METTL3 explained

N6-adenosine-methyltransferase 70 kDa subunit (METTL3) is an enzyme that in humans is encoded by the METTL3 gene.^[1] METTL3 is located on the human chromosome 14q11.2 (Cancer Biology) and out of the METTL protein family, it is the most studied. ^[2]

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.^[3] 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.^[4] 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.^[5]

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 . A probability-based approach for high-throughput protein phosphorylation analysis and site localization . Nature Biotechnology . 24 . 10 . 1285–1292 . October 2006 . 16964243 . 10.1038/nbt1240 . 14294292 .
• Bujnicki JM, Feder M, Radlinska M, Blumenthal RM . 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 . October 2002 . 12355263 . 10.1007/s00239-002-2339-8 . 2002JMolE..55..431B . 34823321 .
• Leach RA, Tuck MT . 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 . October 2001 . 11470232 . 10.1016/S1357-2725(01)00071-1 .
• Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM . Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase . RNA . 3 . 11 . 1233–1247 . November 1997 . 9409616 . 1369564 .

Notes and References

1. Web site: Entrez Gene: METTL3 methyltransferase like 3.
2. Qi YN, Liu Z, Hong LL, Li P, Ling ZQ . Methyltransferase-like proteins in cancer biology and potential therapeutic targeting . Journal of Hematology & Oncology . 16 . 1 . 89 . August 2023 . 37533128 . 10394802 . 10.1186/s13045-023-01477-7 . free .
3. Xu P, Ge R . Roles and drug development of METTL3 (methyltransferase-like 3) in anti-tumor therapy . European Journal of Medicinal Chemistry . 230 . 114118 . February 2022 . 35063732 . 10.1016/j.ejmech.2022.114118 .
4. Jin Q, Qu H, Quan C . New insights into the regulation of METTL3 and its role in tumors . Cell Communication and Signaling . 21 . 1 . 334 . November 2023 . 37996892 . 10732098 . 10.1186/s12964-023-01360-5 . free .
5. Zeng C, Huang W, Li Y, Weng H . Roles of METTL3 in cancer: mechanisms and therapeutic targeting . Journal of Hematology & Oncology . 13 . 1 . 117 . August 2020 . 32854717 . 7457244 . 10.1186/s13045-020-00951-w . free .