Protein: N(6)-adenosine-methyltransferase catalytic subunit METTL3 (EC 2.1.1.348) (Methyltransferase-like protein 3) (hMETTL3) (N(6)-adenosine-methyltransferase 70 kDa subunit) (MT-A70) (Q86U44)
Organism: Homo sapiens (Human)
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. In the heterodimer formed with METTL14, METTL3 constitutes the catalytic core. 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. 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. 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. 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. 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. M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs). 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. 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. 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. Its overexpression in a number of cancer cells suggests that it may participate in cancer cell proliferation by promoting mRNA translation. During human coronorivus 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.
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}.
InterPro domains:
- IPR007757: MT-A70-like (family) [351-570]
- IPR029063: S-adenosyl-L-methionine-dependent methyltransferase superfamily (homologous_superfamily) [375-545]
- IPR025848: N6-adenosine-methyltransferase MT-A70-like (family) [1-580]
Sequence:
MSDTWSSIQAHKKQLDSLRERLQRRRKQDSGHLDLRNPEAALSPTFRSDSPVPTAPTSGGPKPSTASAVPELATDPELEKKLLHHLSDLALTLPTDAVSICLAISTPDAPATQDGVESLLQKFAAQELIEVKRGLLQDDAHPTLVTYADHSKLSAMMGAVAEKKGPGEVAGTVTGQKRRAEQDSTTVAAFASSLVSGLNSSASEPAKEPAKKSRKHAASDVDLEIESLLNQQSTKEQQSKKVSQEILELLNTTTAKEQSIVEKFRSRGRAQVQEFCDYGTKEECMKASDADRPCRKLHFRRIINKHTDESLGDCSFLNTCFHMDTCKYVHYEIDACMDSEAPGSKDHTPSQELALTQSVGGDSSADRLFPPQWICCDIRYLDVSILGKFAVVMADPPWDIHMELPYGTLTDDEMRRLNIPVLQDDGFLFLWVTGRAMELGRECLNLWGYERVDEIIWVKTNQLQRIIRTGRTGHWLNHGKEHCLVGVKGNPQGFNQGLDCDVIVAEVRSTSHKPDEIYGMIERLSPGTRKIELFGRPHNVQPNWITLGNQLDGIHLLDPDVVARFKQRYPDGIISKPKNL
Predicted GO terms:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0140640 (catalytic activity, acting on a nucleic acid), GO:0016740 (transferase activity), GO:0005515 (protein binding), GO:0140098 (catalytic activity, acting on RNA), GO:0016741 (transferase activity, transferring one-carbon groups), GO:0008173 (RNA methyltransferase activity), GO:0008168 (methyltransferase activity), GO:0008174 (mRNA methyltransferase activity), GO:0008757 (S-adenosylmethionine-dependent methyltransferase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0065007 (biological regulation), GO:0009987 (cellular process), GO:0048519 (negative regulation of biological process), GO:0032259 (methylation), GO:0019222 (regulation of metabolic process), GO:0006807 (nitrogen compound metabolic process), GO:0071704 (organic substance metabolic process), GO:0009056 (catabolic process), GO:0009892 (negative regulation of metabolic process), GO:0065008 (regulation of biological quality), GO:0044237 (cellular metabolic process), GO:0050794 (regulation of cellular process), GO:0009893 (positive regulation of metabolic process), GO:0048523 (negative regulation of cellular process), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0051172 (negative regulation of nitrogen compound metabolic process), GO:0043487 (regulation of RNA stability), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0046483 (heterocycle metabolic process), GO:0044248 (cellular catabolic process), GO:0060255 (regulation of macromolecule metabolic process), GO:0043414 (macromolecule methylation), GO:0006725 (cellular aromatic compound metabolic process), GO:0034641 (cellular nitrogen compound metabolic process), GO:0031324 (negative regulation of cellular metabolic process), GO:0043170 (macromolecule metabolic process), GO:0009894 (regulation of catabolic process), GO:1901360 (organic cyclic compound metabolic process), GO:0006139 (nucleobase-containing compound metabolic process), GO:0031325 (positive regulation of cellular metabolic process), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0009889 (regulation of biosynthetic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0031323 (regulation of cellular metabolic process), GO:0009890 (negative regulation of biosynthetic process), GO:0080090 (regulation of primary metabolic process), GO:1901575 (organic substance catabolic process), GO:0044260 (cellular macromolecule metabolic process), GO:0009896 (positive regulation of catabolic process), GO:0034655 (nucleobase-containing compound catabolic process), GO:0044270 (cellular nitrogen compound catabolic process), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0051246 (regulation of protein metabolic process), GO:0043488 (regulation of mRNA stability), GO:0019439 (aromatic compound catabolic process), GO:0051248 (negative regulation of protein metabolic process), GO:0046700 (heterocycle catabolic process), GO:0001510 (RNA methylation), GO:0050779 (RNA destabilization), GO:0010468 (regulation of gene expression), GO:0009057 (macromolecule catabolic process), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0051254 (positive regulation of RNA metabolic process), GO:0034248 (regulation of amide metabolic process), GO:0043412 (macromolecule modification), GO:0090304 (nucleic acid metabolic process), GO:0044265 (cellular macromolecule catabolic process), GO:0031326 (regulation of cellular biosynthetic process), GO:1901361 (organic cyclic compound catabolic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0031331 (positive regulation of cellular catabolic process), GO:0010558 (negative regulation of macromolecule biosynthetic process), GO:0031327 (negative regulation of cellular biosynthetic process), GO:0051252 (regulation of RNA metabolic process), GO:0031329 (regulation of cellular catabolic process), GO:0010629 (negative regulation of gene expression), GO:0034249 (negative regulation of amide metabolic process), GO:0017148 (negative regulation of translation), GO:0016070 (RNA metabolic process), GO:0061013 (regulation of mRNA catabolic process), GO:0061014 (positive regulation of mRNA catabolic process), GO:0006402 (mRNA catabolic process), GO:0006401 (RNA catabolic process), GO:0009451 (RNA modification), GO:2000112 (regulation of cellular macromolecule biosynthetic process), GO:0006417 (regulation of translation), GO:1903311 (regulation of mRNA metabolic process), GO:0061157 (mRNA destabilization), GO:2000113 (negative regulation of cellular macromolecule biosynthetic process), GO:1903313 (positive regulation of mRNA metabolic process), GO:0010608 (post-transcriptional regulation of gene expression), GO:0016556 (mRNA modification), GO:0016071 (mRNA metabolic process), GO:0016556 (mRNA modification)
Cellular Component (CC): GO:0005575 (cellular component), GO:0032991 (protein-containing complex), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:1902494 (catalytic complex), GO:0031974 (membrane-enclosed lumen), GO:0005654 (nucleoplasm), GO:0043233 (organelle lumen), GO:1990234 (transferase complex), GO:0043229 (intracellular organelle), GO:0034708 (methyltransferase complex), GO:0045293 (mRNA editing complex), GO:0043227 (membrane-bounded organelle), GO:0036396 (RNA N6-methyladenosine methyltransferase complex), GO:0043231 (intracellular membrane-bounded organelle), GO:0070013 (intracellular organelle lumen), GO:0031981 (nuclear lumen), GO:0005634 (nucleus)