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 02-OCT-2024, entry version 174. DE RecName: Full=N6-adenosine-methyltransferase catalytic subunit {ECO:0000305}; DE EC=2.1.1.348 {ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078, ECO:0000269|PubMed:9409616}; DE AltName: Full=Methyltransferase-like protein 3 {ECO:0000305}; DE Short=hMETTL3 {ECO:0000303|PubMed:27373337}; DE AltName: Full=N6-adenosine-methyltransferase 70 kDa subunit; DE Short=MT-A70; GN Name=METTL3 {ECO:0000312|HGNC:HGNC:17563}; Synonyms=MTA70; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), PROTEIN SEQUENCE OF 48-56; RP 134-149 AND 509-522, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP AND CATALYTIC ACTIVITY. 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 human RT 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., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., 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., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY RP 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 phosphorylation RT 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, Hurov K.E., RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., RA 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, AND RP 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, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT 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 BY RP 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., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT 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., Buerckstuemmer T., RA 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-seq."; RL Nature 485:201-206(2012). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43; SER-219 AND THR-348, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [14] RP IDENTIFICATION IN THE WMM COMPLEX. RX PubMed=24407421; DOI=10.1038/cr.2014.3; RA Ping X.L., Sun B.F., Wang L., Xiao W., Yang X., Wang W.J., Adhikari S., RA Shi Y., Lv Y., Chen Y.S., Zhao X., Li A., Yang Y., Dahal U., Lou X.M., RA Liu X., Huang J., Yuan W.P., Zhu X.F., Cheng T., Zhao Y.L., Wang X., RA Danielsen J.M., Liu F., Yang Y.G.; RT "Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine RT methyltransferase."; RL Cell Res. 24:177-189(2014). RN [15] RP IDENTIFICATION IN THE WMM COMPLEX. RX PubMed=24981863; DOI=10.1016/j.celrep.2014.05.048; RA Schwartz S., Mumbach M.R., Jovanovic M., Wang T., Maciag K., Bushkin G.G., RA Mertins P., Ter-Ovanesyan D., Habib N., Cacchiarelli D., Sanjana N.E., RA Freinkman E., Pacold M.E., Satija R., Mikkelsen T.S., Hacohen N., Zhang F., RA Carr S.A., Lander E.S., Regev A.; RT "Perturbation of m6A writers reveals two distinct classes of mRNA RT methylation at internal and 5' sites."; RL Cell Rep. 8:284-296(2014). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [17] 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., Parisien M., RA 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). RN [18] RP FUNCTION. RX PubMed=25719671; DOI=10.1038/nature14234; RA Liu N., Dai Q., Zheng G., He C., Parisien M., Pan T.; RT "N(6)-methyladenosine-dependent RNA structural switches regulate RNA- RT protein interactions."; RL Nature 518:560-564(2015). RN [19] RP FUNCTION, AND MUTAGENESIS OF 395-ASP--TRP-398. RX PubMed=25799998; DOI=10.1038/nature14281; RA Alarcon C.R., Lee H., Goodarzi H., Halberg N., Tavazoie S.F.; RT "N6-methyladenosine marks primary microRNAs for processing."; RL Nature 519:482-485(2015). RN [20] RP FUNCTION. RX PubMed=26321680; DOI=10.1016/j.cell.2015.08.011; RA Alarcon C.R., Goodarzi H., Lee H., Liu X., Tavazoie S., Tavazoie S.F.; RT "HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing RT events."; RL Cell 162:1299-1308(2015). RN [21] RP FUNCTION. RX PubMed=26593424; DOI=10.1016/j.cell.2015.10.012; RA Meyer K.D., Patil D.P., Zhou J., Zinoviev A., Skabkin M.A., Elemento O., RA Pestova T.V., Qian S.B., Jaffrey S.R.; RT "5' UTR m(6)A promotes cap-independent translation."; RL Cell 163:999-1010(2015). RN [22] RP SUBCELLULAR LOCATION. RX PubMed=26458103; DOI=10.1038/nature15377; RA Zhou J., Wan J., Gao X., Zhang X., Jaffrey S.R., Qian S.B.; RT "Dynamic m(6)A mRNA methylation directs translational control of heat shock RT response."; RL Nature 526:591-594(2015). RN [23] RP FUNCTION, SUBCELLULAR LOCATION, INDUCTION, INTERACTION WITH NCBP1; EIF4E RP AND EIF3B, AND MUTAGENESIS OF 395-ASP--TRP-398. RX PubMed=27117702; DOI=10.1016/j.molcel.2016.03.021; RA Lin S., Choe J., Du P., Triboulet R., Gregory R.I.; RT "The m(6)A methyltransferase METTL3 promotes translation in human cancer RT cells."; RL Mol. Cell 62:335-345(2016). RN [24] RP FUNCTION, AND IDENTIFICATION IN THE WMM COMPLEX. RX PubMed=27602518; DOI=10.1038/nature19342; RA Patil D.P., Chen C.K., Pickering B.F., Chow A., Jackson C., Guttman M., RA Jaffrey S.R.; RT "m(6)A RNA methylation promotes XIST-mediated transcriptional repression."; RL Nature 537:369-373(2016). RN [25] RP FUNCTION. RX PubMed=28637692; DOI=10.1101/gad.301036.117; RA Ke S., Pandya-Jones A., Saito Y., Fak J.J., Vaagboe C.B., Geula S., RA Hanna J.H., Black D.L., Darnell J.E. Jr., Darnell R.B.; RT "m(6)A mRNA modifications are deposited in nascent pre-mRNA and are not RT required for splicing but do specify cytoplasmic turnover."; RL Genes Dev. 31:990-1006(2017). RN [26] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 395-ASP--TRP-398. RX PubMed=28297716; DOI=10.1038/nature21671; RA Xiang Y., Laurent B., Hsu C.H., Nachtergaele S., Lu Z., Sheng W., Xu C., RA Chen H., Ouyang J., Wang S., Ling D., Hsu P.H., Zou L., Jambhekar A., RA He C., Shi Y.; RT "RNA m(6)A methylation regulates the ultraviolet-induced DNA damage RT response."; RL Nature 543:573-576(2017). RN [27] RP ERRATUM OF PUBMED:28297716. RX PubMed=29186122; DOI=10.1038/nature24007; RA Xiang Y., Laurent B., Hsu C.H., Nachtergaele S., Lu Z., Sheng W., Xu C., RA Chen H., Ouyang J., Wang S., Ling D., Hsu P.H., Zou L., Jambhekar A., RA He C., Shi Y.; RL Nature 552:430-430(2017). RN [28] RP IDENTIFICATION IN THE WMM COMPLEX. RX PubMed=29507755; DOI=10.1038/s41421-018-0019-0; RA Yue Y., Liu J., Cui X., Cao J., Luo G., Zhang Z., Cheng T., Gao M., Shu X., RA Ma H., Wang F., Wang X., Shen B., Wang Y., Feng X., He C., Liu J.; RT "VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop RT codon and associates with alternative polyadenylation."; RL Cell Discov. 4:10-10(2018). RN [29] RP FUNCTION. RX PubMed=30428350; DOI=10.1016/j.celrep.2018.10.068; RA Zhong X., Yu J., Frazier K., Weng X., Li Y., Cham C.M., Dolan K., Zhu X., RA Hubert N., Tao Y., Lin F., Martinez-Guryn K., Huang Y., Wang T., Liu J., RA He C., Chang E.B., Leone V.; RT "Circadian clock regulation of hepatic lipid metabolism by modulation of RT m6A mRNA methylation."; RL Cell Rep. 25:1816-1828(2018). RN [30] RP FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, RP IDENTIFICATION IN THE WMM COMPLEX, SUMOYLATION AT LYS-177; LYS-211; LYS-212 RP AND LYS-215, AND MUTAGENESIS OF LYS-177 AND 211-LYS--LYS-215. RX PubMed=29506078; DOI=10.1093/nar/gky156; RA Du Y., Hou G., Zhang H., Dou J., He J., Guo Y., Li L., Chen R., Wang Y., RA Deng R., Huang J., Jiang B., Xu M., Cheng J., Chen G.Q., Zhao X., Yu J.; RT "SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its RT function."; RL Nucleic Acids Res. 46:5195-5208(2018). RN [31] RP FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN THE WMM COMPLEX, RP PHOSPHORYLATION AT SER-2; SER-43; SER-48; SER-50; SER-219; SER-243; THR-348 RP AND SER-350, AND MUTAGENESIS OF SER-2; SER-43; SER-48; SER-50; SER-219; RP SER-243; 211-LYS--LYS-215 AND 348-THR--SER-350. RX PubMed=29348140; DOI=10.1261/rna.064063.117; RA Schoeller E., Weichmann F., Treiber T., Ringle S., Treiber N., Flatley A., RA Feederle R., Bruckmann A., Meister G.; RT "Interactions, localization, and phosphorylation of the m6A generating RT METTL3-METTL14-WTAP complex."; RL RNA 24:499-512(2018). RN [32] RP FUNCTION. RX PubMed=30559377; DOI=10.1038/s41590-018-0275-z; RA Winkler R., Gillis E., Lasman L., Safra M., Geula S., Soyris C., RA Nachshon A., Tai-Schmiedel J., Friedman N., Le-Trilling V.T.K., RA Trilling M., Mandelboim M., Hanna J.H., Schwartz S., Stern-Ginossar N.; RT "m6A modification controls the innate immune response to infection by RT targeting type I interferons."; RL Nat. Immunol. 20:173-182(2019). RN [33] RP FUNCTION. RX PubMed=33961823; DOI=10.1016/j.celrep.2021.109091; RA Li N., Hui H., Bray B., Gonzalez G.M., Zeller M., Anderson K.G., Knight R., RA Smith D., Wang Y., Carlin A.F., Rana T.M.; RT "METTL3 regulates viral m6A RNA modification and host cell innate immune RT responses during SARS-CoV-2 infection."; RL Cell Rep. 35:109091-109091(2021). RN [34] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 354-580 IN COMPLEX WITH METTL14 RP AND S-ADENOSYL-L-METHIONINE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND RP MUTAGENESIS OF ASP-395; TYR-406; ASN-549 AND GLN-550. RX PubMed=27627798; DOI=10.7554/elife.18434; RA Sledz P., Jinek M.; RT "Structural insights into the molecular mechanism of the m(6)A writer RT complex."; RL Elife 5:E18434-E18434(2016). RN [35] RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 357-580 IN COMPLEX WITH METTL14 RP AND S-ADENOSYL-L-METHIONINE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, RP MUTAGENESIS OF CYS-294; CYS-326; ASP-395; TRP-475 AND ASN-477, VARIANT RP CYS-406, AND CHARACTERIZATION OF VARIANT CYS-406. RX PubMed=27373337; DOI=10.1016/j.molcel.2016.05.041; RA Wang P., Doxtader K.A., Nam Y.; RT "Structural basis for cooperative function of Mettl3 and Mettl14 RT methyltransferases."; RL Mol. Cell 63:306-317(2016). RN [36] RP X-RAY CRYSTALLOGRAPHY (1.61 ANGSTROMS) OF 369-580 IN COMPLEX WITH METTL14 RP AND S-ADENOSYL-L-METHIONINE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, DOMAIN, RP AND MUTAGENESIS OF ASP-377; ASP-395; 462-GLN--GLY-479; GLU-532; ARG-536; RP HIS-538; ASN-539; ASN-549 AND GLN-550. RX PubMed=27281194; DOI=10.1038/nature18298; RA Wang X., Feng J., Xue Y., Guan Z., Zhang D., Liu Z., Gong Z., Wang Q., RA Huang J., Tang C., Zou T., Yin P.; RT "Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 RT complex."; RL Nature 534:575-578(2016). CC -!- FUNCTION: The METTL3-METTL14 heterodimer forms a N6-methyltransferase CC complex that methylates adenosine residues at the N(6) position of some CC RNAs and regulates various processes such as the circadian clock, CC differentiation of embryonic and hematopoietic stem cells, cortical CC neurogenesis, response to DNA damage, differentiation of T-cells and CC primary miRNA processing (PubMed:22575960, PubMed:24284625, CC PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, CC PubMed:27281194, PubMed:27373337, PubMed:27627798, PubMed:28297716, CC PubMed:29348140, PubMed:29506078, PubMed:30428350, PubMed:9409616). In CC the heterodimer formed with METTL14, METTL3 constitutes the catalytic CC core (PubMed:27281194, PubMed:27373337, PubMed:27627798). N6- CC methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus CC sites of some mRNAs, plays a role in mRNA stability, processing, CC translation efficiency and editing (PubMed:22575960, PubMed:24284625, CC PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, CC PubMed:28297716, PubMed:9409616). M6A acts as a key regulator of mRNA CC stability: methylation is completed upon the release of mRNA into the CC nucleoplasm and promotes mRNA destabilization and degradation CC (PubMed:28637692). In embryonic stem cells (ESCs), m6A methylation of CC mRNAs encoding key naive pluripotency-promoting transcripts results in CC transcript destabilization, promoting differentiation of ESCs (By CC similarity). M6A regulates the length of the circadian clock: acts as CC an early pace-setter in the circadian loop by putting mRNA production CC on a fast-track for facilitating nuclear processing, thereby providing CC an early point of control in setting the dynamics of the feedback loop CC (By similarity). M6A also regulates circadian regulation of hepatic CC lipid metabolism (PubMed:30428350). M6A regulates spermatogonial CC differentiation and meiosis and is essential for male fertility and CC spermatogenesis (By similarity). Also required for oogenesis (By CC similarity). Involved in the response to DNA damage: in response to CC ultraviolet irradiation, METTL3 rapidly catalyzes the formation of m6A CC on poly(A) transcripts at DNA damage sites, leading to the recruitment CC of POLK to DNA damage sites (PubMed:28297716). M6A is also required for CC T-cell homeostasis and differentiation: m6A methylation of transcripts CC of SOCS family members (SOCS1, SOCS3 and CISH) in naive T-cells CC promotes mRNA destabilization and degradation, promoting T-cell CC differentiation (By similarity). Inhibits the type I interferon CC response by mediating m6A methylation of IFNB (PubMed:30559377). M6A CC also takes place in other RNA molecules, such as primary miRNA (pri- CC miRNAs) (PubMed:25799998). Mediates m6A methylation of Xist RNA, CC thereby participating in random X inactivation: m6A methylation of Xist CC leads to target YTHDC1 reader on Xist and promote transcription CC repression activity of Xist (PubMed:27602518). M6A also regulates CC cortical neurogenesis: m6A methylation of transcripts related to CC transcription factors, neural stem cells, the cell cycle and neuronal CC differentiation during brain development promotes their destabilization CC and decay, promoting differentiation of radial glial cells (By CC similarity). METTL3 mediates methylation of pri-miRNAs, marking them CC for recognition and processing by DGCR8 (PubMed:25799998). Acts as a CC positive regulator of mRNA translation independently of the CC methyltransferase activity: promotes translation by interacting with CC the translation initiation machinery in the cytoplasm CC (PubMed:27117702). Its overexpression in a number of cancer cells CC suggests that it may participate in cancer cell proliferation by CC promoting mRNA translation (PubMed:27117702). During human coronavirus CC SARS-CoV-2 infection, adds m6A modifications in SARS-CoV-2 RNA leading CC to decreased RIGI binding and subsequently dampening the sensing and CC activation of innate immune responses (PubMed:33961823). CC {ECO:0000250|UniProtKB:Q8C3P7, ECO:0000269|PubMed:22575960, CC ECO:0000269|PubMed:24284625, ECO:0000269|PubMed:25719671, CC ECO:0000269|PubMed:25799998, ECO:0000269|PubMed:26321680, CC ECO:0000269|PubMed:26593424, ECO:0000269|PubMed:27117702, CC ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, CC ECO:0000269|PubMed:27602518, ECO:0000269|PubMed:27627798, CC ECO:0000269|PubMed:28297716, ECO:0000269|PubMed:28637692, CC ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078, CC ECO:0000269|PubMed:30428350, ECO:0000269|PubMed:30559377, CC ECO:0000269|PubMed:33961823, ECO:0000269|PubMed:9409616}. CC -!- CATALYTIC ACTIVITY: CC Reaction=an adenosine in mRNA + S-adenosyl-L-methionine = an N(6)- CC methyladenosine in mRNA + H(+) + S-adenosyl-L-homocysteine; CC Xref=Rhea:RHEA:55584, Rhea:RHEA-COMP:12414, Rhea:RHEA-COMP:12417, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, CC ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; EC=2.1.1.348; CC Evidence={ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, CC ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:29348140, CC ECO:0000269|PubMed:29506078, ECO:0000269|PubMed:9409616}; CC -!- ACTIVITY REGULATION: Methyltransferase activity is regulated by miRNAs CC via a sequence pairing mechanism (By similarity). Methyltransferase CC activity is inhibited by sumoylation (PubMed:29506078). CC {ECO:0000250|UniProtKB:Q8C3P7, ECO:0000269|PubMed:29506078}. CC -!- SUBUNIT: Heterodimer; heterodimerizes with METTL14 to form an CC antiparallel heterodimer that constitutes an active methyltransferase CC (PubMed:27281194, PubMed:27373337, PubMed:27627798). Component of the CC WMM complex, a N6-methyltransferase complex composed of a catalytic CC subcomplex, named MAC, and of an associated subcomplex, named MACOM CC (PubMed:24407421, PubMed:24981863, PubMed:27602518, PubMed:29348140, CC PubMed:29506078, PubMed:29507755). The MAC subcomplex is composed of CC METTL3 and METTL14 (PubMed:24407421, PubMed:24981863, PubMed:27602518, CC PubMed:29507755). The MACOM subcomplex is composed of WTAP, ZC3H13, CC CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B) CC (PubMed:27602518, PubMed:29507755). Interacts with NCBP1/CBP80 CC (PubMed:27117702). Interacts with EIF4E (PubMed:27117702). Interacts CC with EIF3B (PubMed:27117702). {ECO:0000269|PubMed:24407421, CC ECO:0000269|PubMed:24981863, ECO:0000269|PubMed:27117702, CC ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, CC ECO:0000269|PubMed:27602518, ECO:0000269|PubMed:27627798, CC ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078, CC ECO:0000269|PubMed:29507755}. CC -!- INTERACTION: CC Q86U44; Q9HCE5: METTL14; NbExp=21; IntAct=EBI-11105430, EBI-6661081; CC Q86U44-1; Q9HCE5: METTL14; NbExp=10; IntAct=EBI-16084936, EBI-6661081; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:25719671, CC ECO:0000269|PubMed:26458103, ECO:0000269|PubMed:27117702, CC ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078}. Nucleus CC speckle {ECO:0000269|PubMed:9409616}. Cytoplasm CC {ECO:0000269|PubMed:27117702}. Note=Colocalizes with speckles in CC interphase nuclei, suggesting that it may be associated with nuclear CC pre-mRNA splicing components (PubMed:9409616). In response to CC ultraviolet irradiation, colocalizes to DNA damage sites however, it CC probably does not bind DNA but localizes in the vicinity of DNA damage CC sites (PubMed:28297716). {ECO:0000269|PubMed:28297716, CC ECO:0000269|PubMed:9409616}. 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 -!- TISSUE SPECIFICITY: Widely expressed at low level. Expressed in spleen, CC thymus, prostate, testis, ovary, small intestine, colon and peripheral CC blood leukocytes. {ECO:0000269|PubMed:9409616}. CC -!- INDUCTION: Overexpressed in a number of cancer tissues, such as lung CC adenocarcinoma and colon adenocarcinoma (PubMed:27117702). CC {ECO:0000269|PubMed:27117702}. CC -!- DOMAIN: Gate loop 1 and gate loop 2 regions are adjacent to the S- CC adenosyl-L-homocysteine-binding site and display large conformational CC changes upon ligand-binding. They may play an important role in CC adenosine recognition. The interface loop contributes to the CC heterodimer interaction. {ECO:0000269|PubMed:27281194}. CC -!- PTM: Sumoylation inhibits the N6-adenosine-methyltransferase activity. CC Sumoylation does not affect subcellular location or interaction with CC METTL14. Desumoylated by SENP1. {ECO:0000269|PubMed:29506078}. CC -!- SIMILARITY: Belongs to the MT-A70-like family. {ECO:0000255|PROSITE- CC ProRule:PRU00489}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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_019852.4. [Q86U44-1] DR PDB; 5IL0; X-ray; 1.88 A; A=369-580. DR PDB; 5IL1; X-ray; 1.71 A; A=369-580. DR PDB; 5IL2; X-ray; 1.61 A; A=369-580. DR PDB; 5K7M; X-ray; 1.65 A; A=357-580. DR PDB; 5K7U; X-ray; 1.70 A; A=357-580. DR PDB; 5K7W; X-ray; 1.65 A; A=357-580. DR PDB; 5L6D; X-ray; 1.85 A; A=354-580. DR PDB; 5L6E; X-ray; 1.90 A; A=354-580. DR PDB; 5TEY; X-ray; 1.80 A; A=1-580. DR PDB; 5YZ9; Other; -; A=259-357. DR PDB; 6TTP; X-ray; 2.00 A; A=1-580. DR PDB; 6TTT; X-ray; 2.30 A; A=1-580. DR PDB; 6TTV; X-ray; 2.14 A; A=1-580. DR PDB; 6TTW; X-ray; 2.20 A; A=1-580. DR PDB; 6TTX; X-ray; 2.00 A; A=1-580. DR PDB; 6TU1; X-ray; 2.31 A; A=1-580. DR PDB; 6Y4G; X-ray; 1.90 A; A=1-580. DR PDB; 7ACD; X-ray; 2.50 A; A=354-580. DR PDB; 7NHG; X-ray; 2.50 A; A=354-580. DR PDB; 7NHH; X-ray; 2.10 A; A=354-580. DR PDB; 7NHI; X-ray; 1.85 A; A=354-580. DR PDB; 7NHJ; X-ray; 2.16 A; A=354-580. DR PDB; 7NHV; X-ray; 1.91 A; A=354-580. DR PDB; 7NI7; X-ray; 2.50 A; A=354-580. DR PDB; 7NI8; X-ray; 2.20 A; A=354-580. DR PDB; 7NI9; X-ray; 2.20 A; A=354-580. DR PDB; 7NIA; X-ray; 2.30 A; A=354-580. DR PDB; 7NID; X-ray; 2.30 A; A=354-580. DR PDB; 7O08; X-ray; 2.00 A; A=354-580. DR PDB; 7O09; X-ray; 1.80 A; A=354-580. DR PDB; 7O0L; X-ray; 1.90 A; A=354-580. DR PDB; 7O0M; X-ray; 2.39 A; A=354-580. DR PDB; 7O0P; X-ray; 2.70 A; A=354-580. DR PDB; 7O0Q; X-ray; 2.49 A; A=354-580. DR PDB; 7O0R; X-ray; 2.30 A; A=354-580. DR PDB; 7O27; X-ray; 2.40 A; A=354-580. DR PDB; 7O28; X-ray; 2.47 A; A=354-580. DR PDB; 7O29; X-ray; 2.75 A; A=354-580. DR PDB; 7O2E; X-ray; 2.50 A; A=354-580. DR PDB; 7O2F; X-ray; 2.10 A; A=354-580. DR PDB; 7O2H; X-ray; 2.50 A; A=354-580. DR PDB; 7O2I; X-ray; 3.00 A; A=353-580. DR PDB; 7O2X; X-ray; 2.80 A; A=354-580. DR PDB; 7OED; X-ray; 2.00 A; A=354-580. DR PDB; 7OEE; X-ray; 2.70 A; A=354-580. DR PDB; 7OEF; X-ray; 2.03 A; A=354-580. DR PDB; 7OEG; X-ray; 2.79 A; A=354-580. DR PDB; 7OEH; X-ray; 2.01 A; A=354-580. DR PDB; 7OEI; X-ray; 2.48 A; A=354-580. DR PDB; 7OEJ; X-ray; 2.30 A; A=354-580. DR PDB; 7OEK; X-ray; 1.90 A; A=354-580. DR PDB; 7OEL; X-ray; 1.86 A; A=354-580. DR PDB; 7OEM; X-ray; 2.20 A; A=354-580. DR PDB; 7OQL; X-ray; 2.50 A; A=354-580. DR PDB; 7OQO; X-ray; 3.35 A; A=354-580. DR PDB; 7OQP; X-ray; 2.00 A; A=354-580. DR PDB; 7RX6; X-ray; 1.80 A; A=357-580. DR PDB; 7RX7; X-ray; 1.65 A; A=357-580. DR PDB; 7RX8; X-ray; 1.85 A; A=357-580. DR PDB; 8BN8; X-ray; 2.21 A; AAA=363-580. DR PDB; 8PW8; X-ray; 2.30 A; A=353-580. DR PDB; 8PW9; X-ray; 2.30 A; A=353-580. DR PDB; 8PWA; X-ray; 2.10 A; A=353-580. DR PDB; 8PWB; X-ray; 2.50 A; A=353-580. DR PDBsum; 5IL0; -. DR PDBsum; 5IL1; -. DR PDBsum; 5IL2; -. DR PDBsum; 5K7M; -. DR PDBsum; 5K7U; -. DR PDBsum; 5K7W; -. DR PDBsum; 5L6D; -. DR PDBsum; 5L6E; -. DR PDBsum; 5TEY; -. DR PDBsum; 5YZ9; -. DR PDBsum; 6TTP; -. DR PDBsum; 6TTT; -. DR PDBsum; 6TTV; -. DR PDBsum; 6TTW; -. DR PDBsum; 6TTX; -. DR PDBsum; 6TU1; -. DR PDBsum; 6Y4G; -. DR PDBsum; 7ACD; -. DR PDBsum; 7NHG; -. DR PDBsum; 7NHH; -. DR PDBsum; 7NHI; -. DR PDBsum; 7NHJ; -. DR PDBsum; 7NHV; -. DR PDBsum; 7NI7; -. DR PDBsum; 7NI8; -. DR PDBsum; 7NI9; -. DR PDBsum; 7NIA; -. DR PDBsum; 7NID; -. DR PDBsum; 7O08; -. DR PDBsum; 7O09; -. DR PDBsum; 7O0L; -. DR PDBsum; 7O0M; -. DR PDBsum; 7O0P; -. DR PDBsum; 7O0Q; -. DR PDBsum; 7O0R; -. DR PDBsum; 7O27; -. DR PDBsum; 7O28; -. DR PDBsum; 7O29; -. DR PDBsum; 7O2E; -. DR PDBsum; 7O2F; -. DR PDBsum; 7O2H; -. DR PDBsum; 7O2I; -. DR PDBsum; 7O2X; -. DR PDBsum; 7OED; -. DR PDBsum; 7OEE; -. DR PDBsum; 7OEF; -. DR PDBsum; 7OEG; -. DR PDBsum; 7OEH; -. DR PDBsum; 7OEI; -. DR PDBsum; 7OEJ; -. DR PDBsum; 7OEK; -. DR PDBsum; 7OEL; -. DR PDBsum; 7OEM; -. DR PDBsum; 7OQL; -. DR PDBsum; 7OQO; -. DR PDBsum; 7OQP; -. DR PDBsum; 7RX6; -. DR PDBsum; 7RX7; -. DR PDBsum; 7RX8; -. DR PDBsum; 8BN8; -. DR PDBsum; 8PW8; -. DR PDBsum; 8PW9; -. DR PDBsum; 8PWA; -. DR PDBsum; 8PWB; -. DR AlphaFoldDB; Q86U44; -. DR SMR; Q86U44; -. DR BioGRID; 121139; 290. DR ComplexPortal; CPX-1605; WMM N6-adenosine-methyltransferase complex. DR DIP; DIP-60727N; -. DR IntAct; Q86U44; 246. DR MINT; Q86U44; -. DR STRING; 9606.ENSP00000298717; -. DR BindingDB; Q86U44; -. DR ChEMBL; CHEMBL4739695; -. DR GuidetoPHARMACOLOGY; 3181; -. DR GlyGen; Q86U44; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q86U44; -. DR PhosphoSitePlus; Q86U44; -. DR BioMuta; METTL3; -. DR DMDM; 33301371; -. DR jPOST; Q86U44; -. DR MassIVE; Q86U44; -. DR PaxDb; 9606-ENSP00000298717; -. DR PeptideAtlas; Q86U44; -. DR ProteomicsDB; 69768; -. [Q86U44-1] DR ProteomicsDB; 69769; -. [Q86U44-2] DR Pumba; Q86U44; -. DR Antibodypedia; 53; 233 antibodies from 29 providers. DR DNASU; 56339; -. DR Ensembl; ENST00000298717.9; ENSP00000298717.3; ENSG00000165819.12. [Q86U44-1] DR GeneID; 56339; -. DR KEGG; hsa:56339; -. DR MANE-Select; ENST00000298717.9; ENSP00000298717.3; NM_019852.5; NP_062826.2. DR UCSC; uc001wbc.4; human. [Q86U44-1] DR AGR; HGNC:17563; -. DR CTD; 56339; -. DR DisGeNET; 56339; -. DR GeneCards; METTL3; -. DR HGNC; HGNC:17563; METTL3. DR HPA; ENSG00000165819; Low tissue specificity. DR MIM; 612472; gene. DR neXtProt; NX_Q86U44; -. DR OpenTargets; ENSG00000165819; -. DR PharmGKB; PA134955499; -. DR VEuPathDB; HostDB:ENSG00000165819; -. DR eggNOG; KOG2098; Eukaryota. DR GeneTree; ENSGT00550000075058; -. DR HOGENOM; CLU_018702_4_0_1; -. DR InParanoid; Q86U44; -. DR OMA; YPDGNSM; -. DR OrthoDB; 179166at2759; -. DR PhylomeDB; Q86U44; -. DR TreeFam; TF323854; -. DR BRENDA; 2.1.1.348; 2681. DR PathwayCommons; Q86U44; -. DR Reactome; R-HSA-72203; Processing of Capped Intron-Containing Pre-mRNA. DR SignaLink; Q86U44; -. DR SIGNOR; Q86U44; -. DR BioGRID-ORCS; 56339; 496 hits in 1175 CRISPR screens. DR ChiTaRS; METTL3; human. DR EvolutionaryTrace; Q86U44; -. DR GeneWiki; METTL3; -. DR GenomeRNAi; 56339; -. DR Pharos; Q86U44; Tbio. DR PRO; PR:Q86U44; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q86U44; protein. DR Bgee; ENSG00000165819; Expressed in right uterine tube and 205 other cell types or tissues. DR ExpressionAtlas; Q86U44; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0016604; C:nuclear body; IDA:HPA. DR GO; GO:0016607; C:nuclear speck; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:1990204; C:oxidoreductase complex; TAS:FlyBase. DR GO; GO:0036396; C:RNA N6-methyladenosine methyltransferase complex; IDA:UniProtKB. DR GO; GO:0003729; F:mRNA binding; IDA:UniProtKB. DR GO; GO:0001734; F:mRNA m(6)A methyltransferase activity; IDA:UniProtKB. DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB. DR GO; GO:0008173; F:RNA methyltransferase activity; IDA:UniProtKB. DR GO; GO:1904047; F:S-adenosyl-L-methionine binding; IDA:UniProtKB. DR GO; GO:0034644; P:cellular response to UV; IDA:UniProtKB. DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB. DR GO; GO:0006974; P:DNA damage response; IDA:UniProtKB. DR GO; GO:0009048; P:dosage compensation by inactivation of X chromosome; IDA:UniProtKB. DR GO; GO:0098508; P:endothelial to hematopoietic transition; ISS:UniProtKB. DR GO; GO:0021861; P:forebrain radial glial cell differentiation; ISS:UniProtKB. DR GO; GO:0042063; P:gliogenesis; ISS:UniProtKB. DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW. DR GO; GO:0061157; P:mRNA destabilization; ISS:UniProtKB. DR GO; GO:0016556; P:mRNA modification; IDA:UniProt. DR GO; GO:0006397; P:mRNA processing; IDA:UniProtKB. DR GO; GO:0000398; P:mRNA splicing, via spliceosome; IMP:UniProtKB. DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; ISS:UniProtKB. DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0048477; P:oogenesis; ISS:UniProtKB. DR GO; GO:1903679; P:positive regulation of cap-independent translational initiation; IMP:UniProtKB. DR GO; GO:0045727; P:positive regulation of translation; IMP:UniProtKB. DR GO; GO:0031053; P:primary miRNA processing; IDA:UniProtKB. DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; ISS:UniProtKB. DR GO; GO:0051445; P:regulation of meiotic cell cycle; ISS:UniProtKB. DR GO; GO:0045580; P:regulation of T cell differentiation; ISS:UniProtKB. DR GO; GO:0001510; P:RNA methylation; IMP:UniProtKB. DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB. DR GO; GO:0019827; P:stem cell population maintenance; ISS:UniProtKB. DR Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1. DR InterPro; IPR025848; MT-A70. DR InterPro; IPR007757; MT-A70-like. DR InterPro; IPR029063; SAM-dependent_MTases_sf. DR PANTHER; PTHR12829; N6-ADENOSINE-METHYLTRANSFERASE; 1. DR PANTHER; PTHR12829:SF2; N6-ADENOSINE-METHYLTRANSFERASE CATALYTIC SUBUNIT; 1. DR Pfam; PF05063; MT-A70; 1. DR SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1. DR PROSITE; PS51143; MT_A70; 1. DR PROSITE; PS51563; SAM_MTA70L_1; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Biological rhythms; KW Cytoplasm; Differentiation; Direct protein sequencing; DNA damage; KW Immunity; Innate immunity; Isopeptide bond; Methyltransferase; Nucleus; KW Oogenesis; Phosphoprotein; Proteomics identification; Reference proteome; KW RNA-binding; S-adenosyl-L-methionine; Spermatogenesis; Transferase; KW Ubl conjugation. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19413330" FT CHAIN 2..580 FT /note="N6-adenosine-methyltransferase catalytic subunit" FT /id="PRO_0000207630" FT REGION 1..70 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 198..219 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 396..410 FT /note="Gate loop 1" FT /evidence="ECO:0000303|PubMed:27281194" FT REGION 450..454 FT /note="Interaction with METTL14" FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0007744|PDB:5IL0, ECO:0007744|PDB:5IL1, FT ECO:0007744|PDB:5IL2" FT REGION 462..479 FT /note="Interphase loop" FT /evidence="ECO:0000303|PubMed:27281194" FT REGION 464..480 FT /note="Interaction with METTL14" FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0007744|PDB:5IL0, ECO:0007744|PDB:5IL1, FT ECO:0007744|PDB:5IL2" FT REGION 465..478 FT /note="Positively charged region required for RNA-binding" FT /evidence="ECO:0000269|PubMed:27281194" FT REGION 507..515 FT /note="Gate loop 2" FT /evidence="ECO:0000303|PubMed:27281194" FT MOTIF 210..215 FT /note="Nuclear localization signal" FT /evidence="ECO:0000269|PubMed:29348140" FT COMPBIAS 13..34 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 43..64 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 377..378 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27627798, FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2, FT ECO:0007744|PDB:5K7U, ECO:0007744|PDB:5K7W, FT ECO:0007744|PDB:5L6D, ECO:0007744|PDB:5L6E" FT BINDING 395 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0000269|PubMed:27373337, ECO:0007744|PDB:5IL1, FT ECO:0007744|PDB:5IL2, ECO:0007744|PDB:5K7U, FT ECO:0007744|PDB:5K7W" FT BINDING 513 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0000269|PubMed:27373337, ECO:0007744|PDB:5IL1, FT ECO:0007744|PDB:5IL2, ECO:0007744|PDB:5K7U, FT ECO:0007744|PDB:5K7W" FT BINDING 536..539 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27627798, FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2, FT ECO:0007744|PDB:5K7U, ECO:0007744|PDB:5K7W, FT ECO:0007744|PDB:5L6D, ECO:0007744|PDB:5L6E" FT BINDING 549..550 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27627798, FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2, FT ECO:0007744|PDB:5K7U, ECO:0007744|PDB:5K7W, FT ECO:0007744|PDB:5L6D, ECO:0007744|PDB:5L6E" FT SITE 438 FT /note="Interaction with METTL14" FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2" FT SITE 441 FT /note="Interaction with METTL14" FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0007744|PDB:5IL1, ECO:0007744|PDB:5IL2" FT MOD_RES 2 FT /note="N-acetylserine; alternate" FT /evidence="ECO:0007744|PubMed:19413330" FT MOD_RES 2 FT /note="Phosphoserine; alternate" FT /evidence="ECO:0000269|PubMed:29348140" FT MOD_RES 43 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:29348140, FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 48 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:29348140" FT MOD_RES 50 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:29348140" FT MOD_RES 219 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:29348140, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163" FT MOD_RES 243 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:29348140, FT ECO:0007744|PubMed:18669648" FT MOD_RES 348 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:29348140, FT ECO:0007744|PubMed:23186163" FT MOD_RES 350 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:29348140" FT CROSSLNK 177 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000269|PubMed:29506078" FT CROSSLNK 211 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000269|PubMed:29506078" FT CROSSLNK 212 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000269|PubMed:29506078" FT CROSSLNK 215 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO1)" FT /evidence="ECO:0000269|PubMed:29506078" FT VAR_SEQ 1..284 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_007864" FT VAR_SEQ 486..505 FT /note="GVKGNPQGFNQGLDCDVIVA -> SSSGAQFNRWSTKKNHLISY (in FT isoform 2)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_007865" FT VAR_SEQ 506..580 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_007866" FT VARIANT 406 FT /note="Y -> C (found in patients with large intestine FT cancer; uncertain significance; does not affect interaction FT with METTL14; abolished RNA methyltransferase activity in FT vitro)" FT /evidence="ECO:0000269|PubMed:27373337" FT /id="VAR_076859" FT MUTAGEN 2 FT /note="S->A: Does not affect nuclear localization, FT interaction with METTL14 or WTAP or catalytic activity; FT when associated with A-43; A-48 and A-50." FT /evidence="ECO:0000269|PubMed:29348140" FT MUTAGEN 43 FT /note="S->A: Does not affect nuclear localization, FT interaction with METTL14 or WTAP or catalytic activity; FT when associated with A-2; A-48 and A-50." FT /evidence="ECO:0000269|PubMed:29348140" FT MUTAGEN 48 FT /note="S->A: Does not affect nuclear localization, FT interaction with METTL14 or WTAP or catalytic activity; FT when associated with A-2; A-43 and A-50." FT /evidence="ECO:0000269|PubMed:29348140" FT MUTAGEN 50 FT /note="S->A: Does not affect nuclear localization, FT interaction with METTL14 or WTAP or catalytic activity; FT when associated with A-2; A-43 and A-48." FT /evidence="ECO:0000269|PubMed:29348140" FT MUTAGEN 177 FT /note="K->R: In 4KR; strongly decreased sumoylation; when FT associated with 211-R--R-215." FT /evidence="ECO:0000269|PubMed:29506078" FT MUTAGEN 211..215 FT /note="KKSRK->GGSGG: Abolishes localization to the FT nucleus." FT /evidence="ECO:0000269|PubMed:29348140" FT MUTAGEN 211..215 FT /note="KKSRK->RRSRR: In 3KR; decreased sumoylation. In 4KR; FT strongly decreased sumoylation; when associated with R- FT 177." FT /evidence="ECO:0000269|PubMed:29506078" FT MUTAGEN 219 FT /note="S->A: Does not affect nuclear localization, FT interaction with METTL14 or WTAP or catalytic activity; FT when associated with A-243 and 348-A--A-350." FT /evidence="ECO:0000269|PubMed:29348140" FT MUTAGEN 243 FT /note="S->A: Does not affect nuclear localization, FT interaction with METTL14 or WTAP or catalytic activity; FT when associated with A-219 and 348-A--A-350." FT /evidence="ECO:0000269|PubMed:29348140" FT MUTAGEN 294 FT /note="C->A: Abolishes methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27373337" FT MUTAGEN 326 FT /note="C->A: Abolishes methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27373337" FT MUTAGEN 348..350 FT /note="TPS->APA: Does not affect nuclear localization, FT interaction with METTL14 or WTAP or catalytic activity; FT when associated with A-219 and A-243." FT /evidence="ECO:0000269|PubMed:29348140" FT MUTAGEN 377 FT /note="D->A: Abolishes methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27281194" FT MUTAGEN 395..398 FT /note="DPPW->APPA: Loss of function. Abolishes ability to FT regulate primary miRNA processing. Does not affect ability FT to promote mRNA translation. Abolishes formation of m6A at FT DNA damage sites." FT /evidence="ECO:0000269|PubMed:25799998, FT ECO:0000269|PubMed:27117702, ECO:0000269|PubMed:27627798, FT ECO:0000269|PubMed:28297716" FT MUTAGEN 395 FT /note="D->A: Abolishes methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0000269|PubMed:27373337" FT MUTAGEN 406 FT /note="Y->A: Strong reduction in methyltransferase FT activity." FT /evidence="ECO:0000269|PubMed:27627798" FT MUTAGEN 462..479 FT /note="QLQRIIRTGRTGHWLNHG->AAAAAA: Impaired RNA-binding and FT methyltransferase activities." FT /evidence="ECO:0000269|PubMed:27281194" FT MUTAGEN 475 FT /note="W->A: Decreased methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27373337" FT MUTAGEN 477 FT /note="N->A: Decreased methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27373337" FT MUTAGEN 532 FT /note="E->A: Abolishes methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27281194" FT MUTAGEN 536 FT /note="R->A: Slight reduction in methyltransferase FT activity." FT /evidence="ECO:0000269|PubMed:27281194" FT MUTAGEN 538 FT /note="H->A: Slight reduction in methyltransferase FT activity." FT /evidence="ECO:0000269|PubMed:27281194" FT MUTAGEN 539 FT /note="N->A: Abolishes methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27281194" FT MUTAGEN 549 FT /note="N->A: Slight reduction in methyltransferase FT activity. Strong reduction in methyltransferase activity; FT when associated with A-550." FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0000269|PubMed:27627798" FT MUTAGEN 550 FT /note="Q->A: Slight reduction in methyltransferase FT activity. Strong reduction in methyltransferase activity; FT when associated with A-549." FT /evidence="ECO:0000269|PubMed:27281194, FT ECO:0000269|PubMed:27627798" FT CONFLICT 251 FT /note="N -> I (in Ref. 1; AAB71850)" FT /evidence="ECO:0000305" FT CONFLICT 263..264 FT /note="KF -> I (in Ref. 1; AAB71850)" FT /evidence="ECO:0000305" FT CONFLICT 382 FT /note="D -> V (in Ref. 1; AAB71850)" FT /evidence="ECO:0000305" FT CONFLICT 568 FT /note="R -> K (in Ref. 4; AAH52244)" FT /evidence="ECO:0000305" FT STRAND 372..376 FT /evidence="ECO:0007829|PDB:5IL2" FT TURN 378..380 FT /evidence="ECO:0007829|PDB:5IL2" FT HELIX 383..386 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 390..394 FT /evidence="ECO:0007829|PDB:5IL2" FT TURN 405..407 FT /evidence="ECO:0007829|PDB:7NID" FT HELIX 411..416 FT /evidence="ECO:0007829|PDB:5IL2" FT HELIX 419..422 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 424..432 FT /evidence="ECO:0007829|PDB:5IL2" FT HELIX 436..446 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 450..460 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 464..466 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 473..477 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 480..489 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 498..506 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 510..512 FT /evidence="ECO:0007829|PDB:5IL2" FT HELIX 516..524 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 530..534 FT /evidence="ECO:0007829|PDB:5IL2" FT HELIX 537..539 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 544..548 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 553..555 FT /evidence="ECO:0007829|PDB:5IL2" FT HELIX 559..568 FT /evidence="ECO:0007829|PDB:5IL2" FT STRAND 570..572 FT /evidence="ECO:0007829|PDB:7NHG" 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 //