MTA70_MOUSE
ID MTA70_MOUSE Reviewed; 580 AA.
AC Q8C3P7; Q9CV54; Q9ERS9; Q9WUI4;
DT 25-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT 25-JUL-2003, sequence version 2.
DT 03-AUG-2022, entry version 140.
DE RecName: Full=N6-adenosine-methyltransferase subunit METTL3;
DE EC=2.1.1.348 {ECO:0000269|PubMed:24394384};
DE AltName: Full=Methyltransferase-like protein 3;
DE AltName: Full=N6-adenosine-methyltransferase 70 kDa subunit;
DE Short=MT-A70;
GN Name=Mettl3 {ECO:0000312|MGI:MGI:1927165}; Synonyms=Mta70;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RC STRAIN=129/Sv;
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 [MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6 X DBA/2;
RX PubMed=11389549; DOI=10.1002/mrd.1017;
RA Hwang S.-Y., Oh B., Knowles B.B., Solter D., Lee J.-S.;
RT "Expression of genes involved in mammalian meiosis during the transition
RT from egg to embryo.";
RL Mol. Reprod. Dev. 59:144-158(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Stomach, and Tongue;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Mammary tumor;
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-219, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP FUNCTION, AND MUTAGENESIS OF 395-ASP--TRP-398.
RX PubMed=24209618; DOI=10.1016/j.cell.2013.10.026;
RA Fustin J.M., Doi M., Yamaguchi Y., Hida H., Nishimura S., Yoshida M.,
RA Isagawa T., Morioka M.S., Kakeya H., Manabe I., Okamura H.;
RT "RNA-methylation-dependent RNA processing controls the speed of the
RT circadian clock.";
RL Cell 155:793-806(2013).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=25456834; DOI=10.1016/j.stem.2014.09.019;
RA Batista P.J., Molinie B., Wang J., Qu K., Zhang J., Li L., Bouley D.M.,
RA Lujan E., Haddad B., Daneshvar K., Carter A.C., Flynn R.A., Zhou C.,
RA Lim K.S., Dedon P., Wernig M., Mullen A.C., Xing Y., Giallourakis C.C.,
RA Chang H.Y.;
RT "m(6)A RNA modification controls cell fate transition in mammalian
RT embryonic stem cells.";
RL Cell Stem Cell 15:707-719(2014).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND INTERACTION WITH
RP METTL14.
RX PubMed=24394384; DOI=10.1038/ncb2902;
RA Wang Y., Li Y., Toth J.I., Petroski M.D., Zhang Z., Zhao J.C.;
RT "N-methyladenosine modification destabilizes developmental regulators in
RT embryonic stem cells.";
RL Nat. Cell Biol. 16:191-198(2014).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX PubMed=25683224; DOI=10.1016/j.stem.2015.01.016;
RA Chen T., Hao Y.J., Zhang Y., Li M.M., Wang M., Han W., Wu Y., Lv Y.,
RA Hao J., Wang L., Li A., Yang Y., Jin K.X., Zhao X., Li Y., Ping X.L.,
RA Lai W.Y., Wu L.G., Jiang G., Wang H.L., Sang L., Wang X.J., Yang Y.G.,
RA Zhou Q.;
RT "m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming
RT to pluripotency.";
RL Cell Stem Cell 16:289-301(2015).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=25569111; DOI=10.1126/science.1261417;
RA Geula S., Moshitch-Moshkovitz S., Dominissini D., Mansour A.A., Kol N.,
RA Salmon-Divon M., Hershkovitz V., Peer E., Mor N., Manor Y.S.,
RA Ben-Haim M.S., Eyal E., Yunger S., Pinto Y., Jaitin D.A., Viukov S.,
RA Rais Y., Krupalnik V., Chomsky E., Zerbib M., Maza I., Rechavi Y.,
RA Massarwa R., Hanna S., Amit I., Levanon E.Y., Amariglio N.,
RA Stern-Ginossar N., Novershtern N., Rechavi G., Hanna J.H.;
RT "Stem cells. m6A mRNA methylation facilitates resolution of naive
RT pluripotency toward differentiation.";
RL Science 347:1002-1006(2015).
RN [11]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=28809392; DOI=10.1038/cr.2017.100;
RA Xu K., Yang Y., Feng G.H., Sun B.F., Chen J.Q., Li Y.F., Chen Y.S.,
RA Zhang X.X., Wang C.X., Jiang L.Y., Liu C., Zhang Z.Y., Wang X.J., Zhou Q.,
RA Yang Y.G., Li W.;
RT "Mettl3-mediated m(6)A regulates spermatogonial differentiation and meiosis
RT initiation.";
RL Cell Res. 27:1100-1114(2017).
RN [12]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=28965759; DOI=10.1016/j.cell.2017.09.003;
RA Yoon K.J., Ringeling F.R., Vissers C., Jacob F., Pokrass M.,
RA Jimenez-Cyrus D., Su Y., Kim N.S., Zhu Y., Zheng L., Kim S., Wang X.,
RA Dore L.C., Jin P., Regot S., Zhuang X., Canzar S., He C., Ming G.L.,
RA Song H.;
RT "Temporal control of mammalian cortical neurogenesis by m(6)A
RT methylation.";
RL Cell 0:0-0(2017).
RN [13]
RP FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND TISSUE
RP SPECIFICITY.
RX PubMed=28914256; DOI=10.1038/cr.2017.117;
RA Lin Z., Hsu P.J., Xing X., Fang J., Lu Z., Zou Q., Zhang K.J., Zhang X.,
RA Zhou Y., Zhang T., Zhang Y., Song W., Jia G., Yang X., He C., Tong M.H.;
RT "Mettl3-/Mettl14-mediated mRNA N(6)-methyladenosine modulates murine
RT spermatogenesis.";
RL Cell Res. 27:1216-1230(2017).
RN [14]
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 [15]
RP FUNCTION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF 395-ASP--TRP-398.
RX PubMed=28792938; DOI=10.1038/nature23450;
RA Li H.B., Tong J., Zhu S., Batista P.J., Duffy E.E., Zhao J., Bailis W.,
RA Cao G., Kroehling L., Chen Y., Wang G., Broughton J.P., Chen Y.G.,
RA Kluger Y., Simon M.D., Chang H.Y., Yin Z., Flavell R.A.;
RT "m(6)A mRNA methylation controls T cell homeostasis by targeting the IL-
RT 7/STAT5/SOCS pathways.";
RL Nature 548:338-342(2017).
RN [16]
RP FUNCTION.
RX PubMed=28869969; DOI=10.1038/nature23883;
RA Zhang C., Chen Y., Sun B., Wang L., Yang Y., Ma D., Lv J., Heng J.,
RA Ding Y., Xue Y., Lu X., Xiao W., Yang Y.G., Liu F.;
RT "m(6)A modulates haematopoietic stem and progenitor cell specification.";
RL Nature 549:273-276(2017).
RN [17]
RP IDENTIFICATION IN THE WMM COMPLEX.
RX PubMed=29535189; DOI=10.1101/gad.309146.117;
RA Knuckles P., Lence T., Haussmann I.U., Jacob D., Kreim N., Carl S.H.,
RA Masiello I., Hares T., Villasenor R., Hess D., Andrade-Navarro M.A.,
RA Biggiogera M., Helm M., Soller M., Buehler M., Roignant J.Y.;
RT "Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-
RT binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d.";
RL Genes Dev. 32:415-429(2018).
RN [18]
RP IDENTIFICATION IN THE WMM COMPLEX, AND SUBCELLULAR LOCATION.
RX PubMed=29547716; DOI=10.1016/j.molcel.2018.02.015;
RA Wen J., Lv R., Ma H., Shen H., He C., Wang J., Jiao F., Liu H., Yang P.,
RA Tan L., Lan F., Shi Y.G., He C., Shi Y., Diao J.;
RT "Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell
RT self-renewal.";
RL Mol. Cell 69:1028-1038(2018).
RN [19]
RP FUNCTION.
RX PubMed=32943573; DOI=10.1101/gad.340695.120;
RA Lasman L., Krupalnik V., Viukov S., Mor N., Aguilera-Castrejon A.,
RA Schneir D., Bayerl J., Mizrahi O., Peles S., Tawil S., Sathe S.,
RA Nachshon A., Shani T., Zerbib M., Kilimnik I., Aigner S., Shankar A.,
RA Mueller J.R., Schwartz S., Stern-Ginossar N., Yeo G.W., Geula S.,
RA Novershtern N., Hanna J.H.;
RT "Context-dependent functional compensation between Ythdf m6A reader
RT proteins.";
RL Genes Dev. 34:1373-1391(2020).
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:25456834, PubMed:24394384,
CC PubMed:25569111, PubMed:28809392, PubMed:28792938, PubMed:28869969,
CC PubMed:28965759). In the heterodimer formed with METTL14, METTL3
CC constitutes the catalytic core (By similarity). N6-methyladenosine
CC (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some
CC mRNAs, plays a role in mRNA stability, processing, translation
CC efficiency and editing (By similarity). M6A acts as a key regulator of
CC mRNA stability: methylation is completed upon the release of mRNA into
CC the 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
CC (PubMed:25456834, PubMed:24394384, PubMed:25569111). M6A regulates the
CC length of the circadian clock: acts as an early pace-setter in the
CC circadian loop by putting mRNA production on a fast-track for
CC facilitating nuclear processing, thereby providing an early point of
CC control in setting the dynamics of the feedback loop (PubMed:24209618).
CC M6A also regulates circadian regulation of hepatic lipid metabolism (By
CC similarity). M6A regulates spermatogonial differentiation and meiosis
CC and is essential for male fertility and spermatogenesis
CC (PubMed:28809392, PubMed:28914256, PubMed:32943573). Also required for
CC oogenesis (PubMed:32943573). Involved in the response to DNA damage: in
CC response to ultraviolet irradiation, METTL3 rapidly catalyzes the
CC formation of m6A on poly(A) transcripts at DNA damage sites, leading to
CC the recruitment of POLK to DNA damage sites (By similarity). M6A is
CC also required for T-cell homeostasis and differentiation: m6A
CC methylation of transcripts of SOCS family members (SOCS1, SOCS3 and
CC CISH) in naive T-cells promotes mRNA destabilization and degradation,
CC promoting T-cell differentiation (PubMed:28792938). Inhibits the type I
CC interferon response by mediating m6A methylation of IFNB (By
CC similarity). M6A also regulates cortical neurogenesis: m6A methylation
CC of transcripts related to transcription factors, neural stem cells, the
CC cell cycle and neuronal differentiation during brain development
CC promotes their destabilization and decay, promoting differentiation of
CC radial glial cells (PubMed:28965759). M6A also takes place in other RNA
CC molecules, such as primary miRNA (pri-miRNAs) (By similarity). Mediates
CC m6A methylation of Xist RNA, thereby participating in random X
CC inactivation: m6A methylation of Xist leads to target YTHDC1 reader on
CC Xist and promote transcription repression activity of Xist (By
CC similarity). METTL3 mediates methylation of pri-miRNAs, marking them
CC for recognition and processing by DGCR8 (By similarity). 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 (By similarity).
CC {ECO:0000250|UniProtKB:Q86U44, ECO:0000269|PubMed:24209618,
CC ECO:0000269|PubMed:24394384, ECO:0000269|PubMed:25456834,
CC ECO:0000269|PubMed:25569111, ECO:0000269|PubMed:28637692,
CC ECO:0000269|PubMed:28792938, ECO:0000269|PubMed:28809392,
CC ECO:0000269|PubMed:28869969, ECO:0000269|PubMed:28914256,
CC ECO:0000269|PubMed:28965759, ECO:0000269|PubMed:32943573}.
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:24394384};
CC -!- ACTIVITY REGULATION: Methyltransferase activity is regulated by miRNAs
CC via a sequence pairing mechanism (PubMed:25683224). Methyltransferase
CC activity is inhibited by sumoylation (By similarity).
CC {ECO:0000250|UniProtKB:Q86U44, ECO:0000269|PubMed:25683224}.
CC -!- SUBUNIT: Heterodimer; heterodimerizes with METTL14 to form an
CC antiparallel heterodimer that constitutes an active methyltransferase
CC (By similarity). Component of the WMM complex, a N6-methyltransferase
CC complex composed of a catalytic subcomplex, named MAC, and of an
CC associated subcomplex, named MACOM (PubMed:29535189, PubMed:29547716).
CC The MAC subcomplex is composed of METTL3 and METTL14 (PubMed:29535189,
CC PubMed:29547716). The MACOM subcomplex is composed of WTAP, ZC3H13,
CC CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B)
CC (PubMed:29535189, PubMed:29547716). Interacts with NCBP1/CBP80 (By
CC similarity). Interacts with EIF4E (By similarity). Interacts with EIF3B
CC (By similarity). {ECO:0000250|UniProtKB:Q86U44,
CC ECO:0000269|PubMed:29535189, ECO:0000269|PubMed:29547716}.
CC -!- INTERACTION:
CC Q8C3P7; Q3UIK4: Mettl14; NbExp=2; IntAct=EBI-8311763, EBI-16089028;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:28914256}. Nucleus
CC speckle {ECO:0000269|PubMed:24394384, ECO:0000269|PubMed:25683224}.
CC Cytoplasm {ECO:0000250|UniProtKB:Q86U44}. Note=Colocalizes with
CC speckles in interphase nuclei. Suggesting that it may be associated
CC with nuclear pre-mRNA splicing components (PubMed:24394384). In
CC response to ultraviolet irradiation, colocalizes to DNA damage sites
CC however, it probably does not bind DNA but localizes in the vicinity of
CC DNA damage site (By similarity). {ECO:0000250|UniProtKB:Q86U44,
CC ECO:0000269|PubMed:24394384}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8C3P7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8C3P7-2; Sequence=VSP_007867, VSP_007868;
CC -!- TISSUE SPECIFICITY: Present in both germ cells and somatic cells during
CC testis development (at protein level) (PubMed:28809392).
CC {ECO:0000269|PubMed:28809392, ECO:0000269|PubMed:28914256}.
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:0000250|UniProtKB:Q86U44}.
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:0000250|UniProtKB:Q86U44}.
CC -!- DISRUPTION PHENOTYPE: Embryonic lethality (PubMed:25569111).
CC Blastocysts retain normal morphology and expression of pluripotency
CC markers and yield embryonic stem cells (ESCs) at the expected ratio.
CC However, they fail to adequately terminate their naive state and
CC undergo aberrant and restricted lineage priming at the postimplantation
CC stage, leading to early embryonic lethality (PubMed:25456834,
CC PubMed:25569111). mRNAs show a nearly complete absence of N6-
CC methyladenosine (m6A) methylation (PubMed:25456834, PubMed:25569111).
CC RNAs show defects in splicing and adenosine to inosine editing
CC (PubMed:25569111). Conditional knockout mice lacking Mettl3 in germ
CC cells show male infertility caused by defects in meiosis at the
CC zygotene stage during spermatogenesis (PubMed:28809392). Conditional
CC knockout mice lacking Mettl3 and Mettl14 in germ cells show impaired
CC spermatogenesis (PubMed:28914256). Conditional knockout mice lacking
CC Mettl3 in T-cells show impaired homeostatic expansion of naive T-cells,
CC T-cells remaining in the naive state for up to 12 weeks, thereby
CC preventing colitis (PubMed:28792938). Naive T-cells show loss of m6A
CC modification leading to increased Socs1, Socs3 and Cish mRNA half-life
CC and protein levels, thereby suppressing the IL-7/STAT5 signaling
CC pathway (PubMed:28792938). Conditional knockout mice lacking Mettl3 in
CC the developing nervous system display protracted cell-cycle progression
CC of cortical neural progenitor cells and reduced differentiation of
CC radial glial cells during embryonic cortical neurogenesis
CC (PubMed:28965759). {ECO:0000269|PubMed:25456834,
CC ECO:0000269|PubMed:25569111, ECO:0000269|PubMed:28792938,
CC ECO:0000269|PubMed:28809392, ECO:0000269|PubMed:28914256,
CC ECO:0000269|PubMed:28965759}.
CC -!- SIMILARITY: Belongs to the MT-A70-like family. {ECO:0000255|PROSITE-
CC ProRule:PRU00489}.
CC -!- CAUTION: While different publications agree on the role of N6-
CC methyladenosine (m6A) on RNA stability and its role in embryonic stem
CC cells (ESCs) pluripotency, the precise function of Mettl3 in ESCs self-
CC renewal is unclear. A first paper reported that Mettl3 promotes self-
CC renewal of ESCs by maintaining the groung state of ESCs
CC (PubMed:24394384). However, opposite conclusions were drawn by
CC publications from other groups (PubMed:25456834, PubMed:25569111). The
CC differences may be explained by different experimental conditions (such
CC as cell types or RNAi off-target effects).
CC {ECO:0000269|PubMed:24394384, ECO:0000269|PubMed:25456834,
CC ECO:0000269|PubMed:25569111}.
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DR EMBL; AF283992; AAG13957.1; -; Genomic_DNA.
DR EMBL; AF135789; AAD33673.1; -; mRNA.
DR EMBL; AK009492; BAB26322.1; -; mRNA.
DR EMBL; AK085189; BAC39385.1; -; mRNA.
DR EMBL; BC012526; AAH12526.1; -; mRNA.
DR CCDS; CCDS27053.1; -. [Q8C3P7-1]
DR RefSeq; NP_062695.2; NM_019721.2.
DR AlphaFoldDB; Q8C3P7; -.
DR SMR; Q8C3P7; -.
DR BioGRID; 207910; 4.
DR ComplexPortal; CPX-1609; WMM N6-adenosine-methyltransferase complex.
DR DIP; DIP-60724N; -.
DR IntAct; Q8C3P7; 1.
DR STRING; 10090.ENSMUSP00000022767; -.
DR iPTMnet; Q8C3P7; -.
DR PhosphoSitePlus; Q8C3P7; -.
DR EPD; Q8C3P7; -.
DR jPOST; Q8C3P7; -.
DR MaxQB; Q8C3P7; -.
DR PaxDb; Q8C3P7; -.
DR PeptideAtlas; Q8C3P7; -.
DR PRIDE; Q8C3P7; -.
DR ProteomicsDB; 291357; -. [Q8C3P7-1]
DR ProteomicsDB; 291358; -. [Q8C3P7-2]
DR DNASU; 56335; -.
DR GeneID; 56335; -.
DR KEGG; mmu:56335; -.
DR UCSC; uc007tpc.1; mouse. [Q8C3P7-1]
DR CTD; 56339; -.
DR MGI; MGI:1927165; Mettl3.
DR eggNOG; KOG2098; Eukaryota.
DR InParanoid; Q8C3P7; -.
DR OrthoDB; 788192at2759; -.
DR PhylomeDB; Q8C3P7; -.
DR TreeFam; TF323854; -.
DR BRENDA; 2.1.1.348; 3474.
DR Reactome; R-MMU-72203; Processing of Capped Intron-Containing Pre-mRNA.
DR BioGRID-ORCS; 56335; 28 hits in 73 CRISPR screens.
DR ChiTaRS; Mettl3; mouse.
DR PRO; PR:Q8C3P7; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q8C3P7; protein.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0016607; C:nuclear speck; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0036396; C:RNA N6-methyladenosine methyltransferase complex; IDA:UniProtKB.
DR GO; GO:0008168; F:methyltransferase activity; IBA:GO_Central.
DR GO; GO:0016422; F:mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity; IEA:InterPro.
DR GO; GO:0001734; F:mRNA (N6-adenosine)-methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0003729; F:mRNA binding; ISS:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0008173; F:RNA methyltransferase activity; ISO:MGI.
DR GO; GO:1904047; F:S-adenosyl-L-methionine binding; ISS:UniProtKB.
DR GO; GO:0006382; P:adenosine to inosine editing; IMP:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0034644; P:cellular response to UV; ISS:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; IMP:UniProtKB.
DR GO; GO:0009048; P:dosage compensation by inactivation of X chromosome; ISS:UniProtKB.
DR GO; GO:0098508; P:endothelial to hematopoietic transition; ISS:UniProtKB.
DR GO; GO:0021861; P:forebrain radial glial cell differentiation; IMP:UniProtKB.
DR GO; GO:0042063; P:gliogenesis; IMP:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0006402; P:mRNA catabolic process; IMP:UniProtKB.
DR GO; GO:0061157; P:mRNA destabilization; IMP:UniProtKB.
DR GO; GO:0080009; P:mRNA methylation; IDA:UniProtKB.
DR GO; GO:0016556; P:mRNA modification; ISO:MGI.
DR GO; GO:0006397; P:mRNA processing; IMP: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; ISS:UniProtKB.
DR GO; GO:0048477; P:oogenesis; IMP:UniProtKB.
DR GO; GO:1903679; P:positive regulation of cap-independent translational initiation; ISS:UniProtKB.
DR GO; GO:0045727; P:positive regulation of translation; ISS:UniProtKB.
DR GO; GO:0031053; P:primary miRNA processing; ISS:UniProtKB.
DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; ISS:UniProtKB.
DR GO; GO:0051445; P:regulation of meiotic cell cycle; IMP:UniProtKB.
DR GO; GO:0045580; P:regulation of T cell differentiation; IMP:UniProtKB.
DR GO; GO:0001510; P:RNA methylation; IMP:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; IMP:UniProtKB.
DR GO; GO:0019827; P:stem cell population maintenance; IMP: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_sf.
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; Cytoplasm;
KW Differentiation; DNA damage; Immunity; Innate immunity; Isopeptide bond;
KW Methyltransferase; Nucleus; Oogenesis; Phosphoprotein; Reference proteome;
KW RNA-binding; S-adenosyl-L-methionine; Spermatogenesis; Transferase;
KW Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT CHAIN 2..580
FT /note="N6-adenosine-methyltransferase subunit METTL3"
FT /id="PRO_0000207631"
FT REGION 1..70
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 198..217
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 396..410
FT /note="Gate loop 1"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 450..454
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 462..479
FT /note="Interphase loop"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 464..480
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 465..478
FT /note="Positively charged region required for RNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT REGION 507..515
FT /note="Gate loop 2"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MOTIF 210..215
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT COMPBIAS 13..34
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 43..70
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:0000250|UniProtKB:Q86U44"
FT BINDING 395
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 513
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 536..539
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT BINDING 549..550
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT SITE 438
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT SITE 441
FT /note="Interaction with METTL14"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MOD_RES 2
FT /note="N-acetylserine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MOD_RES 2
FT /note="Phosphoserine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MOD_RES 43
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MOD_RES 48
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MOD_RES 50
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MOD_RES 219
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 243
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT MOD_RES 350
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT CROSSLNK 177
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT CROSSLNK 211
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT CROSSLNK 212
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT CROSSLNK 215
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000250|UniProtKB:Q86U44"
FT VAR_SEQ 34..106
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11389549"
FT /id="VSP_007867"
FT VAR_SEQ 241..299
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11389549"
FT /id="VSP_007868"
FT MUTAGEN 395..398
FT /note="DPPW->APPA: Loss of activity."
FT /evidence="ECO:0000269|PubMed:24209618,
FT ECO:0000269|PubMed:28792938"
FT CONFLICT 162
FT /note="D -> E (in Ref. 2; AAD33673 and 3; BAC39385)"
FT /evidence="ECO:0000305"
FT CONFLICT 471
FT /note="R -> P (in Ref. 3; BAB26322)"
FT /evidence="ECO:0000305"
FT CONFLICT 475
FT /note="W -> L (in Ref. 3; BAB26322)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 580 AA; 64616 MW; 0DBDA2392A37A018 CRC64;
MSDTWSSIQA HKKQLDSLRE RLQRRRKQDS GHLDLRNPEA ALSPTFRSDS PVPTAPTSSG
PKPSTTSVAP ELATDPELEK KLLHHLSDLA LTLPTDAVSI RLAISTPDAP ATQDGVESLL
QKFAAQELIE VKRGLLQDDA HPTLVTYADH SKLSAMMGAV ADKKGLGEVA GTIAGQKRRA
EQDLTTVTTF ASSLASGLAS SASEPAKEPA KKSRKHAASD VDLEIESLLN QQSTKEQQSK
KVSQEILELL NTTTAKEQSI VEKFRSRGRA QVQEFCDYGT KEECMKASDA DRPCRKLHFR
RIINKHTDES LGDCSFLNTC FHMDTCKYVH YEIDACVDSE SPGSKEHMPS QELALTQSVG
GDSSADRLFP PQWICCDIRY LDVSILGKFA VVMADPPWDI HMELPYGTLT DDEMRRLNIP
VLQDDGFLFL WVTGRAMELG RECLNLWGYE RVDEIIWVKT NQLQRIIRTG RTGHWLNHGK
EHCLVGVKGN PQGFNQGLDC DVIVAEVRST SHKPDEIYGM IERLSPGTRK IELFGRPHNV
QPNWITLGNQ LDGIHLLDPD VVARFKQRYP DGIISKPKNL
