Affinage

METTL3

N(6)-adenosine-methyltransferase catalytic subunit METTL3 · UniProt Q86U44

Length
580 aa
Mass
64.5 kDa
Annotated
2026-04-28
100 papers in source corpus 45 papers cited in narrative 47 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

METTL3 is the catalytic subunit of the principal N6-methyladenosine (m6A) methyltransferase complex in mammals, responsible for >95% of mRNA m6A deposition and thereby governing mRNA stability, translation, splicing, and miRNA maturation across virtually all cell types (PMID:35853000, PMID:29348140). It forms an obligate heterodimer with METTL14, which contributes RNA-substrate binding through its C-terminal RGG repeats, and is targeted to nuclear speckles by WTAP; its catalytic activity is repressed by SUMO1 modification and its protein levels are controlled by TRIP12-mediated K48-linked polyubiquitination, while lactylation of its zinc-finger domain is required for RNA capture (PMID:29348140, PMID:29506078, PMID:38902548, PMID:35320754). m6A marks deposited by METTL3 are decoded by distinct reader proteins—YTHDF1/2/3 and IGF2BP1/2/3—to direct target mRNA degradation or translational enhancement in a transcript-specific manner, controlling processes including immune cell maturation, spermatogenesis, autophagy, chromatin modifier expression, and telomere maintenance via m6A-modified TERRA lncRNA (PMID:31015515, PMID:28809392, PMID:36399511, PMID:38180812, PMID:37656787). Independent of its methyltransferase activity, cytoplasmic METTL3 associates with ribosomes and directly promotes translation of specific mRNAs through the translation initiation machinery (PMID:27117702).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2002 Low

    Before any biochemical characterization, computational analysis identified METTL3 (MT-A70) as a candidate SAM-binding catalytic subunit of the mRNA m6A methyltransferase, establishing the structural framework for all subsequent enzymatic studies.

    Evidence Bioinformatic sequence analysis and structural prediction identifying a permuted Class B methyltransferase fold

    PMID:12355263

    Open questions at the time
    • Purely computational—no biochemical validation of catalytic activity
    • No binding partner or complex architecture defined
    • No in vivo evidence
  2. 2016 High

    The discovery that METTL3 localizes to ribosomes in the cytoplasm and promotes translation of specific mRNAs even when catalytically inactive revealed a methyltransferase-independent function, establishing METTL3 as both an m6A writer and a direct translational enhancer.

    Evidence Ribosome fractionation, tethering assays with catalytic mutants, and loss/gain-of-function studies in human cells

    PMID:27117702

    Open questions at the time
    • Structural basis for ribosome association undefined
    • Full spectrum of translationally regulated targets unknown
    • Relationship between cytoplasmic and nuclear METTL3 pools not resolved
  3. 2017 High

    Conditional knockout of Mettl3 in mouse germ cells demonstrated that m6A is essential for spermatogonial differentiation and meiosis initiation, providing the first in vivo proof that METTL3-dependent m6A controls a specific developmental program.

    Evidence Germ cell-specific conditional KO mice with transcriptomic and m6A profiling

    PMID:28809392

    Open questions at the time
    • Direct mRNA targets mediating the spermatogenesis block not fully resolved
    • Reader proteins involved not identified in this study
  4. 2018 High

    Biochemical reconstitution established that METTL3 forms an obligate heterodimer with METTL14 (which has a degenerate active site) and that METTL14's RGG repeats are required for RNA binding; SUMO1 modification of METTL3 represses catalytic activity without affecting complex assembly or localization, defining the first post-translational regulatory axis.

    Evidence Recombinant protein reconstitution, in vitro methylation assays, site-directed mutagenesis (4KR SUMO mutant), and m6A quantification

    PMID:29348140 PMID:29506078

    Open questions at the time
    • Structural basis for SUMO-mediated inhibition unresolved
    • Physiological signals controlling SUMO1/SENP1 balance on METTL3 not defined
  5. 2019 High

    DC-specific Mettl3 knockout showed that m6A on CD40, CD80, and Tirap mRNAs enhances their translation and is required for dendritic cell maturation and T cell activation, establishing METTL3 as a central regulator of innate immune cell function.

    Evidence Conditional KO mice, m6A-RIP, in vitro translation assays

    PMID:31015515

    Open questions at the time
    • Specific m6A reader mediating translational enhancement in DCs not identified
    • Whether METTL3's catalytic-independent translational role contributes in DCs is unknown
  6. 2021 High

    Multiple conditional KO studies established that METTL3-deposited m6A controls immune cell differentiation and function broadly—TFH cells (via Tcf7 mRNA stabilization), NK cells (via SHP-2/PTPN11 signaling), and microglia (via BATF stabilization through IGF2BP2)—demonstrating that distinct m6A readers decode METTL3-deposited marks in a cell-type and target-specific manner.

    Evidence Conditional KO mice for CD4+ T cells, NK cells, and myeloid cells; miCLIP-seq, MeRIP-seq, IGF2BP2 RIP, ectopic rescue experiments

    PMID:33637761 PMID:34535671 PMID:38902548

    Open questions at the time
    • How reader specificity is determined for a given target mRNA is unknown
    • Redundancy among readers for individual targets not systematically tested
  7. 2022 High

    True genetic ablation of METTL3 exon 4 revealed that alternative splicing generates functional isoforms that bypass many published CRISPR knockouts, and established that METTL3 accounts for >95% of mRNA m6A, resolving prior conflicting knockout phenotypes.

    Evidence CRISPR/Cas9 exon 4 deletion, quantitative m6A mass spectrometry, RT-PCR isoform analysis

    PMID:35853000

    Open questions at the time
    • Functional significance of individual METTL3 splice isoforms not characterized
    • Whether the remaining ~5% of m6A has distinct function is unknown
  8. 2022 High

    Discovery that TRIP12 mediates K48-linked polyubiquitination and proteasomal degradation of METTL3, counteracted by ERK-USP5 stabilization during inflammation, defined a second post-translational regulatory axis controlling METTL3 protein abundance independently of transcription.

    Evidence Co-IP, ubiquitination assays, conditional KO, pharmacological inhibition in neuroinflammation models

    PMID:38902548

    Open questions at the time
    • Structural basis for TRIP12 recognition of METTL3 not determined
    • Whether other E3 ligases (e.g., PLAA-associated) are redundant or context-specific is unclear
  9. 2022 High

    Lactylation of the METTL3 zinc-finger domain was shown to be essential for RNA substrate capture; tumor-derived lactate drives this modification and enhances m6A deposition on Jak1 mRNA, read by YTHDF1 to boost JAK1 translation and immunosuppression, revealing metabolic reprogramming as a third regulatory input to METTL3 activity.

    Evidence Lactylation site mapping, m6A-RIP, YTHDF1 RIP, translation efficiency assays, conditional KO mice

    PMID:35320754

    Open questions at the time
    • Whether lactylation and SUMOylation compete or cooperate on METTL3 is unknown
    • Structural mechanism by which zinc-finger lactylation enables RNA capture unresolved
  10. 2022 Medium

    METTL3 was shown to methylate TERRA lncRNA at subtelomeric regions, with YTHDC1 stabilizing methylated TERRA to promote R-loop formation needed for ALT-pathway telomere maintenance; a subsequent study identified hnRNPA2B1 as a critical reader bridging m6A-TERRA to telomeric R-loops.

    Evidence METTL3/YTHDC1/hnRNPA2B1 knockdown, MeRIP, RIP, R-loop detection, telomere length assays in ALT+ cancer cells

    PMID:36399511 PMID:38180812

    Open questions at the time
    • Whether METTL3 acts at telomeres in non-ALT contexts is unknown
    • Structural basis for selective TERRA methylation not determined
    • Single-lab findings for each study
  11. 2024 High

    ARID1A was identified as the chromatin-level recruiter of METTL3/METTL14 to R-loops in an ATM-dependent manner; m6A deposited on R-loop RNA facilitates RNase H1 recruitment for R-loop resolution and DNA end resection, directly linking METTL3 to the DNA damage response.

    Evidence Co-IP, m6A-RIP, RNase H1 recruitment assay, depletion studies with DNA damage readouts

    PMID:38358891

    Open questions at the time
    • Whether METTL3's role in R-loop resolution is genome-wide or locus-specific is not resolved
    • How ATM-dependent ARID1A phosphorylation controls METTL3 recruitment mechanistically is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how METTL3 target selectivity is determined genome-wide, the structural basis for reader-specific decoding of METTL3-deposited m6A, whether catalytic and non-catalytic functions are coordinated or spatially segregated, and how the multiple post-translational modifications (SUMOylation, ubiquitination, lactylation, phosphorylation) are integrated to tune METTL3 activity in real time.
  • No structural model of the full METTL3–METTL14–WTAP complex on an RNA substrate
  • Mechanistic basis for transcript selectivity unknown
  • Integration of multiple PTMs on METTL3 not studied systematically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0016740 transferase activity 4 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1 GO:0005829 cytosol 1 GO:0005840 ribosome 1
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-73894 DNA Repair 1
Partners
ARID1AIGF2BP2METTL14TRIP12WTAPYTHDC1YTHDF1YTHDF2
Complex memberships
METTL3–METTL14 m6A methyltransferase complexMETTL3–METTL14–WTAP writer complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 METTL3 associates with ribosomes in the cytoplasm and promotes translation of specific mRNAs (e.g., EGFR, TAZ) through interaction with the translation initiation machinery; both wild-type and catalytically inactive METTL3 promote translation when tethered to a reporter mRNA, indicating a methyltransferase-independent translational role in addition to its m6A writer function. Ribosome fractionation, tethering assays, loss- and gain-of-function studies, catalytic mutant analysis Molecular cell High 27117702
2018 METTL3 forms a heterodimeric catalytic complex with METTL14; METTL3 alone is soluble but inactive, while METTL14 has a degenerate catalytic center and is also inactive alone. The C-terminal RGG repeats of METTL14 are required for complex activity by contributing to RNA substrate binding. WTAP is required for nuclear speckle localization. Nuclear localization signals were identified on the endogenous proteins, and phosphorylation sites were mapped. SUMOylation does not alter complex localization or METTL3–METTL14–WTAP interactions but represses m6A methyltransferase activity. Recombinant protein binding surface mapping, in vitro methylation assay, nuclear localization signal identification, phosphorylation site mapping, Co-IP RNA (New York, N.Y.) High 29348140
2018 METTL3 is SUMOylated primarily at lysine residues K177, K211, K212, and K215 by SUMO1; this modification is reversed by the SUMO1-specific protease SENP1. SUMOylation of METTL3 does not alter its stability, localization, or interaction with METTL14 and WTAP, but significantly represses its m6A methyltransferase activity, leading to decreased m6A levels in mRNAs. Site-directed mutagenesis (4KR mutant), in vitro SUMOylation assay, mRNA m6A quantification, soft-agar colony formation Nucleic acids research High 29506078
2002 Bioinformatic analysis identified METTL3 (MT-A70) as the S-adenosylmethionine-binding catalytic subunit of the mRNA m6A methyltransferase, with a permuted Class B methyltransferase fold domain; it is predicted to be part of a larger family comprising four subfamilies including bacterial DNA:m6A MTases and eukaryotic paralogs. Computational sequence analysis, structural prediction, multiple sequence alignment Journal of molecular evolution Low 12355263
2017 Germ cell-specific knockout of Mettl3 in mice severely inhibits spermatogonial differentiation and blocks meiosis initiation, with altered expression profiles and alternative splicing of spermatogenesis-related genes, demonstrating that Mettl3-mediated m6A is essential for male fertility. Conditional knockout mice, transcriptome and m6A profiling, phenotypic analysis of spermatogenesis Cell research High 28809392
2017 METTL3/METTL14-mediated m6A modification and NSUN2-mediated m5C modification in the p21 3'UTR cooperatively enhance p21 translation; m6A methylation by METTL3/METTL14 facilitates m5C methylation by NSUN2 and vice versa. RNA methylation assays, translation reporter assays, knockdown experiments Journal of cellular biochemistry Medium 28247949
2019 Mettl3-mediated m6A modification of CD40, CD80, and the TLR4 signaling adaptor Tirap mRNAs enhances their translation in dendritic cells, promoting DC maturation, NF-κB signaling-induced cytokine production, and T cell activation; DC-specific Mettl3 knockout impairs phenotypic and functional DC maturation. Conditional knockout mice, in vitro translation assays, loss-of-function studies, m6A-RIP Nature communications High 31015515
2019 METTL3 methylates TFEB mRNA at two m6A residues in the 3'-UTR, promoting association of HNRNPD with TFEB pre-mRNA and subsequently decreasing TFEB expression levels, thereby negatively regulating autophagic flux. Conversely, TFEB inhibits METTL3 expression by reducing its mRNA stability (not transcriptional repression), establishing a negative feedback loop. siRNA knockdown, overexpression, m6A-RIP, RNA-binding protein pulldown, autophagic flux assays Autophagy Medium 30870073
2020 METTL3 mediates m6A modification in the 3' UTR of BMI1 mRNA, and in cooperation with the m6A reader IGF2BP1, promotes BMI1 translation in oral squamous cell carcinoma cells, driving tumor proliferation and metastasis. MeRIP-seq, MeRIP-qPCR, luciferase reporter and mutagenesis assays, Co-IP with IGF2BP1, in vivo xenograft Molecular therapy Medium 32621798
2020 METTL3 promotes m6A modification of SOCS2 mRNA in colon cancer cells, increasing its degradation rate; METTL3 knockout via CRISPR/Cas9 decreases SOCS2 mRNA decay, elevates SOCS2 protein expression, and inhibits LGR5 expression and cell proliferation. CRISPR/Cas9 knockout, MeRIP-qPCR, mRNA decay assay Oncology reports Medium 32705223
2020 METTL3-dependent m6A modification reduces the turnover and increases expression of MIS12 mRNA through IGF2BP2-mediated recognition; METTL3 knockout accelerates human mesenchymal stem cell senescence and loss of m6A on MIS12 mRNA destabilizes it, whereas MIS12 knockout independently accelerates senescence. METTL3 knockout/overexpression, transcriptional m6A profiling, RNA stability assay, RIP for IGF2BP2 Nucleic acids research Medium 33035345
2021 METTL3 catalyzes m6A modification on SHP-2 (PTPN11) mRNA in NK cells, and reduced SHP-2 activity in METTL3-deficient NK cells renders them hyporesponsive to IL-15 and suppresses AKT and MAPK signaling, impairing NK cell homeostasis and anti-tumor function. Conditional KO mice, m6A-seq, tumor models, signaling pathway analysis Nature communications Medium 34535671
2021 METTL3-mediated m6A modification of ATG7 mRNA decreases its RNA stability, reducing ATG7 expression and impairing autophagosome formation, leading to GATA4 accumulation, SASP upregulation, and FLS cellular senescence in osteoarthritis. m6A RNA immunoprecipitation, RNA stability assay, siRNA knockdown, in vivo AAV-siRNA delivery Annals of the rheumatic diseases Medium 34706873
2021 Conditional deletion of METTL3 in CD4+ T cells impairs T follicular helper (TFH) cell differentiation and germinal center responses in a methyltransferase activity-dependent manner. METTL3-dependent m6A modification stabilizes Tcf7 (TCF-1) mRNA at its 3' UTR; loss of METTL3 accelerates Tcf7 mRNA decay and impairs the TFH transcriptional program, which is rescued by ectopic TCF-1 expression. Conditional KO mice, m6A-miCLIP-seq, RNA stability assay, ectopic expression rescue Nature communications High 33637761
2022 METTL3 catalyzes m6A modification on TERRA lncRNA at subtelomeric regions; the m6A reader YTHDC1 recognizes and stabilizes m6A-modified TERRA. METTL3 depletion enhances TERRA degradation, reduces R-loop formation, and leads to telomere shortening and instability. m6A-modified TERRA forms R-loops and promotes homologous recombination for ALT pathway telomere maintenance. METTL3 knockdown, YTHDC1 knockdown, MeRIP, R-loop detection, telomere length assay Nucleic acids research Medium 36399511
2024 METTL3-mediated m6A modification of TERRA enables recruitment of hnRNPA2B1 to TERRA, which is critical for R-loop formation at telomeres and telomere maintenance in ALT+ cancer cells; loss of TERRA m6A/METTL3 causes telomere damage. METTL3 inhibition/knockdown, MeRIP, RIP for hnRNPA2B1, R-loop detection, DNA damage assays Nucleic acids research Medium 38180812
2022 Lactate activates p300-mediated H3K18 lactylation at the METTL3 promoter, upregulating METTL3 expression; METTL3-mediated m6A modification of ACSL4 mRNA is recognized by YTHDC1, increasing ACSL4 mRNA stability and expression, promoting ferroptosis in alveolar epithelial cells during sepsis-associated lung injury. ChIP for H3K18la, MeRIP for ACSL4, YTHDC1 RIP, METTL3 knockdown/inhibition, in vivo mouse model Redox biology Medium 38852200
2022 Lactylation of two sites in the zinc-finger domain of METTL3 (induced by tumor lactate via H3K18 lactylation-driven transcription) is essential for METTL3 to capture target RNA; METTL3-mediated m6A on Jak1 mRNA enhances JAK1 protein translation through the m6A-YTHDF1 axis and subsequent STAT3 phosphorylation, promoting immunosuppression in tumor-infiltrating myeloid cells. Lactylation site mapping, m6A-RIP, YTHDF1 RIP, translation efficiency assay, conditional KO mice Molecular cell High 35320754
2022 METTL3 promotes m6A modification of TAB3 mRNA, and the stability of TAB3 is enhanced through binding of IGF2BP2 to its m6A-modified stop codon region, leading to increased TAB3 expression and NF-κB-mediated renal inflammation. MeRIP-seq, RNA-seq, siRNA knockdown, IGF2BP2 RIP, in vivo conditional KO, pharmacological inhibition Science translational medicine High 35417191
2022 F. nucleatum activates YAP signaling, inhibits FOXD3 expression, and subsequently reduces METTL3 transcription (FOXD3 identified as a transcription factor for METTL3); reduced METTL3 decreases m6A on KIF26B mRNA, diminishing YTHDF2-dependent KIF26B mRNA degradation and promoting CRC metastasis. ChIP for FOXD3, MeRIP, YTHDF2 RIP, xenograft model Nature communications Medium 35273176
2022 METTL3 promotes m6A modification of TIMP2 mRNA, and the m6A reader IGF2BP2 recognizes this modification to stabilize TIMP2 mRNA, activating Notch signaling and producing pro-inflammatory and pro-apoptotic effects in podocytes in diabetic nephropathy. MeRIP-qPCR, IGF2BP2 RIP, podocyte conditional KO mice, AAV9-shMETTL3 in vivo Molecular therapy Medium 34995800
2022 METTL3 promotes m6A modification of TRAF6 mRNA 3'-UTR and can physically bind to TRAF6 protein; METTL3 overexpression promotes TRAF6/NF-κB pathway activation in LPS-stimulated microglia in an m6A-dependent manner. m6A-RIP, Co-IP for METTL3-TRAF6 interaction, Western blot, overexpression/knockdown Neuroreport Medium 33165191
2022 TRIP12, a HECT-domain E3 ubiquitin ligase, is a negative regulator of METTL3 protein expression by facilitating K48-linked polyubiquitination of METTL3, controlling its protein stability in microglia independent of transcriptional changes; METTL3 stabilizes BATF mRNA through the m6A-IGF2BP2-dependent mechanism, promoting pro-inflammatory gene expression in microglia. Co-IP, ubiquitination assay, MeRIP-seq, IGF2BP2 RIP, conditional KO, CUT&Tag sequencing Cell death and differentiation High 38902548
2024 ARID1A recognizes R-loops with high affinity in an ATM-dependent manner and recruits METTL3 and METTL14 to the R-loop, leading to m6A methylation of R-loop RNA; this m6A modification facilitates recruitment of RNase H1 to drive R-loop resolution and promote DNA end resection at DSBs, ensuring genome stability. Co-IP, m6A-RIP, RNase H1 recruitment assay, ARID1A/METTL3/METTL14 depletion, DNA damage readouts Cell reports High 38358891
2022 Alternative splicing of METTL3 generates functionally active methyltransferase isoforms that bypass CRISPR/Cas9 mutations in reported 'knockout' cell lines; using a true exon 4 deletion, METTL3 was shown to be responsible for >95% of m6A in mRNA. CRISPR/Cas9 engineering of exon 4 deletion, m6A quantification, RT-PCR isoform characterization PLoS biology High 35853000
2022 METTL3 represses ACVR2A (activin type 2A receptor) mRNA synthesis via m6A modification, blunting anti-hypertrophic myostatin signaling, thereby controlling skeletal muscle size during hypertrophy; myofiber-specific METTL3 conditional KO causes spontaneous muscle wasting and abrogates overload-induced hypertrophy. Conditional KO mice, METTL3 exogenous delivery, m6A-seq, myostatin inhibitor co-administration rescue Nature communications High 35013323
2021 METTL3-mediated m6A modification of DGCR8-bound pri-miR-126 facilitates its processing and maturation into miR-126, which inhibits migration and invasion of endometrial stromal cells; reduced METTL3 in endometriosis decreases miR-126 maturation and enhances cellular migration and invasion. METTL3 knockdown/overexpression, DGCR8 RIP, miRNA maturation assay, migration/invasion assay Biology of reproduction Medium 34382070
2021 METTL3 promotes m6A modification of ATG5 mRNA, increasing ATG5 expression and autophagy, and reducing cisplatin sensitivity in seminoma cells; knockdown of ATG5 reduces METTL3-induced autophagy. MeRIP-qPCR, METTL3 overexpression/knockdown, ATG5 knockdown rescue, autophagy detection, MTT assay Translational andrology and urology Medium 33968659
2021 METTL3-mediated m6A modification controls splicing factor protein expression through m6A-mediated ribosome recycling and decoding (translational control), leading to splicing dysregulation and aggressive CLL progression. Integrative transcriptomic and proteomic analysis, METTL3 knockdown/overexpression, methyltransferase-dependent functional assays, in vivo models Blood cancer discovery Medium 37067905
2021 Reduced METTL3 in hippocampal neurons leads to decreased m6A modification, causing memory deficits and neuronal death associated with oxidative stress and aberrant cell cycle events; METTL3 overexpression rescues Aβ-induced synaptic damage and cognitive impairment in vivo. METTL3 knockdown/overexpression in vivo (shRNA), behavioral tests, cell cycle analysis, in vivo Aβ mouse model Molecular neurodegeneration Medium 34593014
2021 METTL3-mediated m6A modification of BATF mRNA stabilizes BATF via IGF2BP2; METTL3 protein is stabilized in inflammatory microglia by decreased proteasomal degradation mediated by TRIP12 and ERK-USP5 pathways; pharmacological METTL3 inhibition suppresses neuroinflammation in TBI/stroke models. MeRIP-seq, CUT&Tag, IGF2BP2 RIP, ubiquitination assay, METTL3-specific inhibitor, BBB-penetrating nanoparticle delivery Cell death and differentiation High 38902548
2023 METTL3 mediates m6A modification on LATS1 mRNA; YTHDF2 recognizes the m6A site and reduces LATS1 mRNA stability, suppressing Hippo pathway activity and promoting YAP/TAZ nuclear translocation to drive breast cancer tumorigenesis and glycolysis. MeRIP-seq, RNA-seq, metabolomics, RNA pulldown, RIP-qPCR, RNA stability analysis, METTL3/YTHDF2 KO Journal of experimental & clinical cancer research Medium 36609396
2023 In Xenopus laevis, Mettl3-mediated m6A modification promotes mRNA destabilization through interaction with the m6A reader Ythdf1 and mRNA degradation factors (Lsm1, Tut7); Mettl3 knockdown anteriorizes embryos and causes loss of neural crest and neuronal cells, associated with inhibition of canonical WNT signaling. Morpholino knockdown, in vivo neural patterning assays, epistasis with Ythdf1/Lsm1/Tut7 knockdown Molecular and cellular biology Medium 33972392
2023 METTL3 promotes m6A-dependent degradation of mRNAs encoding critical histone-modifying enzymes in epidermal progenitors; Mettl3 depletion increases expression of these chromatin modifiers and widespread histone modification changes, resulting in impaired hair follicle morphogenesis and epithelial self-renewal. Conditional KO mice, m6A-seq, RNA-seq, chromatin modifier expression analysis Science advances Medium 37656787
2023 METTL3-mediated m6A modification promotes m6A-YTHDF2-dependent stabilization of ID2 mRNA in pancreatic cancer cells, and ID2 in turn regulates NANOG and SOX2 via the PI3K-AKT pathway to support cancer growth and stemness. METTL3 knockdown, MeRIP-qPCR, YTHDF2 RIP, RNA stability assay, rescue experiments Cancer letters Medium 37196908
2023 PLAA inhibits METTL3 expression through ubiquitin-mediated proteasomal degradation; METTL3 stabilizes TRPC3 mRNA expression via m6A modification, promoting intracellular Ca2+ levels and ovarian cancer metastasis. Co-IP, ubiquitination assay, MeRIP, RNA stability assay, xenograft model Oncogene Medium 35869392
2022 NCBP3 interacts with METTL3 and eIF4A2 in hypoxic cardiomyocytes (identified by immunoprecipitation/mass spectrometry); NCBP3 acts as a scaffold to coordinate METTL3 and eIF4A2, and METTL3-mediated m6A methylation is elevated in hypoxia; disruption of this axis compromises hypoxia-induced translational enhancement. Co-IP/mass spectrometry, NCBP3 knockdown, m6A quantification, translation assays Journal of cellular and molecular medicine Medium 34382339
2022 METTL3-mediated m6A modification of Lats2 mRNA promotes its degradation in hepatic stellate cells; depletion of Mettl3 reduces m6A on Lats2 mRNA, elevating Lats2 protein, increasing YAP phosphorylation, suppressing YAP nuclear translocation, and decreasing pro-fibrotic gene expression; YAP overexpression partially rescues METTL3-deficient HSC activation. HSC-specific KO mice, MeRIP-seq, multi-omics, YAP mutant rescue Molecular therapy Medium 35923112
2023 METTL3-mediated m6A modification of SIRT1 mRNA enables YTHDF2 binding, promoting SIRT1 mRNA degradation; reduced SIRT1/FOXO3a signaling promotes cellular senescence of endometrial stromal cells; reduced METTL3 in endometriosis leads to increased SIRT1 and inhibited ESC senescence. MeRIP, YTHDF2 RIP, RNA stability assay, conditional KO mice, xenograft model Journal of translational medicine Medium 37353804
2023 METTL3 ablation in monocyte-derived macrophages attenuates m6A modification on DNMT3A mRNA, impairing YTHDF1-mediated DNMT3A translation; reduced DNMT3A decreases ATAT1 expression, reduces α-tubulin acetylation, and enhances macrophage migration and Aβ clearance in an AD mouse model. Conditional KO mice, YTHDF1 RIP, MeRIP, ChIP for DNMT3A, behavioral tests PLoS biology Medium 36881554
2022 METTL3 promotes m6A modification that increases METTL3-mediated m6A modification of TLR4 mRNA, resulting in increased TLR4 translation and slowed degradation simultaneously, elevating TLR4 protein levels and activating TLR4/MYD88/NF-κB signaling to promote neutrophil activation and CXCR2-dependent bone marrow release. Conditional KO mice, MeRIP-qPCR, translation and mRNA stability assays, flow cytometry, LPS endotoxemia model Cell reports Medium 36920907
2023 METTL3-mediated m6A modification controls RUNX2 mRNA at its 3'-UTR; the m6A reader IGF2BP1 recognizes the m6A site on RUNX2 mRNA to enhance its stability, promoting osteogenic differentiation of BMSCs. RIP, MeRIP-qPCR, ALP activity assay, alizarin red staining, METTL3 KD/OE Oral diseases Medium 36705430
2024 METTL3-mediated m6A modification of SOX4 mRNA at its CDS region stabilizes SOX4 mRNA; the m6A reader YTHDF3 binds SOX4 mRNA to modulate its levels; fluid shear stress induces METTL3 upregulation, promoting osteoblast proliferation and differentiation through this axis. MeRIP-seq, RNA-seq, RIP for YTHDF3, METTL3 KD/OE, in vivo AAV2-SOX4 rescue in OVX mice Cellular signalling Medium 38195035
2025 METTL3-mediated m6A modification of SNAP29 mRNA promotes its degradation via YTHDF2, depleting SNAP29 protein in ischemic flap tissue and disrupting autophagic flux (autolysosome formation), leading to mitochondrial damage and parthanatos. MeRIP-qPCR, RIP-qPCR, RNA stability assay, METTL3/YTHDF2 knockdown, AAV SNAP29 rescue, proteomic analysis Autophagy Medium 40340690
2022 METTL3 promotes m6A modification of SNAIL mRNA, leading to its increased expression; SNAIL then enhances CXCL2 secretion through the NF-κB pathway, recruiting M2-type macrophages to promote colorectal cancer pulmonary metastasis. MeRIP-qPCR, RNA stability analysis, luciferase reporter assay, in vivo BALB/c nude mouse model Journal of experimental & clinical cancer research Medium 38605400
2023 METTL3-mediated m6A modification of circGLIS3 enhances its stability; circGLIS3 sponges miR-661 to upregulate MDM2, activating the p53 signaling pathway to promote prostate cancer proliferation, migration, and invasion. MeRIP, RNA stability assay, miRNA pulldown, luciferase reporter, in vivo xenograft Cellular & molecular biology letters Medium 39143552
2023 METTL3 promotes m6A modification of BATF mRNA, stabilizing it via IGF2BP2, and enables BATF-driven pro-inflammatory gene expression including TNF-dependent neurotoxicity and CXCL2 release in microglia; TRIP12 ubiquitinates METTL3 for proteasomal degradation (K48-linked polyubiquitination), and ERK-USP5 pathway counteracts this to stabilize METTL3 in inflammatory conditions. Ubiquitination assay, Co-IP, MeRIP-seq, CUT&Tag, pharmacological inhibition, conditional KO Cell death and differentiation High 38902548

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Molecular cell 1263 27117702
2022 Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Molecular cell 627 35320754
2019 Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation. Nature communications 429 31015515
2019 METTL3 and ALKBH5 oppositely regulate m6A modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes. Autophagy 413 30870073
2018 Interactions, localization, and phosphorylation of the m6A generating METTL3-METTL14-WTAP complex. RNA (New York, N.Y.) 376 29348140
2017 Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation. Cell research 354 28809392
2017 The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. International journal of oncology 330 29345285
2021 METTL3-mediated m6A modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Annals of the rheumatic diseases 313 34706873
2018 SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function. Nucleic acids research 273 29506078
2022 Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms. Science translational medicine 254 35417191
2017 NSUN2-Mediated m5C Methylation and METTL3/METTL14-Mediated m6A Methylation Cooperatively Enhance p21 Translation. Journal of cellular biochemistry 233 28247949
2022 Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis. Nature communications 206 35273176
2024 Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury. Redox biology 195 38852200
2002 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. Journal of molecular evolution 181 12355263
2021 METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells. Nature communications 171 34535671
2022 METTL3-mediated m6A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy. Molecular therapy : the journal of the American Society of Gene Therapy 166 34995800
2021 METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events. Molecular neurodegeneration 160 34593014
2020 METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA. Nucleic acids research 154 33035345
2021 METTL3-dependent m6A modification programs T follicular helper cell differentiation. Nature communications 145 33637761
2020 METTL3 Promotes Tumorigenesis and Metastasis through BMI1 m6A Methylation in Oral Squamous Cell Carcinoma. Molecular therapy : the journal of the American Society of Gene Therapy 133 32621798
2020 Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer's Disease. eNeuro 118 32847866
2019 The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1. Biochemical and biophysical research communications 116 31253399
2023 The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer. Journal of experimental & clinical cancer research : CR 94 36609396
2022 The m6A methyltransferase METTL3 promotes LPS-induced microglia inflammation through TRAF6/NF-κB pathway. Neuroreport 94 33165191
2022 METTL3-mediated m6A modification stabilizes TERRA and maintains telomere stability. Nucleic acids research 92 36399511
2020 m6A methyltransferase METTL3 maintains colon cancer tumorigenicity by suppressing SOCS2 to promote cell proliferation. Oncology reports 88 32705223
2022 METTL3 promotes colorectal carcinoma progression by regulating the m6A-CRB3-Hippo axis. Journal of experimental & clinical cancer research : CR 87 35012593
2019 RNA m6A methyltransferase METTL3 regulates invasiveness of melanoma cells by matrix metallopeptidase 2. Melanoma research 78 30762711
2022 m6A methyltransferase METTL3-induced lncRNA SNHG17 promotes lung adenocarcinoma gefitinib resistance by epigenetically repressing LATS2 expression. Cell death & disease 73 35902569
2023 METTL3-mediated m6A mRNA methylation regulates neutrophil activation through targeting TLR4 signaling. Cell reports 66 36920907
2020 METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP. Cell biology international 65 32869897
2020 HBXIP promotes gastric cancer via METTL3-mediated MYC mRNA m6A modification. Aging 59 33048840
2022 The m6A methyltransferase METTL3 regulates muscle maintenance and growth in mice. Nature communications 58 35013323
2022 Alternative splicing of METTL3 explains apparently METTL3-independent m6A modifications in mRNA. PLoS biology 58 35853000
2021 Inhibition of METTL3/m6A/miR126 promotes the migration and invasion of endometrial stromal cells in endometriosis†. Biology of reproduction 58 34382070
2023 METTL3 promotes pancreatic cancer proliferation and stemness by increasing stability of ID2 mRNA in a m6A-dependent manner. Cancer letters 56 37196908
2020 m6A methyltransferase METTL3 promotes the progression of prostate cancer via m6A-modified LEF1. European review for medical and pharmacological sciences 56 32329830
2022 The m6A methyltransferase Mettl3 deficiency attenuates hepatic stellate cell activation and liver fibrosis. Molecular therapy : the journal of the American Society of Gene Therapy 54 35923112
2023 Intracellular Fusobacterium nucleatum infection increases METTL3-mediated m6A methylation to promote the metastasis of esophageal squamous cell carcinoma. Journal of advanced research 50 37619934
2023 Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice. PLoS biology 49 36881554
2023 METTL3-dependent m6A methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling. Cell death & disease 49 37270544
2023 METTL3-mediated m6A modification of SIRT1 mRNA inhibits progression of endometriosis by cellular senescence enhancing. Journal of translational medicine 48 37353804
2022 The m6A RNA methyltransferase METTL3/METTL14 promotes leukemogenesis through the mdm2/p53 pathway in acute myeloid leukemia. Journal of Cancer 48 35154467
2024 METTL3 drives telomere targeting of TERRA lncRNA through m6A-dependent R-loop formation: a therapeutic target for ALT-positive neuroblastoma. Nucleic acids research 47 38180812
2021 METTL3-mediated m6A modification regulates cell cycle progression of dental pulp stem cells. Stem cell research & therapy 47 33648590
2021 piRNA-36741 regulates BMP2-mediated osteoblast differentiation via METTL3 controlled m6A modification. Aging 47 34645714
2024 The m6A methyltransferase METTL3 drives neuroinflammation and neurotoxicity through stabilizing BATF mRNA in microglia. Cell death and differentiation 45 38902548
2024 The ARID1A-METTL3-m6A axis ensures effective RNase H1-mediated resolution of R-loops and genome stability. Cell reports 44 38358891
2023 Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2-dependent mechanism. Clinical and translational medicine 43 37537731
2022 The m6A methyltransferase METTL3 affects autophagy and progression of nasopharyngeal carcinoma by regulating the stability of lncRNA ZFAS1. Infectious agents and cancer 39 34980191
2022 m6A transferase METTL3 regulates endothelial-mesenchymal transition in diabetic retinopathy via lncRNA SNHG7/KHSRP/MKL1 axis. Genomics 39 36174881
2022 The methyltransferase METTL3 promotes tumorigenesis via mediating HHLA2 mRNA m6A modification in human renal cell carcinoma. Journal of translational medicine 36 35794583
2020 The m6A methyltransferase METTL3 aggravates the progression of nasopharyngeal carcinoma through inducing EMT by m6A-modified Snail mRNA. Minerva medica 36 32512975
2024 Targeting the m6A RNA methyltransferase METTL3 attenuates the development of kidney fibrosis. Experimental & molecular medicine 35 38297163
2021 METTL3-mediated m6A modification of KIF3C-mRNA promotes prostate cancer progression and is negatively regulated by miR-320d. Aging 35 34537760
2021 Effect of m6A methyltransferase METTL3 -mediated MALAT1/E2F1/AGR2 axis on adriamycin resistance in breast cancer. Journal of biochemical and molecular toxicology 35 34964205
2025 METTL3-dependent m6A modification of SNAP29 induces "autophagy-mitochondrial crisis" in the ischemic microenvironment after soft tissue transplantation. Autophagy 33 40340690
2021 The m6A methyltransferase METTL3 regulates autophagy and sensitivity to cisplatin by targeting ATG5 in seminoma. Translational andrology and urology 33 33968659
2022 PLAA suppresses ovarian cancer metastasis via METTL3-mediated m6A modification of TRPC3 mRNA. Oncogene 31 35869392
2022 METTL3 promotes glycolysis and cholangiocarcinoma progression by mediating the m6A modification of AKR1B10. Cancer cell international 31 36476503
2023 METTL3/YTHDF2 m6A axis mediates the progression of diabetic nephropathy through epigenetically suppressing PINK1 and mitophagy. Journal of diabetes investigation 30 38013600
2024 METTL3 recruiting M2-type immunosuppressed macrophages by targeting m6A-SNAIL-CXCL2 axis to promote colorectal cancer pulmonary metastasis. Journal of experimental & clinical cancer research : CR 29 38605400
2023 ZBTB7C m6A modification incurred by METTL3 aberration promotes osteosarcoma progression. Translational research : the journal of laboratory and clinical medicine 27 37121538
2022 METTL3 promotes proliferation and myogenic differentiation through m6A RNA methylation/YTHDF1/2 signaling axis in myoblasts. Life sciences 27 35351467
2022 METTL3 Contributes to Osteosarcoma Progression by Increasing DANCR mRNA Stability via m6A Modification. Frontiers in cell and developmental biology 26 35096816
2024 The m6A methyltransferase METTL3 drives thyroid cancer progression and lymph node metastasis by targeting LINC00894. Cancer cell international 25 38291427
2024 METTL3-mediated m6A modification of LINC00520 confers glycolysis and chemoresistance in osteosarcoma via suppressing ubiquitination of ENO1. Cancer letters 25 39168299
2023 Mettl3-catalyzed m6A regulates histone modifier and modification expression in self-renewing somatic tissue. Science advances 24 37656787
2021 METTL3-mediated m6A methylation of ASPM drives hepatocellular carcinoma cells growth and metastasis. Journal of clinical laboratory analysis 22 34398984
2021 The M6A methyltransferase METTL3 regulates proliferation in esophageal squamous cell carcinoma. Biochemical and biophysical research communications 22 34624569
2024 METTL3-mediated m6A modification of SIRT1 mRNA affects the progression of diabetic cataracts through cellular autophagy and senescence. Journal of translational medicine 21 39334185
2024 METTL3 facilitates kidney injury through promoting IRF4-mediated plasma cell infiltration via an m6A-dependent manner in systemic lupus erythematosus. BMC medicine 21 39501302
2022 METTL3-Mediated m6A RNA Methylation of ZBTB4 Interferes With Trophoblast Invasion and Maybe Involved in RSA. Frontiers in cell and developmental biology 21 35774226
2024 METTL3-mediated m6A modification of SOX4 regulates osteoblast proliferation and differentiation via YTHDF3 recognition. Cellular signalling 20 38195035
2024 Intracellular C5aR1 inhibits ferroptosis in glioblastoma through METTL3-dependent m6A methylation of GPX4. Cell death & disease 20 39368999
2023 METTL3 potentiates osteogenic differentiation of bone marrow mesenchymal stem cells via IGF2BP1/m6A/RUNX2. Oral diseases 20 36705430
2023 METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL. Blood cancer discovery 20 37067905
2023 METTL3 exerts synergistic effects on m6A methylation and histone modification to regulate the function of VGF in lung adenocarcinoma. Clinical epigenetics 20 37742030
2023 METTL3/YTHDC1-medicated m6A modification of circRNA3634 regulates the proliferation and differentiation of antler chondrocytes by miR-124486-5-MAPK1 axis. Cellular & molecular biology letters 20 38062349
2022 Mechanism of METTL3-mediated m6A modification in depression-induced cognitive deficits. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 19 35591810
2023 METTL3 Mediated MALAT1 m6A Modification Promotes Proliferation and Metastasis in Osteosarcoma Cells. Molecular biotechnology 17 37897586
2021 The effects of NCBP3 on METTL3-mediated m6A RNA methylation to enhance translation process in hypoxic cardiomyocytes. Journal of cellular and molecular medicine 17 34382339
2022 The m6A methyltransferase METTL3 promotes trophoblast cell invasion by regulating MYLK expression. Placenta 16 36170767
2025 Apelin-13-Mediated Upregulation of METTL3 Ameliorates Alzheimer's Disease via Inhibiting Neuroinflammation Through m6A-Dependent Regulation of lncRNA BDNF-AS. Biomolecules 15 40867632
2023 Molecular Mechanism of m6A Methylation Modification Genes METTL3 and FTO in Regulating Heat Stress in Sheep. International journal of molecular sciences 15 37569302
2022 m6A-dependent upregulation of TRAF6 by METTL3 is associated with metastatic osteosarcoma. Journal of bone oncology 15 35145841
2022 Resina Draconis extract exerts anti-HCC effects through METTL3-m6A-Survivin axis. Phytotherapy research : PTR 15 35443090
2025 METTL3-mediated m6A modification of SLC7A11 enhances nasopharyngeal carcinoma radioresistance by inhibiting ferroptosis. International journal of biological sciences 14 39990661
2023 METTL3/IGF2BP2 axis affects the progression of colorectal cancer by regulating m6A modification of STAG3. Scientific reports 14 37828232
2022 Roles of the m6A methyltransferases METTL3, METTL14, and WTAP in pulmonary tuberculosis. Frontiers in immunology 14 36569923
2024 METTL3-mediated m6A modification of circGLIS3 promotes prostate cancer progression and represents a potential target for ARSI therapy. Cellular & molecular biology letters 13 39143552
2021 Depletion of METTL3 alters cellular and extracellular levels of miRNAs containing m6A consensus sequences. Heliyon 13 34934837
2025 METTL3 promotes an immunosuppressive microenvironment in bladder cancer via m6A-dependent CXCL5/CCL5 regulation. Journal for immunotherapy of cancer 12 40234090
2024 The RNA m6A writer METTL3 in tumor microenvironment: emerging roles and therapeutic implications. Frontiers in immunology 12 38322265
2023 Decreased expression of Chrna4 by METTL3-mediated m6A modification participates in BPA-induced spatial memory deficit. Environmental research 12 37495067
2024 METTL3 regulates M6A methylation-modified EBV-pri-miR-BART3-3p to promote NK/T cell lymphoma growth. Cancer letters 11 38880226
2023 METTL3/IGF2BP3-regulated m6A modification of HYOU1 confers doxorubicin resistance in breast cancer. Biochimica et biophysica acta. General subjects 11 38103759
2022 Overexpression of m6A-factors METTL3, ALKBH5, and YTHDC1 alters HPV16 mRNA splicing. Virus genes 11 35190939
2023 METTL3-mediated m6A RNA methylation was involved in aluminum-induced neurotoxicity. Ecotoxicology and environmental safety 10 38150748
2021 RNA m6A Methyltransferase Mettl3 Regulates Spatial Neural Patterning in Xenopus laevis. Molecular and cellular biology 10 33972392