Affinage

METTL1

tRNA (guanine-N(7)-)-methyltransferase · UniProt Q9UBP6

Length
276 aa
Mass
31.5 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

METTL1 is the catalytic subunit of a heterodimeric tRNA methyltransferase that, with its scaffold partner WDR4, deposits N7-methylguanosine (m7G46) in the variable loop of a defined subset of tRNAs bearing a 'RAGGU' motif, thereby coupling tRNA modification to codon-specific translational control of cell growth, differentiation, and immune function (PMID:29983320, PMID:34352207). Structural work shows the composite METTL1-WDR4 surface recognizes the tRNA elbow through shape complementarity, with the predicted-disordered METTL1 N terminus forming part of the catalytic pocket and acting as an allosteric switch that couples cofactor binding to substrate-induced conformational changes; the active heterodimer must be co-assembled with WDR4 to be catalytically competent (PMID:36599982, PMID:36599985, PMID:17382321, PMID:18164779). This activity is regulated by growth-factor signaling: PKB/AKT and RSK phosphorylate METTL1 at Ser27 in the N-terminal region, disrupting the catalytic center and inactivating the enzyme (PMID:36599985, PMID:15861136). m7G modification stabilizes target tRNAs against the rapid tRNA decay pathway and sustains translation; its loss reduces tRNA abundance, drives ribosome stalling at m7G-decoded codons, promotes biogenesis of tRNA-derived small RNAs, and reprograms the translatome, with consequences spanning self-renewal, oncogenic transformation, immune-cell programs, and tissue homeostasis (PMID:29983320, PMID:34352207, PMID:38268051, PMID:38977661). Across many tissues METTL1 selectively enhances translation of mRNAs enriched in m7G-tRNA-decoded codons—including cell cycle regulators, PI3K/AKT/mTOR components, and other oncogenic transcripts—and catalytically dead alleles fail to recapitulate these phenotypes, establishing methyltransferase activity as the operative mechanism (PMID:34352207, PMID:34371184, PMID:34898034, PMID:35179319, PMID:39317727). Beyond tRNA, METTL1 catalyzes internal m7G on select mRNAs and on miRNA precursors, augmenting let-7 biogenesis by disrupting an inhibitory secondary structure (PMID:31031083). It also exerts methyltransferase-independent functions: it binds the multi-tRNA synthetase complex to promote tRNA aminoacylation and polysome formation, and it interacts with XPO5 to restrain pre-miRNA nuclear export via ERK-mediated XPO5 phosphorylation (PMID:39892392, PMID:41591839).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 High

    Established that METTL1 is a growth-factor-regulated enzyme, answering whether its tRNA methyltransferase activity is subject to signaling control.

    Evidence In vitro kinase assays, phospho-specific detection with IGF-1 stimulation, and yeast trm8 complementation with phosphomutant alleles

    PMID:15861136

    Open questions at the time
    • Did not resolve the structural basis for how Ser27 phosphorylation inactivates catalysis
    • Physiological signals beyond IGF-1/PI3K driving Ser27 phosphorylation not mapped
  2. 2007 High

    Defined the substrate requirements and obligate heterodimeric nature of the methyltransferase using the yeast Trm8-Trm82 ortholog, answering how the enzyme recognizes tRNA and assembles.

    Evidence Reconstituted in vitro methyltransferase assays with truncated/mutant tRNAs and wheat-germ co-translation

    PMID:17382321 PMID:18164779

    Open questions at the time
    • Yeast ortholog; human substrate spectrum not yet defined here
    • Atomic basis of co-translational assembly requirement not resolved
  3. 2018 High

    Connected m7G tRNA modification to codon-specific translation and cell fate, answering what the modification does functionally in mammalian cells.

    Evidence m7G tRNA MeRIP-seq, TRAC-seq, ribosome profiling in Mettl1/Wdr4 knockout mouse ESCs with differentiation assays

    PMID:29983320

    Open questions at the time
    • Did not establish disease relevance
    • Mechanism linking tRNA loss to decay not yet defined
  4. 2019 High

    Extended substrate scope beyond tRNA by showing METTL1 m7G-modifies miRNA precursors, answering whether the enzyme acts on other RNA classes.

    Evidence BoRed-seq, RNA-IP, mass-spectrometry site mapping, and catalytic-mutant rescue of migration

    PMID:31031083

    Open questions at the time
    • Breadth of miRNA targets beyond let-7 not fully enumerated
    • Interplay between tRNA and miRNA functions not dissected
  5. 2021 High

    Established METTL1 as an oncogenic driver acting through codon-biased translation, answering how the enzyme contributes to cancer across tissues.

    Evidence m7G tRNA MeRIP-seq, polysome/ribosome profiling, catalytic-dead alleles, and xenograft/in vivo models in liver, lung, and transformation systems

    PMID:34352207 PMID:34371184 PMID:34898034

    Open questions at the time
    • Specific tRNA isoacceptors driving each cancer not uniformly defined
    • Did not address methyltransferase-independent contributions
  6. 2022 High

    Linked METTL1-dependent translation to specific oncogenic signaling output and the tumor immune microenvironment, answering which downstream pathways are selectively translated.

    Evidence Conditional knockout/knockin mouse HNSCC models with PI3K/AKT/mTOR pathway rescue and scRNA-seq

    PMID:35179319

    Open questions at the time
    • Mechanism of immune-landscape remodeling not fully resolved at this step
  7. 2023 High

    Resolved the structural and allosteric basis of m7G catalysis and its regulation, answering how the complex recognizes substrate and how Ser27 phosphorylation inhibits it.

    Evidence Crystal and cryo-EM structures of METTL1-WDR4-tRNA with SAM/SAH, biochemical assays, and mutagenesis of catalytic residues and S27

    PMID:36599982 PMID:36599985

    Open questions at the time
    • Dynamics of the disordered N terminus in cells not directly observed
    • Structural basis for non-tRNA substrate recognition not addressed
  8. 2023 Medium

    Showed METTL1 loss reroutes translation through tRNA-derived small RNAs to favor tumor-suppressive and immune programs, answering how depletion can be exploited therapeutically.

    Evidence m7G tRNA and small-RNA profiling, polysome profiling, and preclinical knockdown plus immunotherapy-response models in prostate cancer

    PMID:37516825

    Open questions at the time
    • Single lab; 5'tRF targets not exhaustively mapped
    • Generalizability across tumor types not established
  9. 2024 High

    Identified the rapid tRNA decay pathway as the mechanistic link between m7G loss and reduced tRNA abundance, answering why modification loss destabilizes tRNAs and triggers stress responses.

    Evidence Ribosome profiling, tRNA stability and RTD assays, and eEF1A rescue in senescence and AML models

    PMID:38268051 PMID:38977661

    Open questions at the time
    • Quantitative contribution of RTD versus tRF biogenesis not fully partitioned
    • Tissue-specific decay thresholds undefined
  10. 2024 High

    Demonstrated in vivo requirement for METTL1 catalytic activity in differentiation and tissue-specific physiology, answering whether m7G activity is essential across developmental and immune contexts.

    Evidence Catalytic-dead rescue in Drosophila spermatogenesis, and B-cell conditional KO/knock-in mice with tRNA, translation, and mitochondrial assays

    PMID:39317727 PMID:39638793

    Open questions at the time
    • Tissue-specific tRNA dependency mechanisms not fully generalized
  11. 2024 High

    Uncovered methyltransferase-independent functions of METTL1, answering whether all of its activity depends on m7G catalysis.

    Evidence Zebrafish liposarcoma model with phosphomimetic/catalytic-dead alleles, co-IP with the multi-tRNA synthetase complex, and aminoacylation/polysome assays

    PMID:39892392

    Open questions at the time
    • Structural basis of multi-tRNA synthetase complex binding unknown
    • Relative weight of catalytic vs non-catalytic roles in human tumors unresolved
  12. 2024 Medium

    Catalogued METTL1 transcriptional and post-transcriptional regulation, answering how its expression is controlled across disease and developmental states.

    Evidence ChIP, promoter reporters, and modification mapping implicating HIF-1α repression, thyroid hormone receptor activation, SP1/P300, YY1, METTL3-m6A, and NSUN5-m5C

    PMID:32391142 PMID:37599359 PMID:37694982 PMID:38118310 PMID:38810124 PMID:39601515

    Open questions at the time
    • Several regulatory links rest on single-lab or low-confidence data
    • Integration of competing upstream regulators not modeled
  13. 2025 Medium

    Identified a non-catalytic METTL1-XPO5 axis controlling pre-miRNA export, answering an additional methyltransferase-independent function in RNA processing.

    Evidence APEX2 proximity labeling with LC-MS/MS, co-IP, METTL1 knockout, and ERK-pathway manipulation/rescue

    PMID:41591839

    Open questions at the time
    • Single lab; reciprocal validation and structural basis of the interaction not established
    • Physiological consequences of altered miRNA export in vivo unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How METTL1's catalytic and non-catalytic activities are coordinated, and which mRNA versus tRNA substrates dominate in any given physiological or disease context, remains unresolved.
  • No unified model partitioning tRNA-, mRNA-, miRNA-, synthetase-, and XPO5-related functions
  • Direct mRNA m7G targets often inferred from single-lab studies without orthogonal site mapping
  • In vivo relevance of Ser27 phosphorylation regulation across tissues not systematically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 7 GO:0003723 RNA binding 4 GO:0016740 transferase activity 4
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1643685 Disease 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-168256 Immune System 2
Partners
QKITMEM11WDR4XPO5
Complex memberships
METTL1-WDR4 m7G methyltransferase complexmulti-tRNA synthetase complex (associated)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 Crystal and cryo-EM structures of METTL1-WDR4 with tRNA substrates (with SAM or SAH) show that the composite protein surface recognizes the tRNA elbow through shape complementarity; the METTL1 N terminus couples cofactor binding with conformational changes in the tRNA, catalytic loop, and WDR4 C terminus, acting as an allosteric switch to activate m7G methylation; structural models explain how post-translational modifications of the N terminus regulate methylation. Crystal structure of METTL1-WDR4 complex; cryo-EM structures of METTL1-WDR4-tRNA with SAM/SAH; multiple active-site conformational states resolved Nature High 36599982
2023 Structural, biochemical and cellular studies show WDR4 serves as a scaffold for METTL1 and the tRNA T-arm; upon tRNA binding the αC region of METTL1 forms a helix to secure the tRNA variable loop; the predicted-disordered N-terminal region is part of the catalytic pocket and essential for methyltransferase activity; S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by disrupting the catalytic centre. Cryo-EM and X-ray crystallography; biochemical methyltransferase assays; cellular phosphorylation studies; mutagenesis of catalytic residues and S27 Nature High 36599985
2005 PKB (AKT) and RSK phosphorylate METTL1 at Ser27 in vitro and in cells; IGF-1 stimulation triggers Ser27 phosphorylation via PI3K/PKB; phosphorylation inactivates METTL1 methyltransferase activity in vitro; phosphomimetic S27D/S27E mutants do not rescue growth of yeast lacking trm8, whereas wild-type or S27A partially rescue, establishing PKB/RSK-mediated inactivation as physiologically relevant. In vitro kinase assay; phospho-specific detection in HEK293 cells with IGF-1 stimulation; PDK1-deficient ES cell genetics; yeast complementation with WT and mutant alleles The EMBO journal High 15861136
2018 METTL1 in complex with WDR4 catalyzes m7G modification at a 'RAGGU' motif in the variable loop of a subset of 22 tRNAs in mouse ESCs; Mettl1 knockout causes increased ribosome occupancy (pausing) at m7G-tRNA-decoded codons, impaired global mRNA translation, and defective ESC self-renewal and neural differentiation. m7G tRNA MeRIP-seq; TRAC-seq; ribosome profiling; Mettl1/Wdr4 knockout mESCs; differentiation assays Molecular cell High 29983320
2019 METTL1 mediates m7G methylation within a subset of miRNAs including let-7e-5p; METTL1-mediated m7G modification augments let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA); this pathway regulates cell migration and depends on METTL1 catalytic activity. BoRed-seq (borohydride reduction sequencing); RNA immunoprecipitation; refined mass spectrometry m7G mapping; catalytic mutant rescue of cell migration assay Molecular cell High 31031083
2021 METTL1 overexpression increases abundance of m7G-modified tRNAs, in particular Arg-TCT-4-1, and enhances translation of mRNAs enriched in the corresponding AGA codon including cell cycle regulators, inducing oncogenic cell transformation; METTL1 depletion reduces m7G-tRNA abundance and inhibits oncogenicity. m7G tRNA MeRIP-seq; ribosome/polysome profiling; gain- and loss-of-function in cancer cells; zebrafish and mouse oncogenic transformation models Molecular cell High 34352207
2007 The yeast Trm8 (METTL1 ortholog)-Trm82 (WDR4 ortholog) heterodimer requires both D-stem and T-stem structures of tRNA for efficient m7G46 methyl-transfer; tertiary base pairs support but are not essential for catalysis (induced-fit of G46 into catalytic pocket); active heterodimer can only be produced by co-translation of both subunits, not by mixing separately translated subunits. In vitro methyltransferase activity assays with truncated/mutant tRNA transcripts; wheat germ cell-free co-translation; 2D-TLC and aniline cleavage confirmation of m7G product FEBS letters / Journal of biotechnology High 17382321 18164779
2021 METTL1/WDR4-mediated m7G tRNA modification promotes lung cancer growth and invasion; highly translated mRNAs in lung cancer have higher frequencies of m7G tRNA-decoded codons; METTL1 knockdown reduces translation efficiency of mRNAs enriched in m7G tRNA-decoded codons; wild-type but not catalytically dead METTL1 promotes cancer phenotypes. TRAC-seq; polysome profiling; mRNA translation profiling; gain-of-function mutagenesis; xenograft models Molecular therapy High 34371184
2021 METTL1-mediated tRNA m7G modification promotes translation of target mRNAs containing higher frequencies of m7G-related codons in hepatocellular carcinoma; forced expression of wild-type METTL1 but not its catalytic dead mutant promotes HCC progression; knockin and conditional knockout mouse models confirm the function in hepatocarcinogenesis. TRAC-seq; polysome profiling and polyribosome-associated mRNA sequencing; catalytic dead mutant; Mettl1 knockin and conditional knockout mice; hydrodynamic transfection HCC model Clinical and translational medicine High 34898034
2023 METTL1 depletion in prostate cancer causes loss of m7G tRNA methylation and promotes biogenesis of 5' tRNA-derived small RNAs (5'tRFs); these 5'tRFs redirect translation to favor synthesis of tumor growth suppressors, interferon pathway components, and immune effectors; Mettl1 knockdown increases intratumoural pro-inflammatory immune cell infiltration and enhances immunotherapy responses. m7G tRNA profiling; small RNA sequencing; polysome profiling; preclinical KD mouse models; immunotherapy response assays Molecular cancer Medium 37516825
2022 METTL1 ablation in HNSCC reduces m7G levels of 16 tRNAs and inhibits translation of oncogenic transcripts enriched in PI3K/AKT/mTOR pathway genes; chemical modulators of PI3K/AKT/mTOR signaling reverse the effects of Mettl1 loss; Mettl1 knockout also alters immune landscape in tumor microenvironment. tRNA modification profiling; mRNA translation profiling; transgenic mouse HNSCC models (conditional knockout/knockin); PI3K/AKT/mTOR pathway rescue experiments; scRNA-seq Cancer communications High 35179319
2023 Heat-mediated METTL1 upregulation after insufficient radiofrequency ablation enhances TGF-β2 translation via m7G tRNA modification, creating an immunosuppressive microenvironment by inducing PMN-MDSC accumulation and decreasing CD8+ T cell infiltration; knockdown of Tgfb2 or METTL1 or TGF-β signaling blockade reverses this effect. Liver-specific Mettl1 overexpression/knockdown; multiplex immunofluorescence; in vivo tumor models; anti-Ly6G treatment; siRNA knockdown of Tgfb2 Hepatology Medium 35598182
2021 METTL1 promotes post-ischemic angiogenesis by promoting VEGFA mRNA translation in an m7G methylation-dependent manner; in vivo METTL1 gene transfer improves blood flow recovery and angiogenesis with enhanced mRNA m7G. In vivo gene transfer; METTL1 plasmid transfection in HUVECs; m7G methylation quantification; proliferation, migration, tube formation assays; polysome profiling Frontiers in cell and developmental biology Medium 34136476
2020 METTL1 silencing in human iPSCs alters the global m7G tRNA/mRNA profile and reduces translational efficiency of stem cell marker genes, leading to reduced pluripotency; METTL1 knockdown accelerates differentiation toward mesoderm and promotes angiogenesis in vivo. METTL1 KD hiPSCs; RNA sequencing; anti-m7G northwestern assay; polysome profiling; embryoid body and teratoma formation assays Stem cell research & therapy Medium 32698871
2023 TMEM11 directly interacts with METTL1 and enhances m7G methylation of Atf5 mRNA, increasing ATF5 expression; elevated ATF5 promotes transcription of Inca1 (CDK inhibitor interacting with cyclin A1), suppressing cardiomyocyte proliferation; TMEM11 deletion enhances cardiomyocyte proliferation and cardiac repair. Co-immunoprecipitation; m7G methylation assays; ATF5 luciferase reporter; loss-of-function in cardiomyocytes; mouse cardiac injury model Cell death and differentiation Medium 37286744
2024 Mettl1 increases SRSF9 expression by inducing m7G modification of SRSF9 mRNA; elevated SRSF9 facilitates alternative splicing and stabilization of NFATc4, thereby promoting cardiac hypertrophy; Mettl1 knockout alleviates cardiac hypertrophy and SRSF9 knockdown protects against TAC- or Mettl1-induced hypertrophic phenotypes; YY1 acts as a transcription factor for Mettl1 during cardiac hypertrophy. m7G MeRIP-seq; alternative splicing analysis; cardiac-specific Mettl1 KO and overexpression mouse models; SRSF9 KD in vivo and in vitro; ChIP for YY1 Advanced science Medium 38810124
2024 METTL1 knockdown leads to decreased m7G modification on tRNAs, destabilization of tRNAs, and facilitation of tsRNA (tRNA-derived small RNA) biogenesis in AML cells; loss of m7G tRNAs decreases global translation efficiency; transfection of tRNAs isolated from METTL1-KD cells is sufficient to decrease global translation. Northern blotting; LC-MS/MS m7G quantification; tRNA stability analysis; small ncRNA sequencing; quantitative proteomics; nascent protein synthesis measurement Experimental hematology & oncology Medium 38268051
2024 METTL1 loss causes tRNA m7G reduction, ribosome stalling at specific codons decoded by m7G-tRNAs, reduced translation efficiency of spermatogenesis genes, and abolishes elongated spermatid and mature sperm production in Drosophila; catalytic-dead Mettl1 transgene cannot rescue, demonstrating the requirement for m7G catalytic activity; m7G modification-dependent tRNA abundance differs between gonadal and non-gonadal tissues. Mettl1 knockout Drosophila; ribosome profiling; tRNA m7G modification profiling; germ cell-specific transgenic rescue; catalytic-dead allele comparison Nature communications High 39317727
2024 Perturbation of METTL1-WDR4-mediated m7G46 tRNA methylation decreases tRNA abundance via the rapid tRNA decay (RTD) pathway, causes ribosome stalling at m7G-tRNA-decoded codons, impedes translation of Wnt signaling and ribosome biogenesis mRNAs, and triggers the ribotoxic and integrative stress responses inducing senescence-associated secretory phenotype; restoring eEF1A protein mitigates senescence from METTL1 deficiency by reducing RTD. METTL1 KD in senescence models; ribosome profiling; tRNA stability assays; RTD pathway analysis; eEF1A rescue experiments; Mettl1/Wdr4 aging measurements Nature communications High 38977661
2024 METTL1 promotes tRNA aminoacylation and polysome formation independent of its methyltransferase activity by binding the multi-tRNA synthetase complex; phosphomimetic (S27D) and catalytically dead METTL1 alleles phenocopy wild-type METTL1 oncogenic activity in a zebrafish liposarcoma model; METTL1-amplified liposarcomas are hypersensitive to actinomycin D. Zebrafish liposarcoma model; overexpression of phosphomimetic and catalytic-dead alleles; co-IP with multi-tRNA synthetase complex; polysome profiling; aminoacylation assays Molecular cell High 39892392
2024 Mettl1 regulates postnatal cardiac metabolic reprogramming primarily through translational control of the rate-limiting ketogenesis enzyme Hmgcs2; loss of Mettl1 causes aberrant metabolic reprogramming and cardiomyocyte immaturity leading to heart failure; β-hydroxybutyrate supplementation partially rescues clinical features. Mettl1 cardiac-specific knockout mice; multi-omics (proteomics + translatomics); polysome profiling; β-hydroxybutyrate rescue; β-hydroxybutyrylation (histone modification) analysis Nature cardiovascular research Medium 39587264
2024 METTL1 catalyzes m7G modification of CYLD deubiquitinase mRNA, increasing CYLD expression; elevated CYLD enhances stability of P53 by preventing its ubiquitination and degradation; P53 in turn transcriptionally activates METTL1 forming a positive feedback loop promoting cardiomyocyte apoptosis during ischemia/reperfusion; CYLD knockdown mitigates Mettl1-overexpression-induced apoptosis. RNA sequencing + m7G-methylated RNA sequencing in Mettl1-overexpressing hearts; m7G MeRIP; CYLD KD rescue; P53 ChIP; ubiquitination assays Acta pharmacologica Sinica Medium 39414959
2023 P300 forms a complex with SP1 and binds the METTL1 promoter via SP1, mediating METTL1 transcriptional upregulation in castration-resistant prostate cancer; METTL1 then adds internal m7G modifications to CDK14 mRNA, enhancing its stability and expression to promote CRPC progression. ChIP-qPCR; Co-IP; luciferase reporter assay; m7G AlkAniline-Seq; mRNA degradation assays; transcriptome sequencing Journal of experimental & clinical cancer research Medium 37599359
2023 METTL1 enhances TXNDC12 mRNA stability via m7G-dependent mechanism; TXNDC12 in turn stabilizes c-Myc protein by promoting its interaction with USP5, preventing proteasomal degradation of c-Myc in HNSCC. m7G-MeRIP; mRNA stability assays; co-IP (TXNDC12-USP5 interaction); RNA transcriptomic analysis Experimental & molecular medicine Low 40750708
2024 METTL1 modulates LSM14A expression via mRNA m7G methylation; LSM14A stabilizes DDX5 in the cytoplasm during G1/S phase, regulating CDK4 and P21 levels in glioblastoma. MeRIP; co-immunoprecipitation; protein half-life assay; mass spectrometry iScience Low 39040050
2025 METTL1-mediated m7G modification of Sarm1 mRNA enhances its stability and expression in macrophages; elevated SARM1 induces NAD+ decline and metabolic reprogramming, promoting macrophage proinflammatory responses; METTL1 deficiency in myeloid cells mitigates multiorgan inflammation. m7G-MeRIP-seq; mRNA stability assay; SARM1 rescue experiments; myeloid-specific Mettl1 KO mice; cecal ligation and puncture / ischemia-reperfusion models Science immunology Medium 40911698
2024 METTL1 mediates m7G methylation of PKM mRNA, enhancing PKM2 expression and glycolysis; increased PKM2 dimer nuclear translocation activates CD155 expression causing CRC immune evasion; elevated glycolysis promotes H3K9 lactylation (H3K9la) which activates METTL1 transcription, forming a positive feedback loop. MeRIP assay; RIP; RNA stability analysis; extracellular acidification rate measurement; Cut&Run for H3K9la; METTL1 KO mice with CD155 blockers Journal of translational medicine Medium 39741310
2023 METTL3-mediated m6A modification of METTL1 mRNA elevates METTL1 expression in HNSCC; METTL1 physically binds the CDK4 transcript and regulates its m7G modification level to stabilize CDK4, promoting cell cycle progression. Database mining (GEPIA); RIP to confirm METTL1-CDK4 mRNA interaction; m7G modification level measurement; CDK4 rescue experiments Biological chemistry Low 37694982
2020 METTL1 knockdown in hiPSC-derived EPCs activates the MAPK/ERK signaling pathway during EPC differentiation, significantly increasing EPC marker expression and functional properties; METTL1-KD EPCs accelerate vascular smooth muscle cell proliferation via co-culture. METTL1 KD hiPSCs; immunofluorescence; FACS; co-culture system; MAPK/ERK pathway analysis Biochemical and biophysical research communications Low 32430183
2023 HIF-1α binds to a hypoxia response element (HRE) in the METTL1 promoter and directly represses METTL1 transcription under hypoxic conditions in CRC cells, leading to decreased m7G tRNA modification. METTL1 promoter activity luciferase assay; HIF-1α siRNA; ChIP assay; LC-MS/MS quantification of RNA modifications Biochemical and biophysical research communications Medium 38118310
2020 Thyroid hormone receptor (TR) directly activates Mettl1 gene transcription via a T3 response element (TRE) in the promoter; TR binding correlates with increased H3K79 methylation and RNA polymerase II recruitment during Xenopus intestinal metamorphosis. T3-induced Xenopus metamorphosis model; ChIP for TR binding, H3K79me, and Pol II at Mettl1 TRE; promoter activation assay Cell & bioscience Medium 32391142
2024 METTL1-mediated m7G modification of TEAD2 mRNA enhances its stability via the binding protein Quaking; elevated TEAD2 transcriptionally represses ACADM, impairing mitochondrial function and amplifying proinflammatory responses in kidney tubular epithelial cells during AKI. m7G-methylated RNA immunoprecipitation sequencing; RNA sequencing; TEC-specific Mettl1 conditional KO mice (multiple AKI models); Quaking binding assays Kidney international Medium 41407011
2024 METTL1 promotes METTL1-mediated m7G modification of SRSF9 mRNA and drives METTL1-mediated hepatic regeneration after partial hepatectomy by selectively augmenting translation of Hippo pathway effectors YAP/TAZ via m7G tRNA modification. Multi-omics (proteomics + translatomics); Mettl1 KO mice; ectopic Mettl1 expression; 70% PHx murine model; polysome profiling Advanced science Medium 41360736
2024 METTL1 loss reduces m7G modification on tRNAPheGAA specifically, decreasing its steady-state levels and causing translation suppression/degradation of mRNAs enriched in corresponding codons including HCK tyrosine kinase; decreased HCK disrupts CXCR4 signaling, impairing leukemia stem cell self-renewal and bone marrow homing; pharmacological METTL1 inhibition (NSC137443) recapitulates these effects. tRNA m7G profiling; translation/proteomics profiling; CXCR4 signaling assays; AML mouse models; high-throughput screening for small-molecule inhibitor Blood Medium 42247311
2025 METTL1 interacts with XPO5 (exportin-5) as identified by APEX2 proximity labeling; METTL1 deletion causes XPO5 redistribution to the cytosol, accelerating pre-miRNA export and enhancing miRNA maturation independent of METTL1 m7G methyltransferase activity; mechanistically METTL1 facilitates ERK-mediated phosphorylation of XPO5 to promote its nuclear retention. APEX2 proximity labeling + LC-MS/MS; co-immunoprecipitation; western blot; METTL1 knockout; ERK pathway manipulation; constitutively active ERK rescue Nucleic acids research Medium 41591839
2024 METTL1 mediates m7G modification of B-cell tRNAs to preferentially translate BCR signaling-related proteins and maintain mitochondrial electron transport chain activity; conditional Mettl1 knockout in B cells blocks germinal center entry and GC formation; conditional knock-in promotes GC responses; METTL1-mediated tRNA m7G controls B-cell autoreactivity in SLE. B cell-specific Mettl1 conditional KO and knock-in mice; m7G tRNA profiling; translation profiling; mitochondrial function assays; lupus-prone mouse model Nature communications High 39638793
2025 In oesophageal cancer cells resistant to METTL1 loss, tRNA balance is preserved upon m7G46 deficiency by compensatory elevation of dihydrouridylation at position 47 (D47) by DUS3L; depletion of DUS-L enzymes sensitises resistant cells to METTL1 loss; concomitant loss of both modifications destabilizes canonical tRNA L-shape and disrupts coaxial helix stacking and anticodon-loop presentation. METTL1 depletion in resistant vs sensitive cell lines; DUS3L/DUS-L depletion; tRNA structural analysis; fitness/proliferation assays bioRxivpreprint Medium 41279591
2025 METTL1 depletion in Mettl1-specific mesenchymal stem cells disrupts m7G modification of Fgfr2 mRNA, reducing its stability; Fgfr2 downregulation impairs PI3K-AKT and MAPK signaling pathways, decreases Sp1 phosphorylation and promotes its ubiquitin-mediated degradation, ultimately reducing Col1a1 and Col2a1 transcription and blocking osteoblast/chondrocyte differentiation; pharmacological Fgfr2 reactivation rescues the bone defects. Mettl1 conditional KO in mesenchymal lineage; m7G-MeRIP sequencing; single-cell RNA sequencing; Fgfr2 mRNA stability assay; Sp1 ubiquitination assay; pharmacological rescue International journal of biological sciences Medium 41079929
2023 NSUN5 (m5C methyltransferase) directly binds the METTL1 transcript and facilitates its m5C modification, positively regulating METTL1 expression; overexpression of METTL1 counteracts tumor-suppressive effects of NSUN5 ablation in esophageal cancer. RNA co-immunoprecipitation; RNA pull-down; NSUN5 KD with METTL1 rescue experiments; xenograft models Molecular carcinogenesis Low 39601515

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation. Molecular cell 402 31031083
2018 Mettl1/Wdr4-Mediated m7G tRNA Methylome Is Required for Normal mRNA Translation and Embryonic Stem Cell Self-Renewal and Differentiation. Molecular cell 379 29983320
2021 METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation. Molecular cell 274 34352207
2021 METTL1/WDR4-mediated m7G tRNA modifications and m7G codon usage promote mRNA translation and lung cancer progression. Molecular therapy : the journal of the American Society of Gene Therapy 224 34371184
2023 METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma. Cancer research 171 36102722
2022 Aberrant translation regulated by METTL1/WDR4-mediated tRNA N7-methylguanosine modification drives head and neck squamous cell carcinoma progression. Cancer communications (London, England) 167 35179319
2021 METTL1 promotes hepatocarcinogenesis via m7 G tRNA modification-dependent translation control. Clinical and translational medicine 160 34898034
2021 METTL1-m7 G-EGFR/EFEMP1 axis promotes the bladder cancer development. Clinical and translational medicine 159 34936728
2022 Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation. Hepatology (Baltimore, Md.) 141 35598182
2019 Overexpressed methyltransferase-like 1 (METTL1) increased chemosensitivity of colon cancer cells to cisplatin by regulating miR-149-3p/S100A4/p53 axis. Aging 104 31866582
2023 Structures and mechanisms of tRNA methylation by METTL1-WDR4. Nature 95 36599982
2023 Structural basis of regulated m7G tRNA modification by METTL1-WDR4. Nature 91 36599985
2005 The tRNA methylase METTL1 is phosphorylated and inactivated by PKB and RSK in vitro and in cells. The EMBO journal 86 15861136
2023 METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer. Molecular cancer 80 37516825
2021 m7G Methyltransferase METTL1 Promotes Post-ischemic Angiogenesis via Promoting VEGFA mRNA Translation. Frontiers in cell and developmental biology 78 34136476
2020 METTL1-mediated m7G methylation maintains pluripotency in human stem cells and limits mesoderm differentiation and vascular development. Stem cell research & therapy 77 32698871
2022 Novel roles of METTL1/WDR4 in tumor via m7G methylation. Molecular therapy oncolytics 75 35784404
2023 P300/SP1 complex mediating elevated METTL1 regulates CDK14 mRNA stability via internal m7G modification in CRPC. Journal of experimental & clinical cancer research : CR 51 37599359
2020 RETRACTED: Methyltransferase-like 1 (METTL1) served as a tumor suppressor in colon cancer by activating 7-methyguanosine (m7G) regulated let-7e miRNA/HMGA2 axis. Life sciences 51 32135185
2012 Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis. Journal of medical genetics 50 23160276
2023 METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promote oncogenesis and doxorubicin resistance. Oncogene 46 37185458
2023 TMEM11 regulates cardiomyocyte proliferation and cardiac repair via METTL1-mediated m7G methylation of ATF5 mRNA. Cell death and differentiation 44 37286744
2024 The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9-Mediated Splicing of NFATc4. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 41 38810124
2022 A Comprehensive Analysis of METTL1 to Immunity and Stemness in Pan-Cancer. Frontiers in immunology 38 35432338
1999 Molecular analysis of METTL1, a novel human methyltransferase-like gene with a high degree of phylogenetic conservation. Genomics 37 10329009
2024 METTL1 mediated tRNA m7G modification promotes leukaemogenesis of AML via tRNA regulated translational control. Experimental hematology & oncology 36 38268051
2024 METTL1 mediates PKM m7G modification to regulate CD155 expression and promote immune evasion in colorectal cancer. Journal of translational medicine 34 39741310
2022 METTL1 promotes neuroblastoma development through m7G tRNA modification and selective oncogenic gene translation. Biomarker research 32 36071474
2024 Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging. Nature communications 30 38977661
2022 METTL1 drives tumor progression of bladder cancer via degrading ATF3 mRNA in an m7G-modified miR-760-dependent manner. Cell death discovery 30 36396627
2007 RNA recognition mechanism of eukaryote tRNA (m7G46) methyltransferase (Trm8-Trm82 complex). FEBS letters 30 17382321
2024 Metabolic reprogramming driven by METTL1-mediated tRNA m7G modification promotes acquired anlotinib resistance in oral squamous cell carcinoma. Translational research : the journal of laboratory and clinical medicine 28 38280546
2023 Mettl1-mediated internal m7G methylation of Sptbn2 mRNA elicits neurogenesis and anti-alzheimer's disease. Cell & bioscience 27 37779199
2024 METTL1-mediated tRNA m7G methylation and translational dysfunction restricts breast cancer tumorigenesis by fueling cell cycle blockade. Journal of experimental & clinical cancer research : CR 26 38822363
2023 Small-Molecule Inhibitors of the m7G-RNA Writer METTL1. ACS bio & med chem Au 26 38645929
2023 Fibroblast-specific knockout of METTL1 attenuates myocardial infarction-induced cardiac fibrosis. Life sciences 21 37437652
2022 TSPAN31 regulates the proliferation, migration, and apoptosis of gastric cancer cells through the METTL1/CCT2 pathway. Translational oncology 20 35429902
2024 Mettl1-dependent m7G tRNA modification is essential for maintaining spermatogenesis and fertility in Drosophila melanogaster. Nature communications 19 39317727
2023 N6-methyladenosine-induced METTL1 promotes tumor proliferation via CDK4. Biological chemistry 16 37694982
2007 Production of yeast tRNA (m(7)G46) methyltransferase (Trm8-Trm82 complex) in a wheat germ cell-free translation system. Journal of biotechnology 14 18164779
2024 WDR4 promotes HCC pathogenesis through N7-methylguanosine by regulating and interacting with METTL1. Cellular signalling 13 38493882
2020 METTL1 limits differentiation and functioning of EPCs derived from human-induced pluripotent stem cells through a MAPK/ERK pathway. Biochemical and biophysical research communications 13 32430183
2024 METTL1-modulated LSM14A facilitates proliferation and migration in glioblastoma via the stabilization of DDX5. iScience 12 39040050
2024 The tRNA methyltransferase Mettl1 governs ketogenesis through translational regulation and drives metabolic reprogramming in cardiomyocyte maturation. Nature cardiovascular research 12 39587264
2025 METTL1 coordinates cutaneous squamous cell carcinoma progression via the m7G modification of the ATF4 mRNA. Cell death discovery 11 39870616
2024 METTL1/FOXM1 promotes lung adenocarcinoma progression and gefitinib resistance by inhibiting PTPN13 expression. Cancer medicine 11 38967523
2024 Nanomole Scale Screening of Fluorescent RNA-Methyltransferase Probes Enables the Discovery of METTL1 Inhibitors. Angewandte Chemie (International ed. in English) 11 39145518
2024 RNA Methyltransferase NSUN5 Promotes Esophageal Cancer via 5-Methylcytosine Modification of METTL1. Molecular carcinogenesis 10 39601515
2020 Direct activation of tRNA methyltransferase-like 1 (Mettl1) gene by thyroid hormone receptor implicates a role in adult intestinal stem cell development and proliferation during Xenopus tropicalis metamorphosis. Cell & bioscience 10 32391142
2025 METTL1 Enhances RRP9 mRNA Stability Through m7G Modification to Drive Colorectal Tumorigenesis. Molecular carcinogenesis 9 39960239
2024 METTL1 facilitates ameloblastoma invasive growth via MAPK signaling pathway. Gene 9 38309318
2023 Diagnostic Values of METTL1-Related Genes and Immune Characteristics in Systemic Lupus Erythematosus. Journal of inflammation research 9 38026241
2023 HIF-1α/METTL1/m7G axis is involved in CRC response to hypoxia. Biochemical and biophysical research communications 8 38118310
2025 METTL1-mediated m7G tRNA modification drives papillary thyroid cancer progression and metastasis by regulating the codon-specific translation of TNF-α. Cell death & disease 7 40360483
2024 Mettl1 knockdown alleviates cardiac I/R injury in mice by inactivating the Mettl1-CYLD-P53 positive feedback loop. Acta pharmacologica Sinica 7 39414959
2024 Aberrant METTL1-mediated tRNA m7G modification alters B-cell responses in systemic autoimmunity in humans and mice. Nature communications 7 39638793
2025 Functions of METTL1/WDR4 and QKI as m7G modification - related enzymes in digestive diseases. Frontiers in pharmacology 6 39850560
2025 A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation. Molecular cell 6 39892392
2025 METTL1-mediated m7G methylation of Sarm1 mRNA promotes macrophage inflammatory responses and multiple organ injury. Science immunology 6 40911698
2022 METTL1 gene polymorphisms synergistically confer hepatoblastoma susceptibility. Discover oncology 6 35986847
2025 METTL1-mediated m7G modification promotes colorectal cancer metastasis via stabilization of ICAM-1. Molecular and cellular biochemistry 5 40252158
2025 METTL1-mediated m7G modification of NEK1 mRNA promotes the proliferation of oral squamous cell carcinoma. Biochimica et biophysica acta. Molecular basis of disease 5 40562282
2025 METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease. Metabolism: clinical and experimental 4 41101688
2024 The 7-Methylguanosine (m7G) methylation METTL1 acts as a potential biomarker of clear cell renal cell carcinoma progression. Translational oncology 4 39571491
2025 Upregulated m7G methyltransferase METTL1 is a potential biomarker and tumor promoter in skin cutaneous melanoma. Frontiers in immunology 3 40443650
2025 METTL1 in human cancers: recognition of their functions, mechanisms and therapeutic value. Oncology reviews 3 40809384
2025 METTL1 drives glioma progression by promoting N7-methylguanosine (m7G) modification of glycolysis-related enzyme PGK1. Pathology, research and practice 3 40815965
2025 The m7G methyltransferase METTL1 promotes acute kidney inflammation by disrupting mitochondrial function. Kidney international 3 41407011
2025 METTL1 mediates m7G modification of PFKFB3 mRNA to promote radioresistance in esophageal cancer by affecting glycolytic metabolism. Pathology, research and practice 2 40633178
2025 METTL1-driven epitranscriptomic enhancement of TXNDC12 boosts c-Myc stability through USP5 in HNSCC. Experimental & molecular medicine 2 40750708
2025 METTL1-mediated internal m7G methylation of cathepsin B mRNA promotes synovial aggression in rheumatoid arthritis. Annals of the rheumatic diseases 2 41130877
2025 Microbial metabolite 5-formamidoimidazole-4-carboxamide ribotide targets METTL1 to inhibit m7G modification of BRCA1 mRNA to inhibit high-grade serous ovarian cancer. Molecular medicine (Cambridge, Mass.) 2 41430564
2023 Comprehensive Analysis of METTLs (METTL1/13/18/21A/23/25/2A/2B/5/6/9) and Associated mRNA Risk Signature in Hepatocellular Carcinoma. Analytical cellular pathology (Amsterdam) 2 38130905
2026 METTL1 interacts with XPO5 to modulate pre-miRNA export. Nucleic acids research 1 41591839
2026 METTL1-mediated m7G tRNA modification promotes colorectal cancer progression and liver metastasis via translational regulation. Cellular oncology (Dordrecht, Netherlands) 1 41627602
2026 Cancer-associated fibroblasts promote osimertinib resistance in non-small cell lung cancer cells via METTL1-mediated NET1 m7G modification. Cell death & disease 1 41723107
2026 Circ_0003323 binds METTL1 to mediate KLK6 m7G methylation modification and promote the progression of colorectal cancer. iScience 1 41782829
2026 Exosomes From Cancer-Associated Fibroblasts Promote Colorectal Cancer Progression and Glutamine Metabolism Through METTL1-Mediated m7G Modification of SLC1A5 mRNA. Journal of gastroenterology and hepatology 1 41820224
2025 METTL1 aggravates sepsis-acute kidney injury by promoting m7G methylation of NLRP3-mediated pyroptosis. Histology and histopathology 1 40181736
2025 METTL1-WDR4 promotes the migration and proliferation of gastric cancer through N7-methylguanosine. Cellular oncology (Dordrecht, Netherlands) 1 40764449
2025 METTL1/WDR4-mediated m7G Hypermethylation of SCLT1 mRNA Promotes Gefitinib Resistance in NSCLC. Genomics, proteomics & bioinformatics 1 40857569
2025 POU4F1 Promotes the Primary Resistance of Melanoma to Anti-PD-1 Therapy by Regulating Glycolysis Through METTL1-Mediated m7G Methylation of PKM2. Molecular carcinogenesis 1 41025963
2025 Mechanistic Insights Into METTL1/WDR4-Mediated m7G Modification in Prostate Cancer Progression and Its Potential as a Therapeutic Target. Journal of biochemical and molecular toxicology 1 41098012
2025 Mettl1 mitigates sepsis-induced cardiomyopathy via inhibition of FDX1-dependent cuproptosis. Gene 1 41232822
2026 The emerging roles of METTL1-mediated tRNA m7G methylation in cancer development and immunotherapy. Frontiers in immunology 0 41562049
2026 METTL1 Aggravates Periodontitis Progression by Inhibiting Osteoblast Differentiation via m7G modification of SEMA4D. International dental journal 0 41830790
2026 METTL1-deficient mesenchymal stem cells protect against metabolic-associated fatty liver disease by increasing NAMPT secretion. Stem cells translational medicine 0 41903937
2026 METTL1-mediated m7G modification of ASNS mRNA regulates asparagine metabolism reprogramming to promote hepatocellular carcinoma progression. Oncogene 0 42045536
2026 Hyperglycemia-driven metabolic memory signaling destabilizes METTL1 to trigger inflammatory hypertrophy and fibrosis in diabetic cardiomyopathy. Acta diabetologica 0 42089956
2026 MYC promotes myocardial fibrosis via METTL1-mediated m7G modification of HILPDA. Biology direct 0 42116160
2026 A context-dependent METTL1-m7G-SLC7A11 axis links metabolic stress to epithelial fate in ulcerative colitis. International journal of biological sciences 0 42212324
2026 Targeting the METTL1/m⁷G axis as a therapeutic strategy in myeloid leukemia. Blood 0 42247311
2026 Epidermal METTL1-Mediated m7G Modification Drives Psoriatic Inflammation by Stabilizing Bdkrb1 and Orchestrating Neutrophil Recruitment. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 42261843
2025 METTL1 promotes cadmium-induced stress granules formation via enhancing translation of G3BP1 and expression of m7G- 3' tiRNA MetCAT. Cell biology and toxicology 0 40762925
2025 Overexpression of m7G writers METTL1 and BUD23 confers oncogenicity in kidney renal clear cell carcinoma. The Journal of pathology 0 40879514
2025 Mettl1-mediated m7G modification of Fgfr2 regulates osteogenic and chondrogenic differentiation of mesenchymal stem cells. International journal of biological sciences 0 41079929
2025 METTL1-mediated m7G modification regulates osteogenic differentiation of human periodontal ligament stem cells. Clinics (Sao Paulo, Brazil) 0 41161258
2025 Compensatory tRNA Modification by DUS3L Confers Resistance to METTL1 Loss in Oesophageal Cancer. bioRxiv : the preprint server for biology 0 41279591
2025 METTL1-Mediated M7G tRNA Modification Promotes Residual Liver Regeneration After Hepatectomy via Translational Control. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41360736
2025 miR-193a-5p-mediated Inhibition of the METTL1/COX-2 axis is critical for Astragalin-induced apoptosis in cervical cancer. Scientific reports 0 41390595

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