UniProt functional annotation for Q86U44



	UniProt functional annotation for Q86U44

UniProt code: Q86U44.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) 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). {ECO:0000250|UniProtKB:Q8C3P7, ECO:0000269|PubMed:22575960, ECO:0000269|PubMed:24284625, ECO:0000269|PubMed:25719671, ECO:0000269|PubMed:25799998, ECO:0000269|PubMed:26321680, ECO:0000269|PubMed:26593424, ECO:0000269|PubMed:27117702, ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27602518, ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:28297716, ECO:0000269|PubMed:28637692, ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078, ECO:0000269|PubMed:30428350, ECO:0000269|PubMed:30559377, ECO:0000269|PubMed:9409616}.

Catalytic activity: Reaction=adenosine in mRNA + S-adenosyl-L-methionine = H(+) + N(6)- methyladenosine in mRNA + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:55584, Rhea:RHEA-COMP:12414, Rhea:RHEA-COMP:12417, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; EC=2.1.1.348; Evidence={ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078, ECO:0000269|PubMed:9409616};

Activity regulation: Methyltransferase activity is regulated by miRNAs via a sequence pairing mechanism (By similarity). Methyltransferase activity is inhibited by sumoylation (PubMed:29506078). {ECO:0000250|UniProtKB:Q8C3P7, ECO:0000269|PubMed:29506078}.

Subunit: Heterodimer; heterodimerizes with METTL14 to form an antiparallel heterodimer that constitutes an active methyltransferase (PubMed:27627798, PubMed:27373337, PubMed:27281194). Component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex, named MAC, and of an associated subcomplex, named MACOM (PubMed:24407421, PubMed:24981863, PubMed:27602518, PubMed:29507755, PubMed:29506078, PubMed:29348140). The MAC subcomplex is composed of METTL3 and METTL14 (PubMed:24407421, PubMed:24981863, PubMed:27602518, PubMed:29507755). The MACOM subcomplex is composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B) (PubMed:27602518, PubMed:29507755). Interacts with NCBP1/CBP80 (PubMed:27117702). Interacts with EIF4E (PubMed:27117702). Interacts with EIF3B (PubMed:27117702). {ECO:0000269|PubMed:24407421, ECO:0000269|PubMed:24981863, ECO:0000269|PubMed:27117702, ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27602518, ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078, ECO:0000269|PubMed:29507755}.

Subcellular location: Nucleus {ECO:0000269|PubMed:25719671, ECO:0000269|PubMed:26458103, ECO:0000269|PubMed:27117702, ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078}. Nucleus speckle {ECO:0000269|PubMed:9409616}. Cytoplasm {ECO:0000269|PubMed:27117702}. 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). {ECO:0000269|PubMed:28297716, ECO:0000269|PubMed:9409616}.

Tissue specificity: Widely expressed at low level. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes. {ECO:0000269|PubMed:9409616}.

Induction: Overexpressed in a number of cancer tissues, such as lung adenocarcinoma and colon adenocarcinoma (PubMed:27117702). {ECO:0000269|PubMed:27117702}.

Domain: Gate loop 1 and gate loop 2 regions are adjacent to the S- adenosyl-L-homocysteine-binding site and display large conformational changes upon ligand-binding. They may play an important role in adenosine recognition. The interface loop contributes to the heterodimer interaction. {ECO:0000269|PubMed:27281194}.

Ptm: Sumoylation inhibits the N6-adenosine-methyltransferase activity. Sumoylation does not affect subcellular location or interaction with METTL14. Desumoylated by SENP1. {ECO:0000269|PubMed:29506078}.

Similarity: Belongs to the MT-A70-like family. {ECO:0000255|PROSITE- ProRule:PRU00489}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) 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). {ECO:0000250\|UniProtKB:Q8C3P7, ECO:0000269\|PubMed:22575960, ECO:0000269\|PubMed:24284625, ECO:0000269\|PubMed:25719671, ECO:0000269\|PubMed:25799998, ECO:0000269\|PubMed:26321680, ECO:0000269\|PubMed:26593424, ECO:0000269\|PubMed:27117702, ECO:0000269\|PubMed:27281194, ECO:0000269\|PubMed:27373337, ECO:0000269\|PubMed:27602518, ECO:0000269\|PubMed:27627798, ECO:0000269\|PubMed:28297716, ECO:0000269\|PubMed:28637692, ECO:0000269\|PubMed:29348140, ECO:0000269\|PubMed:29506078, ECO:0000269\|PubMed:30428350, ECO:0000269\|PubMed:30559377, ECO:0000269\|PubMed:9409616}.


Catalytic activity:		Reaction=adenosine in mRNA + S-adenosyl-L-methionine = H(+) + N(6)- methyladenosine in mRNA + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:55584, Rhea:RHEA-COMP:12414, Rhea:RHEA-COMP:12417, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; EC=2.1.1.348; Evidence={ECO:0000269\|PubMed:27281194, ECO:0000269\|PubMed:27373337, ECO:0000269\|PubMed:27627798, ECO:0000269\|PubMed:29348140, ECO:0000269\|PubMed:29506078, ECO:0000269\|PubMed:9409616};
Activity regulation:		Methyltransferase activity is regulated by miRNAs via a sequence pairing mechanism (By similarity). Methyltransferase activity is inhibited by sumoylation (PubMed:29506078). {ECO:0000250\|UniProtKB:Q8C3P7, ECO:0000269\|PubMed:29506078}.
Subunit:		Heterodimer; heterodimerizes with METTL14 to form an antiparallel heterodimer that constitutes an active methyltransferase (PubMed:27627798, PubMed:27373337, PubMed:27281194). Component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex, named MAC, and of an associated subcomplex, named MACOM (PubMed:24407421, PubMed:24981863, PubMed:27602518, PubMed:29507755, PubMed:29506078, PubMed:29348140). The MAC subcomplex is composed of METTL3 and METTL14 (PubMed:24407421, PubMed:24981863, PubMed:27602518, PubMed:29507755). The MACOM subcomplex is composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B) (PubMed:27602518, PubMed:29507755). Interacts with NCBP1/CBP80 (PubMed:27117702). Interacts with EIF4E (PubMed:27117702). Interacts with EIF3B (PubMed:27117702). {ECO:0000269\|PubMed:24407421, ECO:0000269\|PubMed:24981863, ECO:0000269\|PubMed:27117702, ECO:0000269\|PubMed:27281194, ECO:0000269\|PubMed:27373337, ECO:0000269\|PubMed:27602518, ECO:0000269\|PubMed:27627798, ECO:0000269\|PubMed:29348140, ECO:0000269\|PubMed:29506078, ECO:0000269\|PubMed:29507755}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:25719671, ECO:0000269\|PubMed:26458103, ECO:0000269\|PubMed:27117702, ECO:0000269\|PubMed:29348140, ECO:0000269\|PubMed:29506078}. Nucleus speckle {ECO:0000269\|PubMed:9409616}. Cytoplasm {ECO:0000269\|PubMed:27117702}. 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). {ECO:0000269\|PubMed:28297716, ECO:0000269\|PubMed:9409616}.
Tissue specificity:		Widely expressed at low level. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes. {ECO:0000269\|PubMed:9409616}.
Induction:		Overexpressed in a number of cancer tissues, such as lung adenocarcinoma and colon adenocarcinoma (PubMed:27117702). {ECO:0000269\|PubMed:27117702}.
Domain:		Gate loop 1 and gate loop 2 regions are adjacent to the S- adenosyl-L-homocysteine-binding site and display large conformational changes upon ligand-binding. They may play an important role in adenosine recognition. The interface loop contributes to the heterodimer interaction. {ECO:0000269\|PubMed:27281194}.
Ptm:		Sumoylation inhibits the N6-adenosine-methyltransferase activity. Sumoylation does not affect subcellular location or interaction with METTL14. Desumoylated by SENP1. {ECO:0000269\|PubMed:29506078}.
Similarity:		Belongs to the MT-A70-like family. {ECO:0000255\|PROSITE- ProRule:PRU00489}.