arginine residues in RNA-binding
CC proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-
CC stabilizing properties and the half-life of their target mRNAs.
CC -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine + arginine-[histone] =
CC S-adenosyl-L-homocysteine + N(omega)-methyl-arginine-[histone].
CC -!- ENZYME REGULATION: Methylation of H3R17 (H3R17me) by CARM1 is
CC stimulated by preacetylation of H3 'Lys-18' (H3K18ac) H3 'Lys-23'
CC (H3K23ac) by EP300 and blocked by citrullination of H3 'Arg-17'
CC (H3R17ci) by PADI4 (By similarity).
CC -!- SUBUNIT: Homodimer (Probable). Interacts with the C-terminus of
CC NCOA2/GRIP1, NCO3/ACTR and NCOA1/SRC1. Part of a complex
CC consisting of CARM1, EP300/P300 and NCOA2/GRIP1. Interacts with
CC FLII, TP53, myogenic factor MEF2, EP300/P300, TRIM24, CREBBP and
CC CTNNB1. Identified in a complex containing CARM1, TRIM24 and
CC NCOA2/GRIP1. Interacts with NCOA3/SRC3. Interacts with SNRPC (By
CC similarity). Interacts with NR1H4. Interacts with RELA. Interacts
CC with HTLV-1 Tax-1.
CC -!- INTERACTION:
CC P17676:CEBPB; NbExp=2; IntAct=EBI-2339854, EBI-969696;
CC Q05826:CEBPB (xeno); NbExp=3; IntAct=EBI-2339854, EBI-7774198;
CC Q96EY1:DNAJA3; NbExp=2; IntAct=EBI-2339854, EBI-356767;
CC O43809:NUDT21; NbExp=2; IntAct=EBI-2339854, EBI-355720;
CC Q96PU8:QKI; NbExp=2; IntAct=EBI-2339854, EBI-945792;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Note=Mainly nuclear
CC during the G1, S and G2 phases of the cell cycle. Cytoplasmic
CC during mitosis, after breakup of the nuclear membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=3;
CC IsoId=Q86X55-3; Sequence=Displayed;
CC Name=1;
CC IsoId=Q86X55-1; Sequence=VSP_039876;
CC Name=2;
CC IsoId=Q86X55-2; Sequence=VSP_012506, VSP_012507;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Overexpressed in prostate adenocarcinomas and
CC high-grade prostatic intraepithelial neoplasia.
CC -!- PTM: Auto-methylated on Arg-550. Methylation enhances
CC transcription coactivator activity. Methylation is required for
CC its role in the regulation of pre-mRNA alternative splicing (By
CC similarity).
CC -!- PTM: Phosphorylation at Ser-216 interferes with S-adenosyl-L-
CC methionine binding and strongly reduces methyltransferase activity
CC (By similarity). Phosphorylation at Ser-216 is strongly increased
CC during mitosis, and decreases rapidly to a very low, basal level
CC after entry into the G1 phase of the cell cycle. Phosphorylation
CC at Ser-216 may promote location in the cytosol.
CC -!- SIMILARITY: Belongs to the class I-like SAM-binding
CC methyltransferase superfamily. Protein arginine N-
CC methyltransferase family.
CC -!- SIMILARITY: Contains 1 SAM-dependent MTase PRMT-type domain.
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DR EMBL; AC007565; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC011442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471106; EAW84156.1; -; Genomic_DNA.
DR EMBL; BC046240; AAH46240.1; -; mRNA.
DR EMBL; BC172490; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AL833242; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_954592.1; NM_199141.1.
DR RefSeq; XP_005259765.1; XM_005259708.1.
DR UniGene; Hs.323213; -.
DR PDB; 2Y1W; X-ray; 2.10 A; A/B/C/D=135-482.
DR PDB; 2Y1X; X-ray; 2.40 A; A/B/C/D=135-482.
DR PDB; 4IKP; X-ray; 2.00 A; A/B/C/D=140-480.
DR PDBsum; 2Y1W; -.
DR PDBsum; 2Y1X; -.
DR PDBsum; 4IKP; -.
DR ProteinModelPortal; Q86X55; -.
DR SMR; Q86X55; 27-130, 143-476.
DR IntAct; Q86X55; 20.
DR MINT; MINT-3379851; -.
DR STRING; 9606.ENSP00000325690; -.
DR BindingDB; Q86X55; -.
DR ChEMBL; CHEMBL5406; -.
DR PhosphoSite; Q86X55; -.
DR DMDM; 308153622; -.
DR PaxDb; Q86X55; -.
DR PRIDE; Q86X55; -.
DR DNASU; 10498; -.
DR Ensembl; ENST00000327064; ENSP00000325690; ENSG00000142453.
DR Ensembl; ENST00000344150; ENSP00000340934; ENSG00000142453.
DR GeneID; 10498; -.
DR KEGG; hsa:10498; -.
DR UCSC; uc002mpz.3; human.
DR CTD; 10498; -.
DR GeneCards; GC19P010982; -.
DR H-InvDB; HIX0014757; -.
DR HGNC; HGNC:23393; CARM1.
DR HPA; CAB032961; -.
DR MIM; 603934; gene.
DR neXtProt; NX_Q86X55; -.
DR PharmGKB; PA134959553; -.
DR eggNOG; COG0500; -.
DR HOGENOM; HOG000198522; -.
DR HOVERGEN; HBG050797; -.
DR KO; K05931; -.
DR OMA; HAKKYLR; -.
DR OrthoDB; EOG72NRPM; -.
DR PhylomeDB; Q86X55; -.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; CARM1; human.
DR GenomeRNAi; 10498; -.
DR NextBio; 39836; -.
DR PRO; PR:Q86X55; -.
DR ArrayExpress; Q86X55; -.
DR Bgee; Q86X55; -.
DR CleanEx; HS_CARM1; -.
DR Genevestigator; Q86X55; -.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0008013; F:beta-catenin binding; TAS:AgBase.
DR GO; GO:0070577; F:histone acetyl-lysine binding; ISS:UniProtKB.
DR GO; GO:0035642; F:histone methyltransferase activity (H3-R17 specific); ISS:UniProtKB.
DR GO; GO:0030374; F:ligand-dependent nuclear receptor transcription coactivator activity; ISS:UniProtKB.
DR GO; GO:0035242; F:protein-arginine omega-N asymmetric methyltransferase activity; ISS:UniProtKB.
DR GO; GO:0044212; F:transcription regulatory region DNA binding; ISS:UniProtKB.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0060350; P:endochondral bone morphogenesis; IEA:Ensembl.
DR GO; GO:0034970; P:histone H3-R2 methylation; IMP:UniProtKB.
DR GO; GO:0030520; P:intracellular estrogen receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0032091; P:negative regulation of protein binding; IEA:Ensembl.
DR GO; GO:0009405; P:pathogenesis; IEA:InterPro.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0003420; P:regulation of growth plate cartilage chondrocyte proliferation; IEA:Ensembl.
DR GO; GO:0033146; P:regulation of intracellular estrogen receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; ISS:UniProtKB.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR InterPro; IPR025799; Arg_MeTrfase.
DR InterPro; IPR020989; Histone-Arg_MeTrfase_N.
DR PANTHER; PTHR11006; PTHR11006; 1.
DR Pfam; PF11531; CARM1; 1.
DR Pfam; PF05185; PRMT5; 1.
DR PROSITE; PS51678; SAM_MT_PRMT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Chromatin regulator;
KW Complete proteome; Cytoplasm; Host-virus interaction; Methylation;
KW Methyltransferase; Nucleus; Phosphoprotein; Reference proteome;
KW S-adenosyl-L-methionine; Transcription; Transcription regulation;
KW Transferase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 608 Histone-arginine methyltransferase CARM1.
FT /FTId=PRO_0000212338.
FT DOMAIN 146 453 SAM-dependent MTase PRMT-type.
FT REGION 499 608 Transactivation domain (By similarity).
FT BINDING 159 159 S-adenosyl-L-methionine.
FT BINDING 168 168 S-adenosyl-L-methionine.
FT BINDING 192 192 S-adenosyl-L-methionine; via carbonyl
FT oxygen.
FT BINDING 214 214 S-adenosyl-L-methionine.
FT BINDING 243 243 S-adenosyl-L-methionine.
FT BINDING 271 271 S-adenosyl-L-methionine.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 216 216 Phosphoserine.
FT MOD_RES 550 550 Dimethylated arginine (By similarity).
FT VAR_SEQ 369 384 RIEIPFKFHMLHSGLV -> SACLASPAATALCLPG (in
FT isoform 2).
FT /FTId=VSP_012506.
FT VAR_SEQ 385 608 Missing (in isoform 2).
FT /FTId=VSP_012507.
FT VAR_SEQ 539 561 Missing (in isoform 1).
FT /FTId=VSP_039876.
FT HELIX 136 140
FT HELIX 145 152
FT HELIX 156 163
FT HELIX 166 177
FT HELIX 178 182
FT TURN 183 185
FT STRAND 187 192
FT HELIX 197 204
FT STRAND 208 214
FT HELIX 218 228
FT TURN 232 234
FT STRAND 235 240
FT TURN 242 244
FT STRAND 251 256
FT TURN 264 266
FT HELIX 268 274
FT HELIX 275 278
FT STRAND 279 287
FT STRAND 289 297
FT HELIX 300 310
FT HELIX 311 314
FT HELIX 324 326
FT HELIX 327 335
FT STRAND 339 341
FT HELIX 345 347
FT STRAND 353 358
FT TURN 359 361
FT HELIX 364 368
FT STRAND 369 377
FT STRAND 382 396
FT STRAND 401 405
FT STRAND 417 428
FT STRAND 433 442
FT STRAND 446 456
FT TURN 457 459
FT STRAND 462 468
SQ SEQUENCE 608 AA; 65854 MW; 094AC60D4A70B263 CRC64;
MAAAAAAVGP GAGGAGSAVP GGAGPCATVS VFPGARLLTI GDANGEIQRH AEQQALRLEV
RAGPDSAGIA LYSHEDVCVF KCSVSRETEC SRVGKQSFII TLGCNSVLIQ FATPNDFCSF
YNILKTCRGH TLERSVFSER TEESSAVQYF QFYGYLSQQQ NMMQDYVRTG TYQRAILQNH
TDFKDKIVLD VGCGSGILSF FAAQAGARKI YAVEASTMAQ HAEVLVKSNN LTDRIVVIPG
KVEEVSLPEQ VDIIISEPMG YMLFNERMLE SYLHAKKYLK PSGNMFPTIG DVHLAPFTDE
QLYMEQFTKA NFWYQPSFHG VDLSALRGAA VDEYFRQPVV DTFDIRILMA KSVKYTVNFL
EAKEGDLHRI EIPFKFHMLH SGLVHGLAFW FDVAFIGSIM TVWLSTAPTE PLTHWYQVRC
LFQSPLFAKA GDTLSGTCLL IANKRQSYDI SIVAQVDQTG SKSSNLLDLK NPFFRYTGTT
PSPPPGSHYT SPSENMWNTG STYNLSSGMA VAGMPTAYDL SSVIASGSSV GHNNLIPLAN
TGIVNHTHSR MGSIMSTGIV QGSSGAQGSG GGSTSAHYAV NSQFTMGGPA ISMASPMSIP
TNTMHYGS
//
MIM
603934
*RECORD*
*FIELD* NO
603934
*FIELD* TI
*603934 COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1; CARM1
;;PROTEIN ARGININE N-METHYLTRANSFERASE 4; PRMT4
read more*FIELD* TX
DESCRIPTION
Protein arginine N-methyltransferases, such as CARM1, catalyze the
transfer of a methyl group from S-adenosyl-L-methionine to the side
chain nitrogens of arginine residues within proteins to form methylated
arginine derivatives and S-adenosyl-L-homocysteine. Protein arginine
methylation has been implicated in signal transduction, metabolism of
nascent pre-RNA, and transcriptional activation (Frankel et al., 2002).
CLONING
Members of the p160 family of proteins, which includes SRC1 (NCOA1;
602691) and GRIP1 (NCOA2; 601993), mediate transcriptional activation by
nuclear hormone receptors. The AD2 activation domain, found in the
C-terminal region of p160 proteins, plays an important role in p160
coactivator function. Using a yeast 2-hybrid system to screen a mouse 17
day-embryo cDNA library, Chen et al. (1999) isolated a cDNA clone
encoding a 608-amino acid protein that bound to the C-terminal amino
acids of GRIP1. The central portion of the coding region had extensive
homology to a family of proteins with arginine-specific protein
methyltransferase activity. The protein, coactivator-associated arginine
methyltransferase-1 (CARM1), has a 3.8-kb mRNA that is widely but not
evenly expressed in adult mouse tissues.
Ohkura et al. (2005) identified 4 alternatively-spliced rat Carm1 cDNAs,
Carm1-v1 through Carm1-v4. The deduced proteins have between 573 and 608
amino acids. All contain the arginine methyltransferase domain and
Grip1-binding domain, but they differ in their C-terminal domains.
RT-PCR detected tissue-specific expression of the 4 transcripts.
By database analysis, Frankel et al. (2002) identified human PRMT4,
which encodes a 608-amino acid protein. The catalytic core region of
PRMT4 shares 29 to 36% amino acid identity with those of other PRMTs.
GENE FUNCTION
Because CARM1 is homologous to protein arginine methyltransferases, Chen
et al. (1999) tested it for methyltransferase activity. Protein arginine
methyltransferases transfer a methyl group from S-adenosylmethionine to
the guanidino group nitrogen atoms in arginine residues of specific
proteins. In vitro protein substrates for these enzymes include histones
(see 142711) and proteins involved in RNA metabolism such as hnRNPA1
(164017), fibrillarin (134795), and nucleolin (164035). CARM1
preferentially methylated histone H3, either in a bulk histone
preparation or in individually purified form. CARM1 coactivator function
was specific for AD2 and correlated with its ability to bind GRIP1.
CARM1 enhanced GRIP1 coactivator function for nuclear hormone receptors.
The presence of both protein methyltransferase and transcriptional
coactivator activities in CARM1 suggested that methylation of histones
or other proteins, or both, may play a role in transcriptional
regulation. CARM1 cDNA with the mutation in the putative
S-adenosylmethionine-binding domain substantially reduced both
methyltransferase and coactivator activities. In addition to GRIP1,
CARM1 was also able to interact with other members of the p160 family of
coactivators, including SRC1. Thus, coactivator-mediated methylation of
proteins in the transcription machinery may contribute to
transcriptional regulation.
Xu et al. (2001) described a molecular switch based on the controlled
methylation of nucleosomes and the transcriptional cofactors, CBP
(CREBBP; 600140)/p300 (EP300; 602700). These proteins share a
methylation site localized to an arginine residue that is essential for
stabilizing the structure of the KIX domain, which mediates CREB (CREB1;
123810) recruitment. Methylation of KIX by CARM1 blocks CREB activation
by disabling the interaction between KIX and the kinase-inducible domain
of CREB. Methylation analysis indicated that CARM1 methylates H3
acetylated nucleosomes in core histones and also, preferentially, p300.
Xu et al. (2001) concluded that CARM1 functions as a corepressor in the
cAMP signaling pathway via its methyltransferase activity while acting
as a coactivator for nuclear hormones. CARM1 thus has chromatin and
nonchromatin substrates. On the basis of in vitro and in vivo analyses,
they proposed that histone methylation plays a key role in
hormone-induced gene activation and that cofactor methylation is a
regulatory mechanism in hormone signaling. Xu et al. (2001) suggested
that their findings support the methylation 'code' hypothesis of
Jenuwein and Allis (2001).
Using systems reconstituted with recombinant chromatin templates and
coactivators, An et al. (2004) demonstrated the involvement of PRMT1
(602950) and CARM1 in p53 (191170) function; both independent and
ordered cooperative functions of p300, PRMT1, and CARM1; and mechanisms
involving direct interactions with p53 and obligatory modifications of
corresponding histone substrates. Chromatin immunoprecipitation analyses
confirmed the ordered accumulation of these (and other) coactivators and
cognate histone modifications on a p53-responsive gene, GADD45 (126335),
following ectopic p53 expression and/or ultraviolet irradiation.
HuR (ELAVL1; 603466) is an RNA-binding protein that stabilizes mRNAs
carrying AU-rich instability elements (AREs). Li et al. (2002) found
that mammalian Carm1 associated with HuR and activated HuR via
methylation in vitro and in vivo. HuR methylation increased in cells
that overexpressed Carm1, and lipopolysaccharide stimulation of mouse
macrophages caused increased methylation of endogenous HuR, leading to
the stabilization of TNF-alpha (TNF; 191160) mRNA.
Chen et al. (2002) demonstrated that Carm1 and Grip1 cooperatively
stimulated the activity of Mef2c (600662) in mouse mesenchymal stem
cells and found that there was direct interaction among Mef2c, Grip1,
and Carm1. Chromatin immunoprecipitation assays demonstrated the in vivo
recruitment of Mef2 and Carm1 to the endogenous muscle creatine kinase
(CKM; 123310) promoter in a differentiation-dependent manner.
Furthermore, Carm1 was expressed in somites during mouse embryogenesis
and in the nuclei of muscle cells. Treatment of myogenic cells with a
methylation inhibitor or antisense Carm1 did not affect expression of
Myod (see MYOD1; 159970), but it inhibited differentiation and abrogated
the expression of key transcription factors myogenin (MYOG; 159980) and
Mef2 that initiate the differentiation cascade.
Ohkura et al. (2005) showed that rat Carm1-v3 associated with SNRPC
(603522) and affected 5-prime splice site selection during pre-mRNA
splicing. Carm1-v3, but not the other isoforms, stimulated a shift to
the distal 5-prime splice site of the pre-mRNA when the adenoviral E1A
minigene was used as a reporter and enhanced exons skipping in the CD44
(107269) reporter. The v3-specific C terminal and regions conserved
among the isoforms were required for this activity, but arginine
methyltransferase activity was not. Among the 4 rat Carm1 isoforms,
Carm1-v3 showed the highest activity as a cofactor for reporter activity
from an estrogen-responsive element (ERE), both in the presence and
absence of Grip1. Carm1-v1, but not Carm1-v3, showed reduced coactivator
activity from the ERE when arginine methyltransferase activity was lost.
All Carm1 variants showed comparable methylation of histone H3.
Using mouse and human cells, El Messaoudi et al. (2006) showed that
CARM1 is a regulator of cyclin E1 (CCNE1; 123837) and DHFR (126060) mRNA
expression.
By screening for methylated proteins in a mouse B-cell line, followed by
in vitro and in vivo methylation assays, Cheng et al. (2007) identified
Smb (SNRPB; 182282), Sap49 (SF3B4; 605593), U1c (SNRPC), and Ca150
(TCERG1; 605409) as splicing factors targeted by Carm1. Human CARM1
altered the patterns of exon choice in splicing a CD44 reporter minigene
and endogenous CD44 in mouse and human cell lines.
The carboxy-terminal domain of RNA polymerase II (see 180660) in mammals
undergoes extensive posttranslational modification, which is essential
for transcriptional initiation and elongation. Sims et al. (2011) showed
that the carboxy-terminal domain of RNA polymerase II is methylated at a
single arginine (R1810) by CARM1. Although methylation at R1810 is
present on the hyperphosphorylated form of RNA polymerase II in vivo,
ser2 or ser5 phosphorylation inhibits CARM1 activity toward this site in
vitro, suggesting that methylation occurs before transcription
initiation. Mutation of R1810 results in the misexpression of a variety
of small nuclear RNAs and small nucleolar RNAs, an effect that is also
observed in Carm1 -/- mouse embryo fibroblasts. Sims et al. (2011)
concluded that carboxy-terminal domain methylation facilitates the
expression of select RNAs, perhaps serving to discriminate the RNA
polymerase II-associated machinery recruited to distinct gene types.
Sanchez et al. (2013) found that Carm1 mRNA coimmunoprecipitated with
Smn1 (600354) in polyribosomes isolated from mouse motoneuron-derived
MN-1 cells. In vitro-translated human SMN1 repressed translation of
Carm1 mRNA, but had no effect on global mRNA translation, in MN-1 cells.
GENE STRUCTURE
Frankel et al. (2002) determined that the CARM1 gene contains 16 exons.
MAPPING
By genomic sequence analysis, Frankel et al. (2002) mapped the CARM1
gene to chromosome 19.
ANIMAL MODEL
Yadav et al. (2003) showed that mouse embryos with a targeted disruption
of the Carm1 gene were small in size and died perinatally. The
methylation of 2 Carm1 substrates, Pabp1 (604679) and the
transcriptional cofactor p300 (602303), was abolished in knockout
embryos and cells. Furthermore, estrogen-responsive gene expression was
aberrant in Carm1 -/- fibroblasts and embryos.
*FIELD* RF
1. An, W.; Kim, J.; Roeder, R. G.: Ordered cooperative functions
of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117:
735-748, 2004.
2. Chen, D.; Ma, H.; Hong, H.; Koh, S. S.; Huang, S.-M.; Schurter,
B. T.; Aswad, D. W.; Stallcup, M. R.: Regulation of transcription
by a protein methyltransferase. Science 284: 2174-2177, 1999.
3. Chen, S. L.; Loffler, K. A.; Chen, D.; Stallcup, M. R.; Muscat,
G. E. O.: The coactivator-associated arginine methyltransferase is
necessary for muscle differentiation: CARM1 coactivates myocyte enhancer
factor-2. J. Biol. Chem. 277: 4324-4333, 2002.
4. Cheng, D.; Cote, J.; Shaaban, S.; Bedford, M. T.: The arginine
methyltransferase CARM1 regulates the coupling of transcription and
mRNA processing. Molec. Cell 25: 71-83, 2007.
5. El Messaoudi, S. E.; Fabbrizio, E.; Rodriguez, C.; Chuchana, P.;
Fauquier, L.; Cheng, D.; Theillet, C.; Vandel, L.; Bedford, M. T.;
Sardet, C.: Coactivator-associated arginine methyltransferase 1 (CARM1)
is a positive regulator of the cyclin E1 gene. Proc. Nat. Acad. Sci. 103:
13351-13356, 2006.
6. Frankel, A.; Yadav, N.; Lee, J.; Branscombe, T. L.; Clarke, S.;
Bedford, M. T.: The novel human protein arginine N-methyltransferase
PRMT6 is a nuclear enzyme displaying unique substrate specificity. J.
Biol. Chem. 277: 3537-3543, 2002.
7. Jenuwein, T.; Allis, C. D.: Translating the histone code. Science 293:
1074-1080, 2001.
8. Li, H.; Park, S.; Kilburn, B.; Jelinek, M. A.; Henschen-Edman,
A.; Aswad, D. W.; Stallcup, M. R.; Laird-Offringa, I. A.: Lipopolysaccharide-induced
methylation of HuR, an mRNA-stabilizing protein, by CARM1. J. Biol.
Chem. 277: 44623-44630, 2002.
9. Ohkura, N.; Takahashi, M.; Yaguchi, H.; Nagamura, Y.; Tsukada,
T.: Coactivator-associated arginine methyltransferase 1, CARM1, affects
pre-mRNA splicing in an isoform-specific manner. J. Biol. Chem. 280:
28927-28935, 2005.
10. Sanchez, G.; Dury, A. Y.; Murray, L. M.; Biondi, O.; Tadesse,
H.; El Fatimy, R.; Kothary, R.; Charbonnier, F.; Khandjian, E. W.;
Cote, J.: A novel function for the survival motoneuron protein as
a translational regulator. Hum. Molec. Genet. 22: 668-684, 2013.
11. Sims, R. J., III; Rojas, L. A.; Beck, D.; Bonasio, R.; Schuller,
R.; Drury, W. J., III; Eick, D.; Reinberg, D.: The C-terminal domain
of RNA polymerase II is modified by site-specific methylation. Science 332:
99-103, 2011.
12. Xu, W.; Chen, H.; Du, K.; Asahara, H.; Tini, M.; Emerson, B. M.;
Montminy, M.; Evans, R. M.: A transcriptional switch mediated by
cofactor methylation. Science 294: 2507-2511, 2001.
13. Yadav, N.; Lee, J.; Kim, J.; Shen, J.; Hu, M. C.-T.; Aldaz, C.
M.; Bedford, M. T.: Specific protein methylation defects and gene
expression perturbations in coactivator-associated arginine methyltransferase
1-deficient mice. Proc. Nat. Acad. Sci. 100: 6464-6468, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 07/17/2013
Ada Hamosh - updated: 5/3/2011
Patricia A. Hartz - updated: 2/9/2007
Patricia A. Hartz - updated: 10/4/2006
Patricia A. Hartz - updated: 8/14/2006
Patricia A. Hartz - updated: 8/9/2006
Stylianos E. Antonarakis - updated: 8/5/2004
Victor A. McKusick - updated: 6/25/2003
Paul J. Converse - updated: 1/2/2002
*FIELD* CD
Ada Hamosh: 6/25/1999
*FIELD* ED
mgross: 07/17/2013
alopez: 5/6/2011
terry: 5/3/2011
mgross: 2/9/2007
mgross: 10/6/2006
terry: 10/4/2006
wwang: 8/14/2006
terry: 8/9/2006
mgross: 4/27/2006
mgross: 9/14/2004
mgross: 8/5/2004
tkritzer: 6/26/2003
tkritzer: 6/25/2003
mgross: 1/2/2002
alopez: 8/11/1999
carol: 6/27/1999
alopez: 6/25/1999
*RECORD*
*FIELD* NO
603934
*FIELD* TI
*603934 COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1; CARM1
;;PROTEIN ARGININE N-METHYLTRANSFERASE 4; PRMT4
read more*FIELD* TX
DESCRIPTION
Protein arginine N-methyltransferases, such as CARM1, catalyze the
transfer of a methyl group from S-adenosyl-L-methionine to the side
chain nitrogens of arginine residues within proteins to form methylated
arginine derivatives and S-adenosyl-L-homocysteine. Protein arginine
methylation has been implicated in signal transduction, metabolism of
nascent pre-RNA, and transcriptional activation (Frankel et al., 2002).
CLONING
Members of the p160 family of proteins, which includes SRC1 (NCOA1;
602691) and GRIP1 (NCOA2; 601993), mediate transcriptional activation by
nuclear hormone receptors. The AD2 activation domain, found in the
C-terminal region of p160 proteins, plays an important role in p160
coactivator function. Using a yeast 2-hybrid system to screen a mouse 17
day-embryo cDNA library, Chen et al. (1999) isolated a cDNA clone
encoding a 608-amino acid protein that bound to the C-terminal amino
acids of GRIP1. The central portion of the coding region had extensive
homology to a family of proteins with arginine-specific protein
methyltransferase activity. The protein, coactivator-associated arginine
methyltransferase-1 (CARM1), has a 3.8-kb mRNA that is widely but not
evenly expressed in adult mouse tissues.
Ohkura et al. (2005) identified 4 alternatively-spliced rat Carm1 cDNAs,
Carm1-v1 through Carm1-v4. The deduced proteins have between 573 and 608
amino acids. All contain the arginine methyltransferase domain and
Grip1-binding domain, but they differ in their C-terminal domains.
RT-PCR detected tissue-specific expression of the 4 transcripts.
By database analysis, Frankel et al. (2002) identified human PRMT4,
which encodes a 608-amino acid protein. The catalytic core region of
PRMT4 shares 29 to 36% amino acid identity with those of other PRMTs.
GENE FUNCTION
Because CARM1 is homologous to protein arginine methyltransferases, Chen
et al. (1999) tested it for methyltransferase activity. Protein arginine
methyltransferases transfer a methyl group from S-adenosylmethionine to
the guanidino group nitrogen atoms in arginine residues of specific
proteins. In vitro protein substrates for these enzymes include histones
(see 142711) and proteins involved in RNA metabolism such as hnRNPA1
(164017), fibrillarin (134795), and nucleolin (164035). CARM1
preferentially methylated histone H3, either in a bulk histone
preparation or in individually purified form. CARM1 coactivator function
was specific for AD2 and correlated with its ability to bind GRIP1.
CARM1 enhanced GRIP1 coactivator function for nuclear hormone receptors.
The presence of both protein methyltransferase and transcriptional
coactivator activities in CARM1 suggested that methylation of histones
or other proteins, or both, may play a role in transcriptional
regulation. CARM1 cDNA with the mutation in the putative
S-adenosylmethionine-binding domain substantially reduced both
methyltransferase and coactivator activities. In addition to GRIP1,
CARM1 was also able to interact with other members of the p160 family of
coactivators, including SRC1. Thus, coactivator-mediated methylation of
proteins in the transcription machinery may contribute to
transcriptional regulation.
Xu et al. (2001) described a molecular switch based on the controlled
methylation of nucleosomes and the transcriptional cofactors, CBP
(CREBBP; 600140)/p300 (EP300; 602700). These proteins share a
methylation site localized to an arginine residue that is essential for
stabilizing the structure of the KIX domain, which mediates CREB (CREB1;
123810) recruitment. Methylation of KIX by CARM1 blocks CREB activation
by disabling the interaction between KIX and the kinase-inducible domain
of CREB. Methylation analysis indicated that CARM1 methylates H3
acetylated nucleosomes in core histones and also, preferentially, p300.
Xu et al. (2001) concluded that CARM1 functions as a corepressor in the
cAMP signaling pathway via its methyltransferase activity while acting
as a coactivator for nuclear hormones. CARM1 thus has chromatin and
nonchromatin substrates. On the basis of in vitro and in vivo analyses,
they proposed that histone methylation plays a key role in
hormone-induced gene activation and that cofactor methylation is a
regulatory mechanism in hormone signaling. Xu et al. (2001) suggested
that their findings support the methylation 'code' hypothesis of
Jenuwein and Allis (2001).
Using systems reconstituted with recombinant chromatin templates and
coactivators, An et al. (2004) demonstrated the involvement of PRMT1
(602950) and CARM1 in p53 (191170) function; both independent and
ordered cooperative functions of p300, PRMT1, and CARM1; and mechanisms
involving direct interactions with p53 and obligatory modifications of
corresponding histone substrates. Chromatin immunoprecipitation analyses
confirmed the ordered accumulation of these (and other) coactivators and
cognate histone modifications on a p53-responsive gene, GADD45 (126335),
following ectopic p53 expression and/or ultraviolet irradiation.
HuR (ELAVL1; 603466) is an RNA-binding protein that stabilizes mRNAs
carrying AU-rich instability elements (AREs). Li et al. (2002) found
that mammalian Carm1 associated with HuR and activated HuR via
methylation in vitro and in vivo. HuR methylation increased in cells
that overexpressed Carm1, and lipopolysaccharide stimulation of mouse
macrophages caused increased methylation of endogenous HuR, leading to
the stabilization of TNF-alpha (TNF; 191160) mRNA.
Chen et al. (2002) demonstrated that Carm1 and Grip1 cooperatively
stimulated the activity of Mef2c (600662) in mouse mesenchymal stem
cells and found that there was direct interaction among Mef2c, Grip1,
and Carm1. Chromatin immunoprecipitation assays demonstrated the in vivo
recruitment of Mef2 and Carm1 to the endogenous muscle creatine kinase
(CKM; 123310) promoter in a differentiation-dependent manner.
Furthermore, Carm1 was expressed in somites during mouse embryogenesis
and in the nuclei of muscle cells. Treatment of myogenic cells with a
methylation inhibitor or antisense Carm1 did not affect expression of
Myod (see MYOD1; 159970), but it inhibited differentiation and abrogated
the expression of key transcription factors myogenin (MYOG; 159980) and
Mef2 that initiate the differentiation cascade.
Ohkura et al. (2005) showed that rat Carm1-v3 associated with SNRPC
(603522) and affected 5-prime splice site selection during pre-mRNA
splicing. Carm1-v3, but not the other isoforms, stimulated a shift to
the distal 5-prime splice site of the pre-mRNA when the adenoviral E1A
minigene was used as a reporter and enhanced exons skipping in the CD44
(107269) reporter. The v3-specific C terminal and regions conserved
among the isoforms were required for this activity, but arginine
methyltransferase activity was not. Among the 4 rat Carm1 isoforms,
Carm1-v3 showed the highest activity as a cofactor for reporter activity
from an estrogen-responsive element (ERE), both in the presence and
absence of Grip1. Carm1-v1, but not Carm1-v3, showed reduced coactivator
activity from the ERE when arginine methyltransferase activity was lost.
All Carm1 variants showed comparable methylation of histone H3.
Using mouse and human cells, El Messaoudi et al. (2006) showed that
CARM1 is a regulator of cyclin E1 (CCNE1; 123837) and DHFR (126060) mRNA
expression.
By screening for methylated proteins in a mouse B-cell line, followed by
in vitro and in vivo methylation assays, Cheng et al. (2007) identified
Smb (SNRPB; 182282), Sap49 (SF3B4; 605593), U1c (SNRPC), and Ca150
(TCERG1; 605409) as splicing factors targeted by Carm1. Human CARM1
altered the patterns of exon choice in splicing a CD44 reporter minigene
and endogenous CD44 in mouse and human cell lines.
The carboxy-terminal domain of RNA polymerase II (see 180660) in mammals
undergoes extensive posttranslational modification, which is essential
for transcriptional initiation and elongation. Sims et al. (2011) showed
that the carboxy-terminal domain of RNA polymerase II is methylated at a
single arginine (R1810) by CARM1. Although methylation at R1810 is
present on the hyperphosphorylated form of RNA polymerase II in vivo,
ser2 or ser5 phosphorylation inhibits CARM1 activity toward this site in
vitro, suggesting that methylation occurs before transcription
initiation. Mutation of R1810 results in the misexpression of a variety
of small nuclear RNAs and small nucleolar RNAs, an effect that is also
observed in Carm1 -/- mouse embryo fibroblasts. Sims et al. (2011)
concluded that carboxy-terminal domain methylation facilitates the
expression of select RNAs, perhaps serving to discriminate the RNA
polymerase II-associated machinery recruited to distinct gene types.
Sanchez et al. (2013) found that Carm1 mRNA coimmunoprecipitated with
Smn1 (600354) in polyribosomes isolated from mouse motoneuron-derived
MN-1 cells. In vitro-translated human SMN1 repressed translation of
Carm1 mRNA, but had no effect on global mRNA translation, in MN-1 cells.
GENE STRUCTURE
Frankel et al. (2002) determined that the CARM1 gene contains 16 exons.
MAPPING
By genomic sequence analysis, Frankel et al. (2002) mapped the CARM1
gene to chromosome 19.
ANIMAL MODEL
Yadav et al. (2003) showed that mouse embryos with a targeted disruption
of the Carm1 gene were small in size and died perinatally. The
methylation of 2 Carm1 substrates, Pabp1 (604679) and the
transcriptional cofactor p300 (602303), was abolished in knockout
embryos and cells. Furthermore, estrogen-responsive gene expression was
aberrant in Carm1 -/- fibroblasts and embryos.
*FIELD* RF
1. An, W.; Kim, J.; Roeder, R. G.: Ordered cooperative functions
of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117:
735-748, 2004.
2. Chen, D.; Ma, H.; Hong, H.; Koh, S. S.; Huang, S.-M.; Schurter,
B. T.; Aswad, D. W.; Stallcup, M. R.: Regulation of transcription
by a protein methyltransferase. Science 284: 2174-2177, 1999.
3. Chen, S. L.; Loffler, K. A.; Chen, D.; Stallcup, M. R.; Muscat,
G. E. O.: The coactivator-associated arginine methyltransferase is
necessary for muscle differentiation: CARM1 coactivates myocyte enhancer
factor-2. J. Biol. Chem. 277: 4324-4333, 2002.
4. Cheng, D.; Cote, J.; Shaaban, S.; Bedford, M. T.: The arginine
methyltransferase CARM1 regulates the coupling of transcription and
mRNA processing. Molec. Cell 25: 71-83, 2007.
5. El Messaoudi, S. E.; Fabbrizio, E.; Rodriguez, C.; Chuchana, P.;
Fauquier, L.; Cheng, D.; Theillet, C.; Vandel, L.; Bedford, M. T.;
Sardet, C.: Coactivator-associated arginine methyltransferase 1 (CARM1)
is a positive regulator of the cyclin E1 gene. Proc. Nat. Acad. Sci. 103:
13351-13356, 2006.
6. Frankel, A.; Yadav, N.; Lee, J.; Branscombe, T. L.; Clarke, S.;
Bedford, M. T.: The novel human protein arginine N-methyltransferase
PRMT6 is a nuclear enzyme displaying unique substrate specificity. J.
Biol. Chem. 277: 3537-3543, 2002.
7. Jenuwein, T.; Allis, C. D.: Translating the histone code. Science 293:
1074-1080, 2001.
8. Li, H.; Park, S.; Kilburn, B.; Jelinek, M. A.; Henschen-Edman,
A.; Aswad, D. W.; Stallcup, M. R.; Laird-Offringa, I. A.: Lipopolysaccharide-induced
methylation of HuR, an mRNA-stabilizing protein, by CARM1. J. Biol.
Chem. 277: 44623-44630, 2002.
9. Ohkura, N.; Takahashi, M.; Yaguchi, H.; Nagamura, Y.; Tsukada,
T.: Coactivator-associated arginine methyltransferase 1, CARM1, affects
pre-mRNA splicing in an isoform-specific manner. J. Biol. Chem. 280:
28927-28935, 2005.
10. Sanchez, G.; Dury, A. Y.; Murray, L. M.; Biondi, O.; Tadesse,
H.; El Fatimy, R.; Kothary, R.; Charbonnier, F.; Khandjian, E. W.;
Cote, J.: A novel function for the survival motoneuron protein as
a translational regulator. Hum. Molec. Genet. 22: 668-684, 2013.
11. Sims, R. J., III; Rojas, L. A.; Beck, D.; Bonasio, R.; Schuller,
R.; Drury, W. J., III; Eick, D.; Reinberg, D.: The C-terminal domain
of RNA polymerase II is modified by site-specific methylation. Science 332:
99-103, 2011.
12. Xu, W.; Chen, H.; Du, K.; Asahara, H.; Tini, M.; Emerson, B. M.;
Montminy, M.; Evans, R. M.: A transcriptional switch mediated by
cofactor methylation. Science 294: 2507-2511, 2001.
13. Yadav, N.; Lee, J.; Kim, J.; Shen, J.; Hu, M. C.-T.; Aldaz, C.
M.; Bedford, M. T.: Specific protein methylation defects and gene
expression perturbations in coactivator-associated arginine methyltransferase
1-deficient mice. Proc. Nat. Acad. Sci. 100: 6464-6468, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 07/17/2013
Ada Hamosh - updated: 5/3/2011
Patricia A. Hartz - updated: 2/9/2007
Patricia A. Hartz - updated: 10/4/2006
Patricia A. Hartz - updated: 8/14/2006
Patricia A. Hartz - updated: 8/9/2006
Stylianos E. Antonarakis - updated: 8/5/2004
Victor A. McKusick - updated: 6/25/2003
Paul J. Converse - updated: 1/2/2002
*FIELD* CD
Ada Hamosh: 6/25/1999
*FIELD* ED
mgross: 07/17/2013
alopez: 5/6/2011
terry: 5/3/2011
mgross: 2/9/2007
mgross: 10/6/2006
terry: 10/4/2006
wwang: 8/14/2006
terry: 8/9/2006
mgross: 4/27/2006
mgross: 9/14/2004
mgross: 8/5/2004
tkritzer: 6/26/2003
tkritzer: 6/25/2003
mgross: 1/2/2002
alopez: 8/11/1999
carol: 6/27/1999
alopez: 6/25/1999