METTL3
entrez
56339
canonical
uniprot
Q86U44
canonical
ensembl
ENSG00000165819
resolver
ensp
ENSP00000298717
resolver
ensp
ENSP00000564095
resolver
ensp
ENSP00000706892
resolver
genesymbol
METTL3
resolver
genesymbol_syn
MTA70
resolver
hgnc
HGNC:17563
resolver
uniprot
O14736
resolver
uniprot
Q86V05
resolver
uniprot
Q9HB32
resolver
uniprot_entry
MTA70_HUMAN
resolver
uniprot_sec
O14736
resolver
uniprot_sec
Q86V05
resolver
uniprot_sec
Q9HB32
resolver
activity_regulation
ACTIVITY REGULATION: Methyltransferase activity is regulated by miRNAs via a sequence pairing mechanism (By similarity). Methyltransferase activity is inhibited by sumoylation (PubMed:29506078). {ECO:0000250|UniProtKB:Q8C3P7, ECO:0000269|PubMed:29506078}.
uniprot
proteins
amino_acid_sequence
MSDTWSSIQAHKKQLDSLRERLQRRRKQDSGHLDLRNPEAALSPTFRSDSPVPTAPTSGGPKPSTASAVPELATDPELEKKLLHHLSDLALTLPTDAVSICLAISTPDAPATQDGVESLLQKFAAQELIEVKRGLLQDDAHPTLVTYADHSKLSAMMGAVAEKKGPGEVAGTVTGQKRRAEQDSTTVAAFASSLVSGLNSSASEPAKEPAKKSRKHAASDVDLEIESLLNQQSTKEQQSKKVSQEILELLNTTTAKEQSIVEKFRSRGRAQVQEFCDYGTKEECMKASDADRPCRKLHFRRIINKHTDESLGDCSFLNTCFHMDTCKYVHYEIDACMDSEAPGSKDHTPSQELALTQSVGGDSSADRLFPPQWICCDIRYLDVSILGKFAVVMADPPWDIHMELPYGTLTDDEMRRLNIPVLQDDGFLFLWVTGRAMELGRECLNLWGYERVDEIIWVKTNQLQRIIRTGRTGHWLNHGKEHCLVGVKGNPQGFNQGLDCDVIVAEVRSTSHKPDEIYGMIERLSPGTRKIELFGRPHNVQPNWITLGNQLDGIHLLDPDVVARFKQRYPDGIISKPKNL
uniprot
proteins
ec_number
2.1.1.348
uniprot
proteins
function
FUNCTION: The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) position of some RNAs and regulates various processes such as the circadian clock, differentiation of embryonic and hematopoietic stem cells, cortical neurogenesis, response to DNA damage, differentiation of T-cells and primary miRNA processing (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:27281194, PubMed:27373337, PubMed:27627798, PubMed:28297716, PubMed:29348140, PubMed:29506078, PubMed:30428350, PubMed:9409616). In the heterodimer formed with METTL14, METTL3 constitutes the catalytic core (PubMed:27281194, PubMed:27373337, PubMed:27627798). N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability, processing, translation efficiency and editing (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:28297716, PubMed:9409616). M6A acts as a key regulator of mRNA stability: methylation is completed upon the release of mRNA into the nucleoplasm and promotes mRNA destabilization and degradation (PubMed:28637692). In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A regulates the length of the circadian clock: acts as an early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also regulates circadian regulation of hepatic lipid metabolism (PubMed:30428350). M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis (By similarity). Also required for oogenesis (By similarity). Involved in the response to DNA damage: in response to ultraviolet irradiation, METTL3 rapidly catalyzes the formation of m6A on poly(A) transcripts at DNA damage sites, leading to the recruitment of POLK to DNA damage sites (PubMed:28297716). M6A is also required for T-cell homeostasis and differentiation: m6A methylation of transcripts of SOCS family members (SOCS1, SOCS3 and CISH) in naive T-cells promotes mRNA destabilization and degradation, promoting T-cell differentiation (By similarity). Inhibits the type I interferon response by mediating m6A methylation of IFNB (PubMed:30559377). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates m6A methylation of Xist RNA, thereby participating in random X inactivation: m6A methylation of Xist leads to target YTHDC1 reader on Xist and promote transcription repression activity of Xist (PubMed:27602518). M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells (By similarity). METTL3 mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998). Acts as a positive regulator of mRNA translation independently of the methyltransferase activity: promotes translation by interacting with the translation initiation machinery in the cytoplasm (PubMed:27117702). Its overexpression in a number of cancer cells suggests that it may participate in cancer cell proliferation by promoting mRNA translation (PubMed:27117702). During human coronavirus SARS-CoV-2 infection, adds m6A modifications in SARS-CoV-2 RNA leading to decreased RIGI binding and subsequently dampening the sensing and activation of innate immune responses (PubMed:33961823). {ECO:0000250|UniProtKB:Q8C3P7, ECO:0000269|PubMed:22575960, ECO:0000269|PubMed:24284625, ECO:0000269|PubMed:25719671, ECO:0000269|PubMed:25799998, ECO:0000269|PubMed:26321680, ECO:0000269|PubMed:26593424, ECO:0000269|PubMed:27117702, ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27602518, ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:28297716, ECO:0000269|PubMed:28637692, ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078, ECO:0000269|PubMed:30428350, ECO:0000269|PubMed:30559377, ECO:0000269|PubMed:33961823, ECO:0000269|PubMed:9409616}.
uniprot
proteins
mass_dalton
64474
uniprot
proteins
mutagenesis
MUTAGEN 2; /note="S->A: Does not affect nuclear localization, interaction with METTL14 or WTAP or catalytic activity; when associated with A-43; A-48 and A-50."; /evidence="ECO:0000269|PubMed:29348140"; MUTAGEN 43; /note="S->A: Does not affect nuclear localization, interaction with METTL14 or WTAP or catalytic activity; when associated with A-2; A-48 and A-50."; /evidence="ECO:0000269|PubMed:29348140"; MUTAGEN 48; /note="S->A: Does not affect nuclear localization, interaction with METTL14 or WTAP or catalytic activity; when associated with A-2; A-43 and A-50."; /evidence="ECO:0000269|PubMed:29348140"; MUTAGEN 50; /note="S->A: Does not affect nuclear localization, interaction with METTL14 or WTAP or catalytic activity; when associated with A-2; A-43 and A-48."; /evidence="ECO:0000269|PubMed:29348140"; MUTAGEN 177; /note="K->R: In 4KR; strongly decreased sumoylation; when associated with 211-R--R-215."; /evidence="ECO:0000269|PubMed:29506078"; MUTAGEN 211..215; /note="KKSRK->GGSGG: Abolishes localization to the nucleus."; /evidence="ECO:0000269|PubMed:29348140"; MUTAGEN 211..215; /note="KKSRK->RRSRR: In 3KR; decreased sumoylation. In 4KR; strongly decreased sumoylation; when associated with R-177."; /evidence="ECO:0000269|PubMed:29506078"; MUTAGEN 219; /note="S->A: Does not affect nuclear localization, interaction with METTL14 or WTAP or catalytic activity; when associated with A-243 and 348-A--A-350."; /evidence="ECO:0000269|PubMed:29348140"; MUTAGEN 243; /note="S->A: Does not affect nuclear localization, interaction with METTL14 or WTAP or catalytic activity; when associated with A-219 and 348-A--A-350."; /evidence="ECO:0000269|PubMed:29348140"; MUTAGEN 294; /note="C->A: Abolishes methyltransferase activity."; /evidence="ECO:0000269|PubMed:27373337"; MUTAGEN 326; /note="C->A: Abolishes methyltransferase activity."; /evidence="ECO:0000269|PubMed:27373337"; MUTAGEN 348..350; /note="TPS->APA: Does not affect nuclear localization, interaction with METTL14 or WTAP or catalytic activity; when associated with A-219 and A-243."; /evidence="ECO:0000269|PubMed:29348140"; MUTAGEN 377; /note="D->A: Abolishes methyltransferase activity."; /evidence="ECO:0000269|PubMed:27281194"; MUTAGEN 395..398; /note="DPPW->APPA: Loss of function. Abolishes ability to regulate primary miRNA processing. Does not affect ability to promote mRNA translation. Abolishes formation of m6A at DNA damage sites."; /evidence="ECO:0000269|PubMed:25799998, ECO:0000269|PubMed:27117702, ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:28297716"; MUTAGEN 395; /note="D->A: Abolishes methyltransferase activity."; /evidence="ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337"; MUTAGEN 406; /note="Y->A: Strong reduction in methyltransferase activity."; /evidence="ECO:0000269|PubMed:27627798"; MUTAGEN 462..479; /note="QLQRIIRTGRTGHWLNHG->AAAAAA: Impaired RNA-binding and methyltransferase activities."; /evidence="ECO:0000269|PubMed:27281194"; MUTAGEN 475; /note="W->A: Decreased methyltransferase activity."; /evidence="ECO:0000269|PubMed:27373337"; MUTAGEN 477; /note="N->A: Decreased methyltransferase activity."; /evidence="ECO:0000269|PubMed:27373337"; MUTAGEN 532; /note="E->A: Abolishes methyltransferase activity."; /evidence="ECO:0000269|PubMed:27281194"; MUTAGEN 536; /note="R->A: Slight reduction in methyltransferase activity."; /evidence="ECO:0000269|PubMed:27281194"; MUTAGEN 538; /note="H->A: Slight reduction in methyltransferase activity."; /evidence="ECO:0000269|PubMed:27281194"; MUTAGEN 539; /note="N->A: Abolishes methyltransferase activity."; /evidence="ECO:0000269|PubMed:27281194"; MUTAGEN 549; /note="N->A: Slight reduction in methyltransferase activity. Strong reduction in methyltransferase activity; when associated with A-550."; /evidence="ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27627798"; MUTAGEN 550; /note="Q->A: Slight reduction in methyltransferase activity. Strong reduction in methyltransferase activity; when associated with A-549."; /evidence="ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27627798
uniprot
proteins
post_translational_modification
PTM: Sumoylation inhibits the N6-adenosine-methyltransferase activity. Sumoylation does not affect subcellular location or interaction with METTL14. Desumoylated by SENP1. {ECO:0000269|PubMed:29506078}.
uniprot
proteins
protein_family
MT-A70-like family
uniprot
proteins
pubmed
12508121
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16964243
uniprot
proteins
pubmed
17525332
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
19413330
uniprot
proteins
pubmed
19690332
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
22575960
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24284625
uniprot
proteins
pubmed
24407421
uniprot
proteins
pubmed
24981863
uniprot
proteins
pubmed
25719671
uniprot
proteins
pubmed
25799998
uniprot
proteins
pubmed
26321680
uniprot
proteins
pubmed
26458103
uniprot
proteins
pubmed
26593424
uniprot
proteins
pubmed
27117702
uniprot
proteins
pubmed
27281194
uniprot
proteins
pubmed
27373337
uniprot
proteins
pubmed
27602518
uniprot
proteins
pubmed
27627798
uniprot
proteins
pubmed
28297716
uniprot
proteins
pubmed
28637692
uniprot
proteins
pubmed
29186122
uniprot
proteins
pubmed
29348140
uniprot
proteins
pubmed
29506078
uniprot
proteins
pubmed
29507755
uniprot
proteins
pubmed
30428350
uniprot
proteins
pubmed
30559377
uniprot
proteins
pubmed
33961823
uniprot
proteins
pubmed
9409616
uniprot
proteins
sequence_length
580
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:25719671, ECO:0000269|PubMed:26458103, ECO:0000269|PubMed:27117702, ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078}. Nucleus speckle {ECO:0000269|PubMed:9409616}. Cytoplasm {ECO:0000269|PubMed:27117702}. Note=Colocalizes with speckles in interphase nuclei, suggesting that it may be associated with nuclear pre-mRNA splicing components (PubMed:9409616). In response to ultraviolet irradiation, colocalizes to DNA damage sites however, it probably does not bind DNA but localizes in the vicinity of DNA damage sites (PubMed:28297716). {ECO:0000269|PubMed:28297716, ECO:0000269|PubMed:9409616}.
uniprot
proteins