METTL3
Description
The METTL3 (methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit) is a protein-coding gene located on chromosome 14.
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.
METTL3, also known as Methyltransferase-like protein 3 or N6-adenosine-methyltransferase 70 kDa subunit, forms a heterodimer with METTL14, which together create a N6-methyltransferase complex. This complex modifies adenosine residues in certain RNAs at the N(6) position, influencing various cellular processes like the circadian clock, embryonic and hematopoietic stem cell differentiation, cortical neurogenesis, DNA damage response, T-cell differentiation, and primary miRNA processing. Within this heterodimer, METTL3 acts as the catalytic core. N6-methyladenosine (m6A), which occurs at specific 5'‑[AG]GAC‑3' consensus sites within some mRNAs, plays a crucial role in mRNA stability, processing, translation efficiency, and editing. m6A acts as a central regulator of mRNA stability: upon release of mRNA into the nucleoplasm, methylation promotes mRNA destabilization and degradation. In embryonic stem cells, m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, driving differentiation. m6A also governs the length of the circadian clock, acting as an early pace-setter by speeding up mRNA processing and thereby influencing the feedback loop dynamics. Additionally, m6A regulates circadian control of hepatic lipid metabolism. Furthermore, m6A regulates spermatogonial differentiation and meiosis, being essential for male fertility and spermatogenesis, and is also required for oogenesis. In response to ultraviolet irradiation, METTL3 quickly catalyzes the formation of m6A on poly(A) transcripts at DNA damage sites, attracting POLK to these sites, highlighting its involvement in DNA damage response. m6A is also vital for T-cell homeostasis and differentiation, where methylation of SOCS family member transcripts (SOCS1, SOCS3, and CISH) in naive T-cells promotes mRNA degradation and T-cell differentiation. It also inhibits the type I interferon response by mediating m6A methylation of IFNB. m6A modification also occurs in other RNA molecules, such as primary miRNA (pri-miRNAs). METTL3 mediates m6A methylation of Xist RNA, contributing to random X inactivation, as methylation leads to YTHDC1 reader binding to Xist, facilitating Xist's transcription repression activity. m6A further regulates cortical neurogenesis, promoting destabilization and decay of transcripts related to transcription factors, neural stem cells, the cell cycle, and neuronal differentiation during brain development, ultimately driving radial glial cell differentiation. METTL3 participates in methylation of pri-miRNAs, marking them for recognition and processing by DGCR8. Interestingly, METTL3 acts as a positive regulator of mRNA translation, independent of its methyltransferase activity. It promotes translation by interacting with the translation initiation machinery in the cytoplasm. Its overexpression in various cancer cells suggests a potential role in cancer cell proliferation by promoting mRNA translation. During human coronavirus SARS-CoV-2 infection, METTL3 adds m6A modifications to SARS-CoV-2 RNA, decreasing RIGI binding and consequently dampening the innate immune response. METTL3 heterodimerizes with METTL14 to form an active methyltransferase, creating an antiparallel heterodimer. METTL3 is a component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex (MAC) and an associated subcomplex (MACOM). The MAC subcomplex consists of METTL3 and METTL14, while the MACOM subcomplex comprises WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some instances, RBM15 (RBM15 or RBM15B). METTL3 interacts with NCBP1/CBP80, EIF4E, and EIF3B.
METTL3 is also known as IME4, M6A, MT-A70, Spo8, hMETTL3.
