ID   MTA70_HUMAN             Reviewed;         580 AA.
AC   Q86U44; O14736; Q86V05; Q9HB32;
DT   25-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT   25-JUL-2003, sequence version 2.
DT   29-OCT-2014, entry version 103.
DE   RecName: Full=N6-adenosine-methyltransferase 70 kDa subunit;
DE            Short=MT-A70;
DE            EC=2.1.1.62;
DE   AltName: Full=Methyltransferase-like protein 3;
GN   Name=METTL3; Synonyms=MTA70;
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 [GENOMIC DNA] (ISOFORM 1), PROTEIN SEQUENCE OF
RP   48-56; 134-149 AND 509-522, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=9409616;
RA   Bokar J.A., Shambaugh M.E., Polayes D., Matera A.G., Rottman F.M.;
RT   "Purification and cDNA cloning of the AdoMet-binding subunit of the
RT   human mRNA (N6-adenosine)-methyltransferase.";
RL   RNA 3:1233-1247(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Placenta;
RA   Li W.B., Gruber C., Jessee J., Polayes D.;
RT   "Full-length cDNA libraries and normalization.";
RL   Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12508121; DOI=10.1038/nature01348;
RA   Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA   Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA   Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA   Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA   Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA   Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA   Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA   Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA   Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA   Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA   Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA   Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA   Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA   Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA   Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA   Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA   Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA   Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA   Quetier F., Waterston R., Hood L., Weissenbach J.;
RT   "The DNA sequence and analysis of human chromosome 14.";
RL   Nature 421:601-607(2003).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Lung, and Pancreas;
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   [5]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION
RP   BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=16964243; DOI=10.1038/nbt1240;
RA   Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT   "A probability-based approach for high-throughput protein
RT   phosphorylation analysis and site localization.";
RL   Nat. Biotechnol. 24:1285-1292(2006).
RN   [6]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Embryonic kidney;
RX   PubMed=17525332; DOI=10.1126/science.1140321;
RA   Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA   Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA   Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT   "ATM and ATR substrate analysis reveals extensive protein networks
RT   responsive to DNA damage.";
RL   Science 316:1160-1166(2007).
RN   [7]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43; SER-219 AND SER-243,
RP   AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [8]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS], AND CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS].
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   [9]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [10]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION
RP   BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA   Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full
RT   phosphorylation site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [11]
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   [12]
RP   FUNCTION.
RX   PubMed=22575960; DOI=10.1038/nature11112;
RA   Dominissini D., Moshitch-Moshkovitz S., Schwartz S., Salmon-Divon M.,
RA   Ungar L., Osenberg S., Cesarkas K., Jacob-Hirsch J., Amariglio N.,
RA   Kupiec M., Sorek R., Rechavi G.;
RT   "Topology of the human and mouse m6A RNA methylomes revealed by m6A-
RT   seq.";
RL   Nature 485:201-206(2012).
RN   [13]
RP   FUNCTION.
RX   PubMed=24284625; DOI=10.1038/nature12730;
RA   Wang X., Lu Z., Gomez A., Hon G.C., Yue Y., Han D., Fu Y.,
RA   Parisien M., Dai Q., Jia G., Ren B., Pan T., He C.;
RT   "N-methyladenosine-dependent regulation of messenger RNA stability.";
RL   Nature 505:117-120(2014).
CC   -!- FUNCTION: N6-methyltransferase that methylates adenosine residues
CC       of some mRNAs and acts as a regulator of the circadian clock. N6-
CC       methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3'
CC       consensus sites of some mRNAs, plays a role in the efficiency of
CC       mRNA splicing and processing. M6A regulates the length of the
CC       ciracadian clock: acts as a early pace-setter in the circadian
CC       loop by putting mRNA production on a fast-track for facilitating
CC       nuclear processing, thereby providing an early point of control in
CC       setting the dynamics of the feedback loop.
CC       {ECO:0000269|PubMed:22575960, ECO:0000269|PubMed:24284625,
CC       ECO:0000269|PubMed:9409616}.
CC   -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine + m(7)G(5')pppAm = S-
CC       adenosyl-L-homocysteine + m(7)G(5')pppm(6)Am.
CC   -!- SUBCELLULAR LOCATION: Nucleus speckle
CC       {ECO:0000269|PubMed:9409616}. Note=Colocalizes with speckles in
CC       interphase nuclei. Suggesting that it may be associated with
CC       nuclear pre-mRNA splicing components.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q86U44-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q86U44-2; Sequence=VSP_007864, VSP_007865, VSP_007866;
CC         Note=No experimental confirmation available.;
CC   -!- TISSUE SPECIFICITY: Widely expressed at low level. Expressed in
CC       spleen, thymus, prostate, testis, ovary, small intestine, colon
CC       and peripheral blood leukocytes. {ECO:0000269|PubMed:9409616}.
CC   -!- SIMILARITY: Belongs to the MT-A70-like family.
CC       {ECO:0000255|PROSITE-ProRule:PRU00489}.
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DR   EMBL; AF014837; AAB71850.1; -; Genomic_DNA.
DR   EMBL; AF283991; AAG13956.1; -; Genomic_DNA.
DR   EMBL; AE000658; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BX247964; CAD62303.1; -; mRNA.
DR   EMBL; BC003031; AAH03031.1; -; mRNA.
DR   EMBL; BC001650; AAH01650.1; -; mRNA.
DR   EMBL; BC052244; AAH52244.1; -; mRNA.
DR   CCDS; CCDS32044.1; -. [Q86U44-1]
DR   RefSeq; NP_062826.2; NM_019852.3. [Q86U44-1]
DR   UniGene; Hs.168799; -.
DR   ProteinModelPortal; Q86U44; -.
DR   BioGrid; 121139; 3.
DR   DIP; DIP-60727N; -.
DR   STRING; 9606.ENSP00000298717; -.
DR   PhosphoSite; Q86U44; -.
DR   DMDM; 33301371; -.
DR   MaxQB; Q86U44; -.
DR   PaxDb; Q86U44; -.
DR   PeptideAtlas; Q86U44; -.
DR   PRIDE; Q86U44; -.
DR   DNASU; 56339; -.
DR   Ensembl; ENST00000298717; ENSP00000298717; ENSG00000165819. [Q86U44-1]
DR   GeneID; 56339; -.
DR   KEGG; hsa:56339; -.
DR   UCSC; uc001wbb.3; human. [Q86U44-1]
DR   CTD; 56339; -.
DR   GeneCards; GC14M021966; -.
DR   HGNC; HGNC:17563; METTL3.
DR   HPA; HPA001299; -.
DR   MIM; 612472; gene.
DR   neXtProt; NX_Q86U44; -.
DR   PharmGKB; PA134955499; -.
DR   eggNOG; COG4725; -.
DR   GeneTree; ENSGT00550000075058; -.
DR   HOGENOM; HOG000012669; -.
DR   HOVERGEN; HBG052521; -.
DR   InParanoid; Q86U44; -.
DR   KO; K05925; -.
DR   OMA; HTKLWAM; -.
DR   OrthoDB; EOG7PZRWV; -.
DR   PhylomeDB; Q86U44; -.
DR   TreeFam; TF323854; -.
DR   Reactome; REACT_125; Processing of Capped Intron-Containing Pre-mRNA.
DR   GeneWiki; METTL3; -.
DR   GenomeRNAi; 56339; -.
DR   NextBio; 61981; -.
DR   PRO; PR:Q86U44; -.
DR   Bgee; Q86U44; -.
DR   CleanEx; HS_METTL3; -.
DR   ExpressionAtlas; Q86U44; baseline and differential.
DR   Genevestigator; Q86U44; -.
DR   GO; GO:0036396; C:MIS complex; IDA:UniProtKB.
DR   GO; GO:0016607; C:nuclear speck; IDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0016422; F:mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity; IDA:UniProtKB.
DR   GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR   GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR   GO; GO:0010467; P:gene expression; TAS:Reactome.
DR   GO; GO:0061157; P:mRNA destabilization; ISS:UniProtKB.
DR   GO; GO:0080009; P:mRNA methylation; IDA:UniProtKB.
DR   GO; GO:0006397; P:mRNA processing; ISS:UniProtKB.
DR   GO; GO:0001510; P:RNA methylation; IMP:UniProtKB.
DR   GO; GO:0019827; P:stem cell maintenance; ISS:UniProtKB.
DR   Gene3D; 3.40.50.150; -; 1.
DR   InterPro; IPR025848; MT-A70.
DR   InterPro; IPR007757; MT-A70-like.
DR   InterPro; IPR029063; SAM-dependent_MTases-like.
DR   Pfam; PF05063; MT-A70; 1.
DR   SUPFAM; SSF53335; SSF53335; 1.
DR   PROSITE; PS51143; MT_A70; 1.
PE   1: Evidence at protein level;
KW   Acetylation; Alternative splicing; Biological rhythms;
KW   Complete proteome; Direct protein sequencing; Methyltransferase;
KW   Nucleus; Phosphoprotein; Reference proteome; RNA-binding;
KW   S-adenosyl-L-methionine; Transferase.
FT   INIT_MET      1      1       Removed. {ECO:0000269|PubMed:19413330}.
FT   CHAIN         2    580       N6-adenosine-methyltransferase 70 kDa
FT                                subunit.
FT                                /FTId=PRO_0000207630.
FT   MOD_RES       2      2       N-acetylserine.
FT                                {ECO:0000269|PubMed:19413330}.
FT   MOD_RES      43     43       Phosphoserine.
FT                                {ECO:0000269|PubMed:16964243,
FT                                ECO:0000269|PubMed:18669648,
FT                                ECO:0000269|PubMed:20068231}.
FT   MOD_RES     219    219       Phosphoserine.
FT                                {ECO:0000269|PubMed:18669648}.
FT   MOD_RES     243    243       Phosphoserine.
FT                                {ECO:0000269|PubMed:18669648}.
FT   VAR_SEQ       1    284       Missing (in isoform 2).
FT                                {ECO:0000303|Ref.2}.
FT                                /FTId=VSP_007864.
FT   VAR_SEQ     486    505       GVKGNPQGFNQGLDCDVIVA -> SSSGAQFNRWSTKKNHL
FT                                ISY (in isoform 2). {ECO:0000303|Ref.2}.
FT                                /FTId=VSP_007865.
FT   VAR_SEQ     506    580       Missing (in isoform 2).
FT                                {ECO:0000303|Ref.2}.
FT                                /FTId=VSP_007866.
FT   CONFLICT    251    251       N -> I (in Ref. 1; AAB71850).
FT                                {ECO:0000305}.
FT   CONFLICT    263    264       KF -> I (in Ref. 1; AAB71850).
FT                                {ECO:0000305}.
FT   CONFLICT    382    382       D -> V (in Ref. 1; AAB71850).
FT                                {ECO:0000305}.
FT   CONFLICT    568    568       R -> K (in Ref. 4; AAH52244).
FT                                {ECO:0000305}.
SQ   SEQUENCE   580 AA;  64474 MW;  63A7F10195A3C6AC CRC64;
     MSDTWSSIQA HKKQLDSLRE RLQRRRKQDS GHLDLRNPEA ALSPTFRSDS PVPTAPTSGG
     PKPSTASAVP ELATDPELEK KLLHHLSDLA LTLPTDAVSI CLAISTPDAP ATQDGVESLL
     QKFAAQELIE VKRGLLQDDA HPTLVTYADH SKLSAMMGAV AEKKGPGEVA GTVTGQKRRA
     EQDSTTVAAF ASSLVSGLNS SASEPAKEPA KKSRKHAASD VDLEIESLLN QQSTKEQQSK
     KVSQEILELL NTTTAKEQSI VEKFRSRGRA QVQEFCDYGT KEECMKASDA DRPCRKLHFR
     RIINKHTDES LGDCSFLNTC FHMDTCKYVH YEIDACMDSE APGSKDHTPS QELALTQSVG
     GDSSADRLFP PQWICCDIRY LDVSILGKFA VVMADPPWDI HMELPYGTLT DDEMRRLNIP
     VLQDDGFLFL WVTGRAMELG RECLNLWGYE RVDEIIWVKT NQLQRIIRTG RTGHWLNHGK
     EHCLVGVKGN PQGFNQGLDC DVIVAEVRST SHKPDEIYGM IERLSPGTRK IELFGRPHNV
     QPNWITLGNQ LDGIHLLDPD VVARFKQRYP DGIISKPKNL
//