METTL3

This gene encodes the 70 kDa subunit of MT-A which is part of N6-adenosine-methyltransferase. This enzyme is involved in the posttranscriptional methylation of internal adenosine residues in eukaryotic mRNAs, forming N6-methyladenosine. [provided by RefSeq, Jul 2008]

Methyltransferase Like 3

The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N6 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 (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:27627798, PubMed:27373337, PubMed:27281194, PubMed:28297716, PubMed:30428350, PubMed:29506078, PubMed:29348140, PubMed:9409616).

In the heterodimer formed with METTL14, METTL3 constitutes the catalytic core (PubMed:27627798, PubMed:27373337, PubMed:27281194).

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 (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:28297716, PubMed:9409616).

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 (PubMed:28637692).

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 (PubMed:30428350).

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 (PubMed:28297716).

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 (PubMed:30559377).

M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998).

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 (PubMed:27602518).

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 (PubMed:25799998).

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 (PubMed:27117702).

Its overexpression in a number of cancer cells suggests that it may participate in cancer cell proliferation by promoting mRNA translation (PubMed:27117702).

During human coronorivus SARS-CoV-2 infection, adds m6A modifications in SARS-CoV-2 RNA leading to decreased DDX58/RIG-I binding and subsequently dampening the sensing and activation of innate immune responses (PubMed:33961823).

Adenosine to inosine editing Source: UniProtKB
Cellular response to DNA damage stimulus Source: UniProtKB
Cellular response to UV Source: UniProtKB
Circadian rhythm Source: UniProtKB
Dosage compensation by inactivation of X chromosome Source: UniProtKB
Endothelial to hematopoietic transition Source: UniProtKB
Forebrain radial glial cell differentiation Source: UniProtKB
Gliogenesis Source: UniProtKB
Innate immune response Source: UniProtKB-KW
mRNA catabolic process Source: UniProtKB
mRNA destabilization Source: UniProtKB
mRNA methylation Source: UniProtKB
mRNA processing Source: UniProtKB
mRNA splicing, via spliceosome Source: UniProtKB
Negative regulation of Notch signaling pathway Source: UniProtKB
Negative regulation of type I interferon-mediated signaling pathway Source: UniProtKB
Oogenesis Source: UniProtKB
Positive regulation of cap-independent translational initiation Source: UniProtKB
Positive regulation of translation Source: UniProtKB
Primary miRNA methylation Source: UniProtKB
Primary miRNA processing Source: UniProtKB
Regulation of hematopoietic stem cell differentiation Source: UniProtKB
Regulation of meiotic cell cycle Source: UniProtKB
Regulation of T cell differentiation Source: UniProtKB
RNA methylation Source: UniProtKB
Spermatogenesis Source: UniProtKB
Stem cell population maintenance Source: UniProtKB

Nucleus
Nucleus speckle
Cytoplasm
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).

Sumoylation inhibits the N6-adenosine-methyltransferase activity. Sumoylation does not affect subcellular location or interaction with METTL14. Desumoylated by SENP1.