METTL3

METTL3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5IL0, 5IL2, 5IL1, 5K7M, 5K7U, 5K7W
Identifiers
Aliases	METTL3, IME4, M6A, MT-A70, Spo8, methyltransferase like 3, hmethyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit
External IDs	OMIM: 612472 MGI: 1927165 HomoloGene: 10501 GeneCards: METTL3
Gene location (Human) Chr. Chromosome 14 (human) Band 14q11.2 Start 21,498,133 bp End 21,511,342 bp
Gene location (Mouse) Chr. Chromosome 14 (mouse) Band 14|14 C2 Start 52,532,298 bp End 52,542,585 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube left lobe of thyroid gland right lobe of thyroid gland body of pancreas tibial nerve canal of the cervix endothelial cell middle temporal gyrus left uterine tube lymph node Top expressed in saccule Paneth cell primitive streak otic placode facial motor nucleus secondary oocyte thymus urothelium retinal pigment epithelium substantia nigra More reference expression data BioGPS More reference expression data
Gene ontology Molecular function methyltransferase activity transferase activity RNA binding RNA methyltransferase activity mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity mRNA binding S-adenosyl-L-methionine binding protein heterodimerization activity protein binding mRNA (N6-adenosine)-methyltransferase activity Cellular component RNA N6-methyladenosine methyltransferase complex nucleoplasm nuclear speck nucleus cytoplasm Biological process rhythmic process mRNA processing positive regulation of cap-independent translational initiation stem cell population maintenance methylation mRNA methylation mRNA destabilization circadian rhythm primary miRNA processing adenosine to inosine editing RNA methylation mRNA splicing, via spliceosome mRNA catabolic process forebrain radial glial cell differentiation cellular response to UV gliogenesis regulation of T cell differentiation negative regulation of Notch signaling pathway regulation of meiotic cell cycle endothelial to hematopoietic transition regulation of hematopoietic stem cell differentiation cellular response to DNA damage stimulus spermatogenesis cell differentiation dosage compensation by inactivation of X chromosome RNA metabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 56339 56335 Ensembl ENSG00000165819 ENSMUSG00000022160 UniProt Q86U44 Q8C3P7 RefSeq (mRNA) NM_019852 NM_019721 RefSeq (protein) NP_062826 NP_062695 Location (UCSC) Chr 14: 21.5 – 21.51 Mb Chr 14: 52.53 – 52.54 Mb PubMed search
Wikidata
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N6-adenosine-methyltransferase 70 kDa subunit (METTL3) is an enzyme that in humans is encoded by the METTL3 gene. METTL3 is located on the human chromosome 14q11.2 (Cancer Biology) and out of the METTL protein family, it is the most studied.

This gene encodes the 70 kDa subunit of MT-A which is part of N6-adenosine-methyltransferase. This enzyme is involved in the post-transcriptional methylation of internal adenosine residues in eukaryotic mRNAs, forming N6-methyladenosine (m⁶A). METTL3 forms the m⁶ a methyltransferase complex with METTL14 and WTP and is responsible for a majority of the m⁶a modifications of mRNA. The most common modification being the catalyzation of m⁶a with the methyltransferase complex. METTL3 is expressed in a variety of normal tissues, such as the lymphoid, testis, prostate and fallopian tube tissues. The enzyme is also responsible for mechanisms related to tumor development, RNA stability and maturation, and has suggested roles in ensuring animal survival.

Function

The m⁶a methyltransferase complex

In the m⁶a methyltransferase complex (MTC), METTL3 is a part of the m⁶a “writers” and is a core catalytic component. METTL3 interacts with S-adenosylmethionine (SAM), a methyl donor to catalyze the formation of the MTC complex via methyl transfer. METTL3 forms the heterodimer complex with METTL3, binds to SAM and interacts with substrate RNA to transfer methyl groups to target RNA. The complex can also bind to target RNA using WTAP. After a METTL3-METTL14-WTAP complex forms, METTL3 can bind to RBM15. Then, MTC can be recruited at specific sites in the RNA.

In cancer

METTL3 acts as an m6a methyltransferase in cancer, mostly as an oncogene, and sometimes a tumor suppressor. In most examples, METTL3 promotes the initiation and development of cancers such as lung, liver, gastric, prostate and breast cancer. METTL3 does so through applying m6a modifications on crucial mediators and transcripts. An example of this is METTL3 expression in pancreatic cancer. In pancreatic cancer, METTL3 expression applies m6a modifications onto the oncogene primary miR-25, provoking malignant transformation via enhanced maturation of the miRNA.

In a few cases, METTL3 acts as a tumor suppressor. The m6a mRNA modifications from METTL3 can promote tumor suppressor proliferation, migration, and invasion. In colorectal cancer, METTL3 promotes the tumor suppressor through p38/ERK pathways.

Further reading

• Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (October 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology. 24 (10): 1285–1292. doi:10.1038/nbt1240. PMID 16964243. S2CID 14294292.
• Bujnicki JM, Feder M, Radlinska M, Blumenthal RM (October 2002). "Structure prediction and phylogenetic analysis of a functionally diverse family of proteins homologous to the MT-A70 subunit of the human mRNA:m(6)A methyltransferase". Journal of Molecular Evolution. 55 (4): 431–444. Bibcode:2002JMolE..55..431B. doi:10.1007/s00239-002-2339-8. PMID 12355263. S2CID 34823321.
• Leach RA, Tuck MT (October 2001). "Expression of the mRNA (N6-adenosine)-methyltransferase S-adenosyl-L-methionine binding subunit mRNA in cultured cells". The International Journal of Biochemistry & Cell Biology. 33 (10): 984–999. doi:10.1016/S1357-2725(01)00071-1. PMID 11470232.
• Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM (November 1997). "Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase". RNA. 3 (11): 1233–1247. PMC 1369564. PMID 9409616.