N6-adenosine-methyltransferase 70 kDa subunit (METTL3) is an enzyme that in humans is encoded by the METTL3 gene.[5] METTL3 is located on the human chromosome 14q11.2 (Cancer Biology) and out of the METTL protein family, it is the most studied. [6]

METTL3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMETTL3, IME4, M6A, MT-A70, Spo8, methyltransferase like 3, hmethyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit
External IDsOMIM: 612472; MGI: 1927165; HomoloGene: 10501; GeneCards: METTL3; OMA:METTL3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_019852

NM_019721

RefSeq (protein)

NP_062826

NP_062695

Location (UCSC)Chr 14: 21.5 – 21.51 MbChr 14: 52.53 – 52.54 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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).[5] METTL3 forms the m6 a methyltransferase complex with METTL14 and WTP and is responsible for a majority of the m6a modifications of mRNA.[6] The most common modification being the catalyzation of m6a with the methyltransferase complex.[7] 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.[6]

Function

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The m6A methyltransferase complex

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In the m6a methyltransferase complex (MTC), METTL3 is a part of the m6A “writers” and is a core catalytic component.[8] METTL3 interacts with S-adenosylmethionine (SAM), a methyl donor to catalyze the formation of the MTC complex via methyl transfer.[7] 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.[8]

In cancer

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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.[9]

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.[9]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000165819Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022160Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: METTL3 methyltransferase like 3".
  6. ^ a b c Qi YN, Liu Z, Hong LL, Li P, Ling ZQ (August 2023). "Methyltransferase-like proteins in cancer biology and potential therapeutic targeting". Journal of Hematology & Oncology. 16 (1): 89. doi:10.1186/s13045-023-01477-7. PMC 10394802. PMID 37533128.
  7. ^ a b Xu P, Ge R (February 2022). "Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy". European Journal of Medicinal Chemistry. 230: 114118. doi:10.1016/j.ejmech.2022.114118. PMID 35063732.
  8. ^ a b Jin Q, Qu H, Quan C (November 2023). "New insights into the regulation of METTL3 and its role in tumors". Cell Communication and Signaling. 21 (1): 334. doi:10.1186/s12964-023-01360-5. PMC 10732098. PMID 37996892.
  9. ^ a b Zeng C, Huang W, Li Y, Weng H (August 2020). "Roles of METTL3 in cancer: mechanisms and therapeutic targeting". Journal of Hematology & Oncology. 13 (1): 117. doi:10.1186/s13045-020-00951-w. PMC 7457244. PMID 32854717.

Further reading

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