DegronMD - Q86U44(METTL3)

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). 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). {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:33961823, ECO:0000269|PubMed:9409616}. View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.P53S	TCGA-AA-3815	COAD	TCGA	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.6752
p.P53S	DO9924	COAD	ICGC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.6752
p.S64G	TCGA-AP-A1DK	UCEC	TCGA	STASAVPEL	DEG_COP1_1	64:72	Mutation altering degron motif	0.6993
p.S64G	DO42033	UCEC	ICGC	STASAVPEL	DEG_COP1_1	64:72	Mutation altering degron motif	0.6993
p.A55T	TCGA-EO-A22U	UCEC	TCGA	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.7139
p.A55T	DO43755	UCEC	ICGC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.7139
p.E39K	TCGA-FD-A6TB	BLCA	TCGA	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.1667
p.E39K	DO51879	BLCA	ICGC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.1667
p.T45A	TCGA-G4-6314	COAD	TCGA	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.7139
p.T45A	DO10381	COAD	ICGC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.7139
p.S58F	TCGA-MP-A4T4	LUAD	TCGA	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.25
p.S58F	TCGA-MP-A4T4	LUAD	TCGA	STASAVPEL	DEG_COP1_1	64:72	Mutation rewiring degron network	0.1667
p.S58F	DO45357	LUAD	ICGC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.25
p.S58F	DO45357	LUAD	ICGC	STASAVPEL	DEG_COP1_1	64:72	Mutation rewiring degron network	0.1667
p.E71D	DO222960	BTCA	ICGC	STASAVPEL	DEG_COP1_1	64:72	Mutation altering degron motif	0.5647
p.R36W	DO233280	GACA	ICGC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.0833
p.R36W	SIDM00074	Burkitt's Lymphoma	GDSC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.0833
p.R36W	SIDM00401	Melanoma	GDSC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.0833
p.R36W	SIDM00202	Ewing's Sarcoma	GDSC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.0833
p.R36W	SIDM00402	Bladder Carcinoma	GDSC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.0833
p.R36W	SIDM00208	Glioblastoma	GDSC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.0833
p.R36W	SIDM01564	Colorectal Carcinoma	GDSC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.0833
p.A55E	DO228974	LICA	ICGC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.7701
p.P53H	DO229035	LICA	ICGC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.7694
p.R47C	SIDM00496	Thyroid Gland Carcinoma	GDSC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.719
p.R47C	SIDM00242	Osteosarcoma	GDSC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.719
p.R47C	ACH-001350	Thyroid Cancer	CCLE	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.719
p.R47C	ACH-002042	Thyroid Cancer	CCLE	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.719
p.R47C	ACH-002067	Bone Cancer	CCLE	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.719
p.R47C	HTC-C3	thyroid	COSMIC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.719
p.R47C	NOS-1	bone	COSMIC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation altering degron motif	0.719
p.A41G	SIDM00677	Colorectal Carcinoma	GDSC	TFRSDSPVPTA	DEG_COP1_1	45:55	Mutation rewiring degron network	0.2222
p.K80Q	SIDM01490	Small Cell Lung Carcinoma	GDSC	STASAVPEL	DEG_COP1_1	64:72	Mutation substituting flanking lysine	0.2222
p.K80Q	ACH-000382	Lung Cancer	CCLE	STASAVPEL	DEG_COP1_1	64:72	Mutation substituting flanking lysine	0.2222

Kaplan plot for METTL3 in

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*NOTE: the Kaplan plots were collected from OncoLnc

DegronMD: protein-targeted degradation, mutation and drug response to degrons

METTL3

UniProt ID: Q86U44

Entrez ID: 56339

Protein name: N6-adenosine-methyltransferase catalytic subunit (EC 2.1.1.348) (Methyltransferase-like protein 3) (hMETTL3) (N6-adenosine-methyltransferase 70 kDa subunit) (MT-A70)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for METTL3 in