METL4_MOUSE
ID METL4_MOUSE Reviewed; 471 AA.
AC Q3U034;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 1.
DT 03-AUG-2022, entry version 105.
DE RecName: Full=N(6)-adenine-specific methyltransferase METTL4 {ECO:0000305};
DE AltName: Full=Methyltransferase-like protein 4;
DE AltName: Full=N(6)-adenine-specific DNA methyltransferase METTL4 {ECO:0000305};
DE EC=2.1.1.72 {ECO:0000269|PubMed:30982744};
DE AltName: Full=snRNA (2'-O-methyladenosine-N(6)-)-methyltransferase METTL4 {ECO:0000305};
DE EC=2.1.1.- {ECO:0000250|UniProtKB:Q8N3J2};
GN Name=Mettl4 {ECO:0000303|PubMed:30982744, ECO:0000312|MGI:MGI:1924031};
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 [LARGE SCALE MRNA].
RC STRAIN=NOD; TISSUE=Spleen;
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 [2]
RP FUNCTION, CATALYTIC ACTIVITY, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP 287-PRO-PRO-288.
RX PubMed=30982744; DOI=10.1016/j.molcel.2019.03.018;
RA Kweon S.M., Chen Y., Moon E., Kvederaviciute K., Klimasauskas S.,
RA Feldman D.E.;
RT "An adversarial DNA N6-methyladenine-sensor network preserves Polycomb
RT silencing.";
RL Mol. Cell 74:1138-1147(2019).
CC -!- FUNCTION: N(6)-adenine-specific methyltransferase that can methylate
CC both RNAs and DNA (PubMed:30982744). Acts as a N(6)-adenine-specific
CC RNA methyltransferase by catalyzing formation of N6,2'-O-
CC dimethyladenosine (m6A(m)) on internal positions of U2 small nuclear
CC RNA (snRNA): methylates the 6th position of adenine residues with a
CC pre-deposited 2'-O-methylation (By similarity). Internal m6A(m)
CC methylation of snRNAs regulates RNA splicing (By similarity). Also able
CC to act as a N(6)-adenine-specific DNA methyltransferase by mediating
CC methylation of DNA on the 6th position of adenine (N(6)-
CC methyladenosine) (PubMed:30982744). The existence of N(6)-
CC methyladenosine (m6A) on DNA is however unclear in mammals, and
CC additional evidences are required to confirm the role of the N(6)-
CC adenine-specific DNA methyltransferase activity of METTL4 in vivo (By
CC similarity). Acts as a regulator of mitochondrial transcript levels and
CC mitochondrial DNA (mtDNA) copy number by mediating mtDNA N(6)-
CC methylation: m6A on mtDNA reduces transcription by repressing TFAM DNA-
CC binding and bending (By similarity). N(6)-methyladenosine deposition by
CC METTL4 regulates Polycomb silencing by triggering ubiquitination and
CC degradation of sensor proteins ASXL1 and MPND, leading to inactivation
CC of the PR-DUB complex and subsequent preservation of Polycomb silencing
CC (PubMed:30982744). {ECO:0000250|UniProtKB:Q8N3J2,
CC ECO:0000269|PubMed:30982744}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 2'-O-methyladenosine in U2 snRNA + S-adenosyl-L-methionine =
CC an N(6)-methyl-2'-O-methyladenosine in U2 snRNA + H(+) + S-adenosyl-
CC L-homocysteine; Xref=Rhea:RHEA:62672, Rhea:RHEA-COMP:16150,
CC Rhea:RHEA-COMP:16151, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:74477, ChEBI:CHEBI:145853;
CC Evidence={ECO:0000250|UniProtKB:Q8N3J2};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62673;
CC Evidence={ECO:0000250|UniProtKB:Q8N3J2};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 2'-deoxyadenosine in DNA + S-adenosyl-L-methionine = an
CC N(6)-methyl-2'-deoxyadenosine in DNA + H(+) + S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:15197, Rhea:RHEA-COMP:12418, Rhea:RHEA-
CC COMP:12419, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:90615, ChEBI:CHEBI:90616; EC=2.1.1.72;
CC Evidence={ECO:0000269|PubMed:30982744};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15198;
CC Evidence={ECO:0000269|PubMed:30982744};
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q8N3J2}.
CC -!- DISRUPTION PHENOTYPE: Embryonic sublethality and craniofacial
CC dysmorphism (PubMed:30982744). Surviving mice display anatomical
CC defects, including anophthalmia and craniofacial dysmorphism
CC (PubMed:30982744). Adult mice are moribund and exhibited splenomegaly
CC with anemia and severe leukopenia, indicative of aberrant hematopoiesis
CC (PubMed:30982744). {ECO:0000269|PubMed:30982744}.
CC -!- SIMILARITY: Belongs to the MT-A70-like family. {ECO:0000255|PROSITE-
CC ProRule:PRU00489}.
CC -!- CAUTION: The existence of N(6)-methyladenosine on DNA is unclear in
CC mammals (By similarity). According to a report, the majority of N(6)-
CC methyladenosine in DNA originates from RNA catabolism via a nucleotide
CC salvage pathway and is misincorporated by DNA polymerases, arguing
CC against a role as epigenetic DNA mark in mammalian cells (By
CC similarity). Additional evidences are therefore required to confirm the
CC role of METTL4 as a N(6)-adenine-specific DNA methyltransferase in vivo
CC (By similarity). {ECO:0000250|UniProtKB:Q8N3J2}.
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DR EMBL; AK157268; BAE34021.1; -; mRNA.
DR CCDS; CCDS29030.1; -.
DR RefSeq; NP_795891.2; NM_176917.4.
DR RefSeq; XP_006525168.1; XM_006525105.3.
DR RefSeq; XP_006525169.1; XM_006525106.3.
DR AlphaFoldDB; Q3U034; -.
DR SMR; Q3U034; -.
DR STRING; 10090.ENSMUSP00000127142; -.
DR iPTMnet; Q3U034; -.
DR PhosphoSitePlus; Q3U034; -.
DR PaxDb; Q3U034; -.
DR PRIDE; Q3U034; -.
DR ProteomicsDB; 295545; -.
DR Antibodypedia; 21910; 121 antibodies from 24 providers.
DR Ensembl; ENSMUST00000234990; ENSMUSP00000157180; ENSMUSG00000055660.
DR GeneID; 76781; -.
DR KEGG; mmu:76781; -.
DR UCSC; uc008dwk.1; mouse.
DR CTD; 64863; -.
DR MGI; MGI:1924031; Mettl4.
DR VEuPathDB; HostDB:ENSMUSG00000055660; -.
DR eggNOG; KOG2356; Eukaryota.
DR GeneTree; ENSGT00390000016237; -.
DR HOGENOM; CLU_027091_1_0_1; -.
DR InParanoid; Q3U034; -.
DR OMA; MSVTEQD; -.
DR OrthoDB; 1496188at2759; -.
DR PhylomeDB; Q3U034; -.
DR TreeFam; TF314410; -.
DR BioGRID-ORCS; 76781; 2 hits in 72 CRISPR screens.
DR ChiTaRS; Mettl4; mouse.
DR PRO; PR:Q3U034; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; Q3U034; protein.
DR Bgee; ENSMUSG00000055660; Expressed in superior cervical ganglion and 209 other tissues.
DR ExpressionAtlas; Q3U034; baseline and differential.
DR Genevisible; Q3U034; MM.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0008168; F:methyltransferase activity; IBA:GO_Central.
DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro.
DR GO; GO:0008173; F:RNA methyltransferase activity; ISS:UniProtKB.
DR GO; GO:0009007; F:site-specific DNA-methyltransferase (adenine-specific) activity; IDA:UniProtKB.
DR GO; GO:0106347; F:U2 snRNA 2'-O-methyladenosine m6 methyltransferase activity; IEA:RHEA.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0032775; P:DNA methylation on adenine; IDA:UniProtKB.
DR GO; GO:1902275; P:regulation of chromatin organization; IDA:UniProtKB.
DR GO; GO:0090296; P:regulation of mitochondrial DNA replication; ISS:UniProtKB.
DR GO; GO:1903108; P:regulation of mitochondrial transcription; ISS:UniProtKB.
DR GO; GO:0043484; P:regulation of RNA splicing; ISS:UniProtKB.
DR GO; GO:0120049; P:snRNA (adenine-N6)-methylation; ISS:UniProtKB.
DR InterPro; IPR002052; DNA_methylase_N6_adenine_CS.
DR InterPro; IPR007757; MT-A70-like.
DR Pfam; PF05063; MT-A70; 1.
DR PROSITE; PS51143; MT_A70; 1.
DR PROSITE; PS00092; N6_MTASE; 1.
PE 1: Evidence at protein level;
KW Chromatin regulator; Methyltransferase; Nucleus; Reference proteome;
KW S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..471
FT /note="N(6)-adenine-specific methyltransferase METTL4"
FT /id="PRO_0000251226"
FT MUTAGEN 287..288
FT /note="PP->RR: Abolished methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30982744"
SQ SEQUENCE 471 AA; 53306 MW; 66C93ADF8FC0A43F CRC64;
MSVVHHLPPG WLLDHLSFIN KVNYQLCQHQ ESFCSKNNPT SSVYMDSLQL DPGSPFGAPA
MCFAPDFTTV SGNDDEGSCE VITEKYVFRS ELFNVTKPYI VPAVHKERQQ SNKNENLVTD
YKQEVSVSVG KKRKRCIAFN QGELDAMEYH TKIRELILDG SSKLIQEGLR SGFLYPLVEK
QDGSSGCITL PLDACNLSEL CEMAKHLPSL NEMELQTLQL MGDDVSVIEL DLSSQIIENN
SSFSKMITLM GQKYLLPPQS SFLLSDISCM QPLLNCGKTF DAIVIDPPWE NKSVKRSNRY
SSLSPQQIKR MPIPKLAAAD CLIVTWVTNR QKHLCFVKEE LYPSWSVEVV AEWYWVKITN
SGEFVFPLDS PHKKPYECLV LGRVKEKTPL ALRNPDVRIP PVPDQKLIVS VPCVLHSHKP
PLTEVLRDYI KPGGQCLELF ARNLQPGWMS WGNEVLKFQH MDYFIALESG C
