Modomics - A Database of RNA Modifications

Full name:	N6-adenosine-methyltransferase 70 kDa subunit
Synonym:	MTA70
GI:	21361827
Orf:
COG:	COG4725
UniProt:	Q86U44
Structures:	\| \|
Complex:
Enzyme type:	methyltransferase
Position of modification - modification:	m:many - m6A

Comments:

Forms a stable heterodimer with METTL14. The complex catalyses the AdoMet dependent N6-methylation of internal adenosine in mammalian mRNA. METTL3 displays a regulatory role on several cellular functions. METTL3 is critical for viability of mammalian cells. Notice, the methyl group of m6A in mRNA can be removed by the obesity-associated protein FTO (demethylase enzyme.)

Protein sequence:

MSDTWSSIQAHKKQLDSLRERLQRRRKQDSGHLDLRNPEAALSPTFRSDSPVPTAPTSGGPKPSTASAVPELATDPELEKKLLHHLSDLALTLPTDAVSI
CLAISTPDAPATQDGVESLLQKFAAQELIEVKRGLLQDDAHPTLVTYADHSKLSAMMGAVAEKKGPGEVAGTVTGQKRRAEQDSTTVAAFASSLVSGLNS
SASEPAKEPAKKSRKHAASDVDLEIESLLNQQSTKEQQSKKVSQEILELLNTTTAKEQSIVEKFRSRGRAQVQEFCDYGTKEECMKASDADRPCRKLHFR
RIINKHTDESLGDCSFLNTCFHMDTCKYVHYEIDACMDSEAPGSKDHTPSQELALTQSVGGDSSADRLFPPQWICCDIRYLDVSILGKFAVVMADPPWDI
HMELPYGTLTDDEMRRLNIPVLQDDGFLFLWVTGRAMELGRECLNLWGYERVDEIIWVKTNQLQRIIRTGRTGHWLNHGKEHCLVGVKGNPQGFNQGLDC
DVIVAEVRSTSHKPDEIYGMIERLSPGTRKIELFGRPHNVQPNWITLGNQLDGIHLLDPDVVARFKQRYPDGIISKPKNL

Enzymatic activities:

Reaction	Substrate	Type	Position
A:m6A	mRNA (m)		many

Diseases connected to this enzyme:

Description	Reaction	Disease Name
METTL3 and METTL14 protein levels are decreased in whole islets from T2D patients. the Insulin/IGF1 -AKT-PDX1 pathway is significantly affected by hypomethylation in T2D	A:m6A	Type 2 Diabetes
m6A methylation (induced by METTL3) protects against RCCs proliferation, migration and invasion functions , and EMT and PI3K-Akt-mTOR pathways may be involved in the potential mechanisms.	A:m6A	Renal cell carcinoma
METTL3 is overexpressed in prostate cancer cell lines, together with increased m6A content. SHH-GLI signaling positively correlates with the severity of PC and METTL3 regulates the expression level of GLI1	A:m6A	Prostate cancer
m6A methylation is regulating apoptosis and chemo/radioresistance. Methylation of METTL3 target genes is inducing a decrease in apoptotic responses to GEM and it is also protecting from DNA damage after UVC.	A:m6A	Pancreatic cancer
Expression level of METTL3 are up-regulated in human OS tissues and OS cell lines. METTL3 promotes osteosarcoma cell progression by regulating the m6A level of LEF1 and activating Wnt/b-catenin signaling pathway.	A:m6A	Osteosarcoma
Decreased m6A level in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice (impaired bone formation, incompetent osteogenic differentiation potential, and increased marrow adiposity). PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis is an important downstream pathway for m6A regulation in MSCs. METTL3 loss of function reduces the translation efficiency of MSCs lineage allocator Pth1r and disrupts the PTH-induced osteogenic and adipogenic responses in vivo.	A:m6A	Osteoporosis
METTL3 promotes the translation of oncogenes such as EGFR and TAZ independently from its catalytic activity and m6A readers. The expression of these oncogenes mediates NSCLC cells growth, survival and invasion. METTL3 upregulation is reached by the downregulaion of miR-33a in NSCLC cells which normally reduces the expression of METTL3 by targeting its 3'UTR region.	A:m6A	Non-small cell lung cancer
Direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). The METTL3–eIF3h interaction is required for enhanced translation (BRD4), formation of densely packed polyribosomes and oncogenic transformation.	A:m6A	Non-small cell lung cancer
METTL3 is overexpressed in lung cancer tissues and cell lines. The m6A mRNA methylation initiated by METTL3 promotes YAP mRNA translation via recruiting YTHDF1/3 and eIF3b to the translation initiation complex and increases YAP mRNA stability through regulating the MALAT1-miR-1914-3p- YAP axis. The increased YAP expression and activity induce NSCLC drug resistance and metastasis.	A:m6A	Non-small cell lung cancer
miR-143-3p is upregulated in the paired BM tissues as compared with that in primary cancer tissues. m6A methyltransferase Mettl3 can increase the splicing of precursor miR-143-3p to facilitate its biogenesis. It targets the three binding sites of 3’UTR of vasohibin-1 (VASH1) to inhibit its expression. Mechanistically, VASH1 can increase the ubiquitylation of VEGFA to trigger the proteasome mediated degradation, further, it can endow the tubulin depolymerization through detyrosination to increase the cell motility. Thus, miR-143-3p by inhibiting VASH1 t can increase the invasion capability and angiogenesis of lung cancer	A:m6A	Non-small cell lung cancer
Increased m6A methylation level (due to METTL3 upregulation) promotes melanoma cell lines colony formation and invasion. MMP2 and N-cadherin play a crucial role in invasion and metastasis of melanoma cells and their expression was found to be associated to METTL3 upregulation. These results indicate that METTL3 may regulate MMP2 and N-cadherin. Whereas MMP2 expression depends on the catalytic activity of METTL3, regulation of N-cadherin appears to be independent of METTL3 catalytic activity.	A:m6A	Melanoma
Reduced levels of METTL3/METTL14 may lead to pathogenesis and progression of E/R-positive acute lymphoblastic leukemia and increase relapse rates.	A:m6A	Leukemia
Mutations found in m6A regulatory genes are associated with lower OS and EFS rates in patients with AML ( Acute myeloid Leukemia) and presence of p53 mutations.	A:m6A	Leukemia
"METTL3 is overexpressed in AML; Depletion of METTL3 induces cell differentiation and apoptosis and delays leukemia progression; m6A promotes translation of c-MYC, BCL2, PTEN mRNAs in AML. m6A depletion may activate the PI3K/AKT pathway."	A:m6A	Leukemia
METTl3 is upregulated in H/R-induced cardiomyocytes injury. It methylates TFEB at two m6A residues in the 3ʹ-UTR, and promotes the association of the RNA-binding protein HNRNPD with TFEB pre-mRNA and subsequently decreases the expression levels of TFEB. This inhibits the autophagic flux and increases apoptosis in H/R-treated cardiomyocytes.	A:m6A	Ischemic Heart disease
m6A methylation level decreases the expression of tumor suppressor genes like SOCS2. The upregulation of METTL3 in HCC mediates this event through an m6A-YTHDF2-dependent mechanism and increases cancer cells proliferation, migration and metastasis formation	A:m6A	Hepatocellular carcinoma
Snail, a key transcription factor of EMT, has an increased m6A methylation in its CDS and 3′UTR regions, through METTL3. m6A in CDS of Snail can trigger its translation elongation via interaction with YTHDF1 and eEF-2.	A:m6A	Hepatocellular carcinoma
LINC00958 is upregulated in HCC cell lines and tissues. LINC00958 sponges miR-3619-5p which has among its targets HDGF which is important for lipogenesis. LINC00958 is upregulated in HCC cell lines and tissues, thus it icreases the interactions with miR-3619-5p, thus increasing HDGF mRNA expression levels. HDGF has been established as an oncogene that facilitates the progression of HCC. Furthermore, m6A methylation levels are enriched within LINC00958 in HCC cells and they correlate with and increased METTL3 expression level. These results suggest that the increase of LINC00958 in HCC may be attributed to the m6A modification.	A:m6A	Hepatocellular carcinoma
Decreased methylation promotes GSCs growth and self-renewal. METTL3 induced methylation protects against GSCs growth and self-renewal	A:m6A	Glioblastoma
Increased m6A methylation (mediated by METTL3) induces GSCs mantainance and radioresistence, regulation of alternative splicing events and stability, differential regulation of miRNA and lincRNA, and expression of direct and indirect targets in key glioblastoma-related oncogenic pathways ( NOTCH, NFkB, Wnt, c-Myc, and TGF-b)	A:m6A	Glioblastoma
Increased m6A methylation level was found to be correlated with the upregulation of METTL3 in GC patients. The increased methylation influences cell proliferation, migration and invasion by regulting transcription factors like GFI-1, apoptotic-related protein expression, AKT signaling pathway (p-AKT, p70S6K and Cyclin D1).	A:m6A	Gastric cancer
~70% of tumor samples from endometrial cancer patients exhibited decreased m6A levels due to either decreased expression of METTL3 or loss of function mutation in METTL14 (R298P). This generates a reduction in m6A mRNA methylation levels and an enhancement in proliferation and tumorigenicity. Reductions in m6A methylation lead to decreased expression of the negative AKT regulator PHLPP2 and increased expression of the positive AKT regulator mTORC2. Increased AKT activation is one of the main mediators of increased proliferation in cells.	A:m6A	Endometrial cancer
It was found that the negative expression of METTL3 is associated with larger tumor size and higher metastasis rates in CRC. Decreased level of METTL3 increases P38/ERK pathway expression. The increased expression of p-P38 and p-ERK is associated with CRC cells proliferation, migration and invasion.	A:m6A	Colorectal cancer
The increased m6A methylation level in SOX2 transcripts increases SOX2 expression and promotes CRC cells stemness and metastasis. METTL3 is highly expressed in CRC patients, and it induces an increased m6A methylation level in SOX2 transcripts. Methylated SOX2 mRNAs are subsequently recognized by the m6A “reader”, IGF2BP2, which maintains the mRNA stability and expression. Finally, the increased SOX2 expression, through SOX2 downstream targets,npromotes CRC cell stemness and metastasis, leading to CRC progression.	A:m6A	Colorectal cancer
The increased m6A methylation level (by METTL3) induces a RP11 accumulation in the nucleus and on chromatin. RP11 increased expression downregulates Siah1 and Fbxo45 and mediates the RP11-induced stabilization of Zeb1 which is fondamental to trigger CRC cells migration, invasion and EMT both in vitro and in vivo.	A:m6A	Colorectal cancer
METTL3 is upregulated in colorectal cancer. METTL3 can methylate pri-miR-1246, which further promotes the maturation of pri-miR-1246. The anti-oncogene SPRED2 was identified as the downstream target of miR-1246, wherein downregulated SPRED2 further reverses the inhibition of the MAPK pathway. The METTL3/miR-1246/SPRED2 axis plays an important role in tumor metastasis and provides a new m6A modification pattern in CRC development.	A:m6A	Colorectal cancer
m6A upregulates the levels of HBXIP; increases malignant cell growth and proliferation. METTL3 promoted the expression of HBXIP through m6A modification; high expression of METTL3 is related to increased levels of HBXIP in clinical breast cancer tissues and breast cancer cells; METTL3 increases the levels of expression of HBXIP by affecting m6A modification levels on HBXIP mRNA.METTL3 has increased expression in breast cancer cells and has an essential role in progression.	A:m6A	Breast cancer
m6A levels are decreased in immortalized and oncogenically transformed human mammary epithelial cells. The levels of METTL3 are descresed and ALKBH5 are increased. Overexpression of METTL3 and METTL14 and knockdown of ALKBH5 results in increased proliferation and migaration of immortalized cells. m6A levels may be downregulated in immortalized cells. Hypoxia increased m6A levels throgh mechanisms that are independent of METTL3, METTL14 and ALKBH5 expression levels. Increases of m6A levels in hypoxia are regulated by HIF.	A:m6A	Breast cancer
"m6A levels are reduced in breast cancer samples due to a decrease in m6A methylases expression and an increase in demethylases expression; expression levels of METTL3, METTL14, WTAP and FTO were correlated with poor survival and cancer progression; m6A higher levels suppress cancer cell viability, inhibit MDA-MB-231 colony-formation abilities and cell migratory abilities.Expression levels of writers and readers differes according to the subtype of breast cancer ( luminal A/B vs. triple negative)."	A:m6A	Breast cancer
"m6A level are increased in the breast cancer tissue as compared to normal samples; METTL3 overexpression and promotes translation (overexpression) of Bcl-2"	A:m6A	Breast cancer
METTL3 is upregulated in bladder cancer cells and tissues. METTL3 could enhance the recognition of pri-miR221/222, which plays an oncogenic role in bladder cancer, by DGCR8 and the subsequent processing to mature miRNAs in an m6A manner.	A:m6A	Bladder cancer
METTL3 is upregulated in bladder cancer and m6A level is thus increased. AF4/FMR2 family member 4 (AFF4), two key regulators of NF-κB pathway (IKBKB and RELA) and MYC were further identified as direct targets of METTL3-mediated m6A modification	A:m6A	Bladder cancer
METTL3 and CDCP1 are upregulated in bladder cancer patient samples. The increased m6A modification and translation of oncogene CDCP1 in the transformed uroepithelial cells indicates the potential role of METTL3/m6A/CDCP1 axis in bladder cancer oncogenesis.	A:m6A	Bladder cancer
m6A methyltransferase METTL3 is elevated and the m6A demethylase FTO is decreased in AD mice. The related pathways and genes predicted the potential roles of the differentially expressed m6A methylation RNA in AD.	A:m6A	Alzheimer

Publications:

Title	Authors	Journal	Details	PubMed Id	DOI
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.	Bujnicki JM, Feder M, Radlinska M, Blumenthal RM	J Mol Evol	[details]	12355263	-
N6-adenosine methylation in mRNA: substrate specificity and enzyme complexity.	Rottman FM, Bokar JA, Narayan P, Shambaugh ME, Ludwiczak R...	Biochimie	[details]	7748945	-
Expression of the mRNA (N6-adenosine)-methyltransferase S-adenosyl-L-methionine binding subunit mRNA in cultured cells.	Leach RA, Tuck MT...	Int J Biochem Cell Biol	[details]	11470232	-
Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase.	Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM...	RNA	[details]	9409616	-
A METTL3-METTL14 complex mediates mammalian nuclear RNA N-adenosine methylation.	Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C...	Nat Chem Biol	[details]	24316715	-
Molecular biology. Internal mRNA methylation finally finds functions.	Nilsen TW...	Science	[details]	24626918	-

Links:

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