Affinage

METTL16

RNA N(6)-adenosine-methyltransferase METTL16 · UniProt Q86W50

Length
562 aa
Mass
63.6 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

METTL16 is a SAM-dependent N6-methyladenosine (m6A) RNA methyltransferase that uses a Class I Rossmann-fold catalytic domain to recognize structured RNA substrates in which the target adenosine is presented in a bulge or hairpin (PMID:28525753, PMID:30197299, PMID:29593291). It methylates A43 within the ACAGAGA box of U6 spliceosomal snRNA—a position that base-pairs with 5' splice sites—linking the enzyme directly to splice site recognition (PMID:29051200, PMID:37787376). A C-terminal vertebrate-conserved KA-1-like domain recruits U6 snRNA through its internal stem-loop, and SAM binding to the catalytic pocket triggers a conformational rearrangement that repositions the target adenosine for productive catalysis (PMID:32266935, PMID:40841561). Its kinetic mechanism is ordered-sequential, with RNA binding preceding SAM, and slow catalytic turnover underlies a regulatory function: METTL16 methylates conserved hairpins in the MAT2A 3' UTR, and under SAM-limiting conditions increased occupancy on hp1 promotes splicing of a retained intron to induce the SAM synthetase MAT2A, making METTL16 catalytic efficiency the determinant of the intracellular SAM setpoint (PMID:28525753, PMID:36584291, PMID:40644296). Its mRNA m6A marks are decoded by reader proteins (YTHDC1, YTHDF2, IGF2BP1, YTHDC2) to control transcript stability and fate across diverse settings including metabolic reprogramming, hematopoiesis, and cell cycle progression (PMID:29262316, PMID:36795489, PMID:38605226, PMID:41680470). Beyond catalysis, METTL16 acts through m6A-independent routes: in the cytosol it engages eIF3a/eIF3b and rRNA to promote translation-initiation complex assembly and sequesters the repressor eIF4E2 to favor cap recognition, while in the nucleus it binds MRE11 via RNA to restrain DNA end resection until ATM-dependent phosphorylation at Ser329 relieves this inhibition, linking the protein to homologous recombination and genome integrity (PMID:35145225, PMID:36840945, PMID:36138131). METTL16 is essential in vivo, with loss causing peri-implantation embryonic lethality and defects in spermatogenesis, meiosis, and erythropoiesis (PMID:30197299, PMID:39030605, PMID:39607422, PMID:36307435). Its activity and stability are tuned by post-translational modifications including lactylation at K229, CDK13-mediated Ser329 phosphorylation, and UFL1-dependent UFMylation (PMID:37863889, PMID:41680470, PMID:41608626).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2017 High

    Established METTL16's core identity as the m6A writer for U6 snRNA and for the MAT2A 3' UTR, defining its dual role in splicing and SAM homeostasis.

    Evidence In vitro methylation with recombinant enzyme, knockdown, splicing/intron-retention assays, methionine starvation; CRAC mapping and co-IP of U6 biogenesis factors

    PMID:28525753 PMID:29051200

    Open questions at the time
    • Did not resolve the structural basis of substrate selection
    • Reader proteins decoding MAT2A m6A not yet defined
  2. 2017 High

    Identified YTHDC1 as the reader linking METTL16-deposited m6A on MAT2A to SAM-responsive regulation, connecting the writer to a downstream effector.

    Evidence In vitro methylation, siRNA of METTL16 and YTHDC1, mutagenesis of target sites, mRNA stability assays

    PMID:29262316

    Open questions at the time
    • Relative contributions of stability versus splicing regulation not fully partitioned
    • Redundancy among multiple target adenosines limits site-resolution dissection
  3. 2018 High

    Solved crystal structures revealing how the methyltransferase domain reads structured RNA with the target adenosine in a bulge, and demonstrated an in vivo requirement via embryonic lethality of knockout mice.

    Evidence X-ray crystallography of apo, SAH-bound, and MAT2A-RNA-bound forms; SEC and gel-shift; Mettl16 knockout mouse embryos with RNA-seq

    PMID:29593291 PMID:30197297 PMID:30197299

    Open questions at the time
    • The C-terminal VCR/KA-1 contribution to U6 recognition was not captured
    • Oligomeric state in functional context partially unresolved
  4. 2020 High

    Defined how the vertebrate-conserved KA-1-like domain recruits U6 snRNA and remodels the A43 region for productive catalysis, explaining substrate-specific activation.

    Evidence Structural analysis, RNA-binding assays, MTD-KA1 chimera methylation assays, mutagenesis of the VCR basic region

    PMID:32266935

    Open questions at the time
    • Atomic detail of the SAM-triggered rearrangement awaited later cryo-EM
    • Generalization of VCR function to other substrates unaddressed
  5. 2020 Medium

    Revealed METTL16 as substantially cytoplasmic and cell-cycle-regulated in its nuclear distribution, foreshadowing functions beyond nuclear m6A writing.

    Evidence Biochemical fractionation, endogenous vs FLAG-tagged IP; live imaging across cell cycle with co-IP of LBR, Lap2alpha, DDB2, and nucleolar proteins

    PMID:31940410 PMID:34357041

    Open questions at the time
    • Functional consequence of cytoplasmic pool not established at this stage
    • Co-IP partners (LBR, Lap2alpha, DDB2) lack reciprocal/functional validation
  6. 2022 High

    Uncovered m6A-independent cytoplasmic functions: METTL16 promotes translation initiation via eIF3a/eIF3b and rRNA binding and by sequestering the repressor eIF4E2 to favor cap recognition.

    Evidence Reciprocal Co-IP of eIF3a/b and eIF4E2, ribosome/polysome profiling, m6A-seq, methyltransferase-dead complementation, cap-binding assays

    PMID:35145225 PMID:36840945

    Open questions at the time
    • How nuclear writer and cytoplasmic translation roles are partitioned mechanistically is unclear
    • Direct structural basis of eIF interactions not resolved
  7. 2022 High

    Linked METTL16 to genome integrity through an RNA-mediated, catalysis-independent interaction with MRE11 that gates DNA end resection and is released by ATM phosphorylation at Ser329.

    Evidence Co-IP, in vitro exonuclease assays with recombinant proteins, ATM kinase assays, phosphomimetic/phospho-dead mutants

    PMID:36138131

    Open questions at the time
    • Identity of the bridging RNA species not defined
    • Structural model of the METTL16-RNA-MRE11 complex absent
  8. 2022 High

    Demonstrated m6A-dependent control of metabolism and stem cell fate, with METTL16 driving BCAA reprogramming in AML and safeguarding genome integrity during erythropoiesis.

    Evidence CRISPR screens, conditional/genetic depletion in AML mouse models and erythroid cells, m6A-seq, RIP-seq, metabolic profiling, pairwise CRISPRi screen

    PMID:36307435 PMID:36608679

    Open questions at the time
    • Direct versus indirect effects on individual target transcripts not fully separated
    • Role of MTR4-exosome in shaping the substrate pool incompletely defined
  9. 2022 High

    Established METTL16's kinetic mechanism as ordered-sequential (RNA before SAM) with slow turnover, providing the biochemical basis for its SAM-sensing regulatory behavior.

    Evidence Kd measurements, preincubation/isotope partitioning, steady-state and single-turnover kinetics

    PMID:36584291

    Open questions at the time
    • Connection of measured kinetics to cellular SAM setpoint awaited later work
    • MALAT1 triple helix bound but not methylated, leaving its role unexplained
  10. 2022 Medium

    Showed PTM control and reader-dependent target regulation, with lactylation at K229 (inhibited by SIRT2) enhancing FDX1 m6A and YTHDF2-mediated MCP1 degradation extending the m6A output to inflammation and cuproptosis.

    Evidence MS identification of lactylation, SIRT2 manipulation, MeRIP, RIP for YTHDF2/readers, stability and functional assays

    PMID:36795489 PMID:37863889

    Open questions at the time
    • Stoichiometry and generality of K229 lactylation not established
    • Whether PTMs alter catalytic versus non-catalytic functions unresolved
  11. 2024 High

    Defined developmental and germline roles via conditional knockouts, showing METTL16 controls splicing and translation of meiotic genes, MSCI, spermatogonial differentiation, and HSPC cell cycle.

    Evidence Germline/spermatocyte and zebrafish conditional knockouts, m6A-seq, RNA-seq, ribosome profiling, co-IP with splicing factors and MDC1/SCML2, activity-mutant rescue, RIP for IGF2BP1

    PMID:38605226 PMID:39030605 PMID:39607422 PMID:39614650

    Open questions at the time
    • Tissue-specific substrate repertoires only partially mapped
    • Mechanism coupling splicing-factor interactions to specific exon choices not fully defined
  12. 2024 Medium

    Identified additional PTM writers and cofactors—CDK13 phosphorylation at Ser329 boosting activity, UFL1-dependent UFMylation controlling stability, and SSB acting as an RNA-binding cofactor and substrate.

    Evidence In vitro kinase assays, phosphomimetic mutants, MeRIP, Co-IP, RIP for readers, knockdown/overexpression in cancer models

    PMID:40580478 PMID:41608626 PMID:41680470

    Open questions at the time
    • Interplay among Ser329 phosphorylation, UFMylation, and lactylation not integrated
    • Endogenous cofactor stoichiometry of SSB unknown
  13. 2025 High

    Demonstrated that METTL16 catalytic efficiency itself sets the intracellular SAM setpoint and resolved the cryo-EM mechanism of U6 recognition and SAM-triggered substrate repositioning.

    Evidence Degron depletion/complementation with hyperactive and dead mutants, SAM and methylation measurements, MTAP deletion; cryo-EM of METTL16-U6 snRNA complex

    PMID:40644296 PMID:40841561

    Open questions at the time
    • Whether catalytic-efficiency tuning is exploited therapeutically remains untested
    • Structural basis for mRNA hairpin recognition versus U6 not directly compared

Open questions

Synthesis pass · forward-looking unresolved questions
  • How METTL16 partitions between its m6A-writer, translation-promoting, and DNA-repair functions, and how its many PTMs are coordinated to select among these activities, remains unresolved.
  • No unified model integrating catalytic and non-catalytic roles
  • Bridging RNAs in non-catalytic complexes (e.g., MRE11) unidentified
  • Cell-type-specific determinants of substrate choice undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 6 GO:0003723 RNA binding 5 GO:0016740 transferase activity 3 GO:0045182 translation regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005730 nucleolus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 2
Partners
EIF3AEIF3BEIF4E2LARP7MEPCEMRE11SSBYTHDC1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 METTL16 is the N6-methyladenosine (m6A) methyltransferase responsible for methylating the U6 spliceosomal snRNA, and it regulates MAT2A (SAM synthetase) expression by methylating a conserved hairpin (hp1) in the MAT2A 3' UTR. Under SAM-limiting conditions, increased METTL16 occupancy on hp1 due to inefficient enzymatic turnover promotes splicing of a retained intron in MAT2A pre-mRNA, thereby inducing MAT2A expression to restore SAM homeostasis. In vitro methylation assays with recombinant METTL16, siRNA knockdown, intron retention/splicing assays, methionine starvation experiments, mutational analysis of hairpin substrates Cell High 28525753
2017 METTL16 is responsible for N6-methylation of A43 of the U6 snRNA and interacts with early U6 biogenesis factors La, LARP7, and the methylphosphate capping enzyme MEPCE. A43 lies within the ACAGAGA box of U6 that base-pairs with 5' splice sites during splicing, implicating this modification in splicing regulation. CRAC (crosslinking and analysis of cDNA), in vivo methylation assays, co-immunoprecipitation identifying La, LARP7, MEPCE as interaction partners EMBO reports High 29051200
2017 METTL16-mediated m6A modification of the MAT2A 3' UTR is read by the m6A reader YTHDC1, and this METTL16-YTHDC1 axis controls SAM-responsive regulation of MAT2A mRNA stability. In vitro reactions with recombinant METTL16 identified multiple conserved methylation targets in the MAT2A 3' UTR, and mutations of these adenine sites revealed redundancy in regulation. In vitro methylation assays with recombinant METTL16, siRNA knockdown of METTL16 and YTHDC1, mutagenesis of m6A target sites, mRNA stability assays Cell reports High 29262316
2018 Crystal structure of human METTL16 reveals a methyltransferase domain with an extra N-terminal module forming a deep-cut groove essential for RNA binding, showing it selects for structured RNAs where the critical adenosine is present in a bulge. Mouse embryos lacking Mettl16 show reduced Mat2a mRNA levels, massive transcriptome dysregulation at the ~64-cell blastocyst stage, and failure of further development. X-ray crystallography, Mettl16 knockout mouse embryo analysis, RNA-seq of knockout embryos Molecular cell High 30197299
2018 Crystal structures of METTL16 in complex with MAT2A RNA hairpins reveal atomic details of RNA substrate recognition for productive methylation. A polypeptide loop near the SAM binding site has an autoregulatory role; mutations that enhance or repress METTL16 activity in vitro correlate with changes in MAT2A mRNA levels in cells. X-ray crystallography of METTL16-RNA complexes, in vitro methylation assays, mutagenesis correlated with cellular MAT2A levels Molecular cell High 30197297
2018 X-ray crystal structures of the METTL16 N-terminal methyltransferase domain (residues 1-291) in apo form and SAH-bound complex reveal a Rossmann fold with a large positively charged groove as the RNA-binding site. Full-length METTL16 forms a homodimer and METTL16_291 is a monomer; the full-length protein but not the monomeric domain binds the MALAT1 RNA triple helix. The catalytic mechanism involves Class I SAM-dependent methyltransferase chemistry. X-ray crystallography (1.9 Å apo; 2.1 Å SAH complex), size-exclusion chromatography, native gel-shift assays Scientific reports High 29593291
2020 The vertebrate conserved region (VCR) of METTL16 increases affinity toward U6 snRNA via a conserved basic region, and is topologically homologous to the KA1 domain of TUT1. The VCR interacts with the internal stem-loop (ISL) of U6 snRNA, inducing conformational rearrangement of the A43-containing region to make it suitable for productive catalysis by the methyltransferase domain (MTD). A chimera of METTL16 MTD with TUT1 KA1 methylated U6 snRNA more efficiently than MTD alone. Structural analysis, RNA binding assays, chimeric protein construction and methylation assays, mutational analysis of VCR basic region Nucleic acids research High 32266935
2020 Biochemical fractionation reveals that a majority of METTL16 protein resides in the cytoplasm in multiple cell lines, in addition to the nucleus, suggesting METTL16 functions as a cytoplasmic RNA binding protein. Exogenously overexpressed METTL16 differs from endogenous protein in its relative affinity for RNA targets. Biochemical cell fractionation, immunoprecipitation of endogenous and FLAG-tagged METTL16, siRNA knockdown with mRNA target expression analysis PloS one Medium 31940410
2021 METTL16 nuclear distribution is cell cycle-specific: it accumulates in the nucleolus in G1/S phases, increases in the nucleoplasm in G2, is very low in metaphase/anaphase, and reappears at the nuclear lamina in telophase. METTL16 interacts with Lamin B Receptor (LBR) and Lap2α (but not A- or B-type lamins), with Lap2α depletion causing METTL16 downregulation. METTL16 also interacts with DDB2 (NER factor) and nucleolar proteins TCOF, NOLC1, and UBF1/2. Live cell imaging and immunofluorescence for cell cycle stages, co-immunoprecipitation for protein interactions, A-type lamin depletion experiments Life (Basel, Switzerland) Medium 34357041
2022 METTL16 exerts an m6A-independent function in the cytosol by directly interacting with eukaryotic initiation factors eIF3a and eIF3b as well as ribosomal RNA through its methyltransferase domain, thereby facilitating assembly of the translation-initiation complex and promoting translation of >4,000 mRNA transcripts. In the nucleus, METTL16 additionally functions as an m6A writer on hundreds of specific mRNA targets. Co-immunoprecipitation of eIF3a/eIF3b, ribosome profiling, m6A-seq, methyltransferase-dead mutant complementation, dual nuclear/cytoplasmic localization experiments Nature cell biology High 35145225
2022 METTL16 interacts with MRE11 through RNA (in a methyltransferase-independent manner) and this interaction inhibits MRE11's exonuclease activity, thereby repressing DNA end resection. Upon DNA damage, ATM phosphorylates METTL16, causing a conformational change and autoinhibition of its RNA binding, which dissociates the METTL16-RNA-MRE11 complex and releases MRE11 to promote homologous recombination repair. Co-immunoprecipitation, in vitro exonuclease assays with recombinant proteins, ATM kinase assays, phosphomimetic/phospho-dead mutants, RNA-dependent interaction assays Nature cancer High 36138131
2022 METTL16 promotes translation and lung tumorigenesis through an m6A-independent mechanism: cytoplasmic METTL16 directly interacts with eIF4E2, preventing eIF4E2 from competing with eIF4E for 5' cap binding, thereby promoting cap recognition by eIF4E and selective protein synthesis of key oncogenes. Co-immunoprecipitation of eIF4E2, cap-binding assays, methyltransferase-dead mutant analysis, siRNA depletion with polysome profiling, dual localization confirmed Cell reports Medium 36840945
2022 METTL16 promotes expression of BCAT1 and BCAT2 in an m6A-dependent manner, reprogramming branched-chain amino acid (BCAA) metabolism to support AML leukemogenesis and leukemia stem cell self-renewal. CRISPR-Cas9 screening, genetic depletion in AML mouse models, m6A-seq, RIP-seq, metabolic profiling of BCAA metabolism Cell stem cell High 36608679
2022 METTL16 is lactylated at site K229, a modification inhibited by SIRT2. Copper stress promotes METTL16 lactylation, which enhances METTL16-mediated m6A modification of FDX1 mRNA, promoting cuproptosis in gastric cancer. Mass spectrometry identification of lactylation sites, SIRT2 inhibition/overexpression, MeRIP for FDX1 m6A, in vitro and in vivo cuproptosis assays Nature communications High 37863889
2022 METTL16 negatively regulates MCP1 expression in mesenchymal stem cells through m6A modification of MCP1 mRNA at the CDS region, which is recognized by the m6A reader YTHDF2 to promote MCP1 mRNA degradation, thereby controlling monocyte recruitment. siRNA knockdown, MeRIP (m6A-RIP), RIP for YTHDF2, mRNA stability assays, in vivo monocyte recruitment assay JCI insight Medium 36795489
2022 METTL16 is required for proper erythropoiesis by safeguarding genome integrity via m6A deposition on structured motifs in DNA-repair-related transcripts including Brca2 and Fancm mRNAs, upregulating their expression. A pairwise CRISPRi screen revealed that the MTR4-nuclear RNA exosome complex is involved in regulating METTL16 substrate mRNAs in erythroblasts. METTL16 conditional knockout in erythroid cells, m6A-seq, RNA-seq, pairwise CRISPRi screens, DNA damage markers Nature communications High 36307435
2022 METTL16 kinetic mechanism is ordered-sequential: METTL16 binds U6 snRNA before SAM. METTL16 is monomeric when in complex with MALAT1 triple helix or U6 snRNA, with dissociation constants of 31 nM (MALAT1) and 18 nM (U6 snRNA). The MALAT1 triple helix is not methylated by METTL16 under in vitro conditions. The kcat is 0.07 min-1 and kchem is 0.56 min-1; the VCR domains weaken the ternary complex but do not limit the rate of chemical catalysis. In vitro binding assays (Kd measurements), preincubation and isotope partitioning assays, steady-state and single-turnover kinetic assays Biochemistry High 36584291
2023 METTL16 methylation consensus sequence is UACAGARAA (modified A underlined), and structural requirements exist for its known RNA interactors; the methyltransferase domain contains a Rossmann-like fold characteristic of class I SAM-dependent methyltransferases and uses SAM as the methyl donor. Review synthesizing structural and biochemical data (not primary experimental data in this paper) Wiley interdisciplinary reviews. RNA Medium 34227247
2023 Inter-species association mapping links 5' splice site sequence preferences (particularly the +4 position adenosine vs. uridine preference) to the presence of METTL16 and SNRNP27K. Loss of METTL16 orthologs is associated with a preference for +4 U at 5' splice sites, consistent with the role of METTL16-mediated U6 snRNA m6A in splice site recognition. Inter-species association mapping across Saccharomycotina species, genetic analysis of METTL16/SNRNP27K mutants, splice site sequence analysis eLife Medium 37787376
2024 METTL16 controls ribosomal RNA (rRNA) maturation and mRNA translation, and eIF3a mRNA is a bona fide m6A target of METTL16 in HCC. METTL16 depletion dramatically decreases liver cancer stem cell frequency in vitro and in vivo, and attenuates HCC initiation/progression in liver-specific knockout mice. Liver-specific conditional knockout mice, hydrodynamic tail-vein injection HCC model, RNA-seq, RIP-seq, ribosome profiling, limiting dilution assay, CRISPR tiling scan Journal of hematology & oncology High 38302992
2024 METTL16 regulates alternative splicing of meiosis-related genes (e.g., Stag3) by interacting with splicing factors, and controls translation efficiency of meiotic genes; germline conditional knockout of Mettl16 in male mice impairs spermatogonial differentiation and meiosis initiation. The methyltransferase activity site (PP185-186AA) is necessary for spermatogenesis. Germline conditional knockout mice, m6A-seq, RNA-seq, ribosome profiling, in vivo/vitro methyltransferase mutant complementation, co-IP with splicing factors Genome biology High 39030605
2024 METTL16 controls cell cycle progression of embryonic hematopoietic stem and progenitor cells by directly regulating mybl2b mRNA via m6A modification. Mettl16 deficiency destabilizes mybl2b mRNA, likely due to lost binding by the m6A reader Igf2bp1, causing G1/S cell cycle arrest. This METTL16-m6A-MYBL2-IGF2BP1 axis is conserved in humans. Mettl16-deficient zebrafish, single-cell RNA-seq, m6A-seq, RIP for Igf2bp1, cell cycle analysis, methyltransferase-activity mutant rescue experiments The EMBO journal High 38605226
2024 METTL16 is required for meiotic sex chromosome inactivation (MSCI), DSB formation, homologous recombination, and SYCP1 deposition during male meiosis. METTL16 interacts with MDC1/SCML2 to coordinate DNA damage response and XY body epigenetic modifications establishing MSCI; it also regulates m6A levels and translational efficiency of meiosis-related genes including Ubr2. METTL16 spermatocyte-specific knockout mice, multi-omics (m6A-seq, RNA-seq, ribosome profiling, proteomics), Co-IP with MDC1/SCML2 Advanced science High 39607422
2024 METTL16 and its reader YTHDC1 are required for spermatogonial differentiation; deletion of Mettl16 using Stra8-Cre causes blockade in spermatogonial differentiation and progressive loss of spermatogonia. RNA-seq and m6A-seq showed that loss of either METTL16 or YTHDC1 disrupts expression of genes related to chromosome organisation and segregation. Conditional knockout mice (Mettl16vasa-cre, Mettl16Stra8-cre, Ythdc1-sKO), RNA-seq, m6A-seq Cell proliferation Medium 39614650
2024 CDK13 directly phosphorylates METTL16 at Ser329, augmenting its catalytic activity to install m6A on ACLY mRNA. These m6A marks are recognized by YTHDC2, leading to ACLY mRNA stabilization, increased acetyl-CoA production, and lipogenesis in clear cell renal cell carcinoma. In vitro kinase assay (CDK13 phosphorylating METTL16), phosphomimetic/phospho-dead METTL16 mutants, MeRIP for ACLY m6A, RIP for YTHDC2, mRNA stability assays Experimental & molecular medicine Medium 41680470
2024 SSB functions as a cofactor for METTL16 in installing m6A RNA methylation by enhancing METTL16 binding to RNA. SSB is itself a direct target of METTL16-mediated m6A RNA methylation, forming a positive auto-regulatory loop promoting m6A methylation, SSB expression, and chemoresistance. Co-immunoprecipitation, RNA binding assays, MeRIP for SSB mRNA, siRNA knockdown, chemoresistance assays Cell reports Medium 40580478
2025 The catalytic efficiency of METTL16 governs the intracellular SAM setpoint: catalytically hyperactive METTL16 complements methyltransferase activities but decreases intracellular SAM concentrations by abrogating MAT2A regulation, making cells hypersensitive to MAT2A inhibition and MTAP deletion. U6 snRNA pseudogenes are identified as additional METTL16 substrates. Degron-based depletion and complementation strategy in HCT116 cells, hyperactive/catalytically-dead mutant METTL16 constructs, intracellular SAM measurement, histone methylation and RNA methylation assays, MTAP gene deletion Cell reports High 40644296
2025 Cryo-EM structures of METTL16 in complex with U6 snRNA reveal that the C-terminal KA-1 domain recruits U6 snRNA by interacting with the internal stem-loop (ISL). SAM binding to the N-terminal MTD catalytic pocket triggers a structural rearrangement of U6 snRNA that positions the target adenine at the catalytic site, followed by an additional adjustment into a productive conformation bringing the target adenosine closer to SAM for efficient m6A modification. Cryo-EM structure determination of METTL16-U6 snRNA complex Nature communications High 40841561
2025 UFL1 loss decreases METTL16 UFMylation, which reduces METTL16 ubiquitination and increases its protein stability. Stabilized METTL16 installs m6A on EEF1A1 mRNA, activating the IGF2BP1 axis to increase EEF1A1 protein levels and enhance resistance to enzalutamide-induced apoptosis in prostate cancer. Co-immunoprecipitation, MeRIP for EEF1A1 m6A, RIP for IGF2BP1, overexpression/knockdown experiments, in vitro and in vivo xenograft models International journal of biological sciences Medium 41608626
2024 Aminothiazolone compounds were identified as first-in-class small-molecule inhibitors of METTL16 that disrupt METTL16-RNA protein-RNA interaction at single-digit micromolar potency, validated by fluorescence-polarization screening and structural optimization. Fluorescence-polarization (FP)-based screening, medicinal chemistry optimization, cellular m6A modulation assays JACS Au Medium 38665670
2023 METTL16 controls KSHV lytic replication by promoting m6A modification and splicing/maturation of MAT2A transcript, thereby maintaining intracellular SAM levels and redox homeostasis (glutathione levels); SAM treatment is sufficient to inhibit KSHV lytic replication and reverse the effect of METTL16 knockdown. siRNA knockdown, SAM supplementation, MAT2A inhibitor treatment, ROS and glutathione measurements, KSHV lytic gene expression analysis Cell death & disease Medium 37673880
2024 METTL16 collaborates with IGF2BP2 to modulate SENP3 mRNA stability in an m6A-dependent manner; SENP3 in turn impedes proteasome-mediated ubiquitination/degradation of Lactotransferrin (LTF) via de-SUMOylation, elevating LTF to chelate free iron and reduce labile iron pool, conferring ferroptosis resistance in HCC. MeRIP-qPCR, RIP-qPCR, Co-IP, mass spectrometry, luciferase assay, hepatocyte-specific Mettl16 KO and OE mice, HCC organoids, xenografts Journal of hematology & oncology High 39218945

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. Cell 934 28525753
2017 Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs. EMBO reports 553 29051200
2023 Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer. Nature communications 400 37863889
2018 Methylation of Structured RNA by the m6A Writer METTL16 Is Essential for Mouse Embryonic Development. Molecular cell 314 30197299
2017 S-Adenosylmethionine Synthesis Is Regulated by Selective N6-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1. Cell reports 302 29262316
2022 METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis. Nature cell biology 284 35145225
2018 Structural Basis for Regulation of METTL16, an S-Adenosylmethionine Homeostasis Factor. Molecular cell 191 30197297
2023 METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism. Cell stem cell 141 36608679
2021 RNA methyltransferase METTL16: Targets and function. Wiley interdisciplinary reviews. RNA 119 34227247
2022 METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m6A-dependent manner. Cellular & molecular biology letters 107 35596159
2018 Structural insights into the RNA methyltransferase domain of METTL16. Scientific reports 98 29593291
2021 METTL16 promotes cell proliferation by up-regulating cyclin D1 expression in gastric cancer. Journal of cellular and molecular medicine 96 34075693
2020 Mechanistic insights into m6A modification of U6 snRNA by human METTL16. Nucleic acids research 94 32266935
2021 METTL16, Methyltransferase-Like Protein 16: Current Insights into Structure and Function. International journal of molecular sciences 87 33671635
2022 PM2.5 induces pulmonary microvascular injury in COPD via METTL16-mediated m6A modification. Environmental pollution (Barking, Essex : 1987) 78 35259473
2024 METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation. Journal of hematology & oncology 72 38302992
2023 METTL16 promotes glycolytic metabolism reprogramming and colorectal cancer progression. Journal of experimental & clinical cancer research : CR 65 37340443
2022 METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma. Nature cancer 59 36138131
2022 METTL16 epigenetically enhances GPX4 expression via m6A modification to promote breast cancer progression by inhibiting ferroptosis. Biochemical and biophysical research communications 59 36434904
2020 Characterization of METTL16 as a cytoplasmic RNA binding protein. PloS one 59 31940410
2024 METTL16-SENP3-LTF axis confers ferroptosis resistance and facilitates tumorigenesis in hepatocellular carcinoma. Journal of hematology & oncology 58 39218945
2023 METTL16 promotes translation and lung tumorigenesis by sequestering cytoplasmic eIF4E2. Cell reports 53 36840945
2017 Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers. Pathology oncology research : POR 47 28803425
2022 The N6-methyladenosine methyltransferase METTL16 enables erythropoiesis through safeguarding genome integrity. Nature communications 42 36307435
2024 METTL16 inhibits papillary thyroid cancer tumorigenicity through m6A/YTHDC2/SCD1-regulated lipid metabolism. Cellular and molecular life sciences : CMLS 36 38334797
2024 METTL16 suppressed the proliferation and cisplatin-chemoresistance of bladder cancer by degrading PMEPA1 mRNA in a m6A manner through autophagy pathway. International journal of biological sciences 36 38385084
2022 Oxidative Stress Aggravates Apoptosis of Nucleus Pulposus Cells through m6A Modification of MAT2A Pre-mRNA by METTL16. Oxidative medicine and cellular longevity 35 35069973
2024 N6-methyladenosine writer METTL16-mediated alternative splicing and translation control are essential for murine spermatogenesis. Genome biology 30 39030605
2023 The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression. Journal of experimental & clinical cancer research : CR 28 37817227
2023 Hypoxia induces hepatocellular carcinoma metastasis via the HIF-1α/METTL16/lnc-CSMD1-7/RBFOX2 axis. iScience 24 38089592
2022 METTL16-mediated translation of CIDEA promotes non-alcoholic fatty liver disease progression via m6A-dependent manner. PeerJ 24 36518278
2022 METTL16 predicts a favorable outcome and primes antitumor immunity in pancreatic ductal adenocarcinoma. Frontiers in cell and developmental biology 23 36158188
2022 Knockdown of METTL16 disrupts learning and memory by reducing the stability of MAT2A mRNA. Cell death discovery 22 36307396
2022 Elucidating the Kinetic Mechanism of Human METTL16. Biochemistry 21 36584291
2024 A Mettl16/m6A/mybl2b/Igf2bp1 axis ensures cell cycle progression of embryonic hematopoietic stem and progenitor cells. The EMBO journal 20 38605226
2023 m6A methyltransferase METTL16 mediates immune evasion of colorectal cancer cells via epigenetically regulating PD-L1 expression. Aging 20 37647025
2020 The Distinct Function and Localization of METTL3/METTL14 and METTL16 Enzymes in Cardiomyocytes. International journal of molecular sciences 20 33143367
2023 METTL16 controls Kaposi's sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle. Cell death & disease 17 37673880
2023 METTL16 Inhibits the Malignant Progression of Epithelial Ovarian Cancer through the lncRNA MALAT1/β-Catenin Axis. Analytical cellular pathology (Amsterdam) 17 37927399
2024 RNA Binding by the m6A Methyltransferases METTL16 and METTL3. Biology 16 38927271
2024 m6A RNA methyltransferase METTL16 induces Cr(VI) carcinogenesis and lung cancer development through glutamine biosynthesis and GLUL expression. Journal of hazardous materials 16 39405702
2023 METTL16 promotes osteosarcoma progression by downregulating VPS33B in an m6 A-dependent manner. Journal of cellular physiology 16 37357526
2023 METTL16-mediated N6-methyladenosine modification of Soga1 enables proper chromosome segregation and chromosomal stability in colorectal cancer. Cell proliferation 16 38084791
2024 Aminothiazolone Inhibitors Disrupt the Protein-RNA Interaction of METTL16 and Modulate the m6A RNA Modification. JACS Au 14 38665670
2023 The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway. Frontiers in oncology 14 37182151
2022 METTL16 regulates m6A methylation on chronic hepatitis B associated gene HLA-DPB1 involved in liver fibrosis. Frontiers in genetics 14 36406135
2024 METTL16 regulates the mRNA stability of FBXO5 via m6A modification to facilitate the malignant behavior of breast cancer. Cancer & metabolism 13 39061113
2023 Inter-species association mapping links splice site evolution to METTL16 and SNRNP27K. eLife 13 37787376
2023 METTL16 in human diseases: What should we do next? Open medicine (Warsaw, Poland) 13 38045858
2024 METTL16 Promotes Stability of SYNPO2L mRNA and leading to Cancer Cell Lung Metastasis by Secretion of COL10A1 and attract the Cancer-Associated Fibroblasts. International journal of biological sciences 12 39247832
2023 The m6A methyltransferase METTL16 negatively regulates MCP1 expression in mesenchymal stem cells during monocyte recruitment. JCI insight 12 36795489
2025 METTL16 suppresses ferroptosis in cholangiocarcinoma by promoting ATF4 via m6A modification. International journal of biological sciences 11 39744432
2025 RNA methyltransferase METTL16: From molecular mechanisms to therapeutic prospects in cancers. Cancer letters 11 40194654
2023 Suppression of Wnt/β-catenin Signaling in PDAC via METTL16-mediated N6-methyladenosine Modification of DVL2. Journal of Cancer 9 37859814
2021 Localization of METTL16 at the Nuclear Periphery and the Nucleolus Is Cell Cycle-Specific and METTL16 Interacts with Several Nucleolar Proteins. Life (Basel, Switzerland) 9 34357041
2025 The promoting effect of the POU3F2/METTL16/PFKM cascade on glycolysis and tumorigenesis of hepatocellular carcinoma. Annals of hepatology 8 39756795
2024 METTL16 inhibits differentiation and promotes proliferation and slow myofibers formation in chicken myoblasts. Poultry science 8 39418792
2024 METTL16 inhibits pancreatic cancer proliferation and metastasis by promoting MROH8 RNA stability and inhibiting CAPN2 expression - experimental studies. International journal of surgery (London, England) 8 39434688
2023 Brute Force Virtual Drug Screening with Molecular Dynamics Simulation and MM/PBSA to Find Potent Inhibitors of METTL16. IEEE/ACM transactions on computational biology and bioinformatics 8 37018281
2024 METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 7 39607422
2023 METTL16, an evolutionarily conserved m6A methyltransferase member, inhibits the antiviral immune response of miiuy croaker (Miichthys miiuy). Developmental and comparative immunology 7 37085020
2023 Global RNA modifications to the MALAT1 triple helix differentially affect thermostability and weaken binding to METTL16. The Journal of biological chemistry 7 38092148
2025 Role of METTL16 in PPARγ methylation and osteogenic differentiation. Cell death & disease 6 40210616
2024 Methyl-Transferase-Like Protein 16 (METTL16): The Intriguing Journey of a Key Epitranscriptomic Player Becoming an Emerging Biological Target. Journal of medicinal chemistry 6 39150226
2024 METTL16 and YTHDC1 Regulate Spermatogonial Differentiation via m6A. Cell proliferation 6 39614650
2023 RNA Methyltransferase METTL16's Protein Domains Have Differential Functional Effects on Cell Processes. Current issues in molecular biology 6 37504262
2025 The Oncogenic Role of UBXN1 in Gastric Cancer Is Attributed to the METTL16-Mediated m6A Methylation and Histone Modifications. Cancer medicine 5 40095756
2025 METTL16/IGF2BP2 axis enhances malignant progression and DDP resistance through up-regulating COL4A1 by mediating the m6A methylation modification of LAMA4 in hepatocellular carcinoma. Cell division 5 40251670
2025 m6A hypermethylation of TCF-1 regulated by METTL16 promotes acute myeloid leukemia. Clinical and experimental medicine 5 40299085
2025 The catalytic efficiency of METTL16 affects cellular processes by governing the intracellular S-adenosylmethionine setpoint. Cell reports 5 40644296
2024 METTL16 deficiency attenuates apoptosis through translational control of extrinsic death receptor during nutrient deprivation. Biochemical and biophysical research communications 5 38520913
2024 Investigating the mechanism of METTL16-dependent m6A modification regulating the SAMD11 protein signaling pathway to inhibit thyroid cancer phenotypes. International journal of biological macromolecules 5 39362437
2025 METTL16-dependent miR-146b-5p m6A modification remodeling sensitize NSCLC to osimertinib via activating PI3K/AKT signaling. BMC cancer 4 40200229
2025 Effects of m6A methylation of MAT2A mRNA regulated by METTL16 on learning and memory, hippocampal synaptic plasticity and Aβ1-42 in 5 × FAD mice. Frontiers in aging neuroscience 4 40308894
2025 Structures and mechanisms of U6 snRNA m6A modification by METTL16. Nature communications 4 40841561
2024 METTL16 controls airway inflammations in smoking-induced COPD via regulating glutamine metabolism. Ecotoxicology and environmental safety 4 39667326
2023 Corrigendum: The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway. Frontiers in oncology 4 37274238
2023 Genetic Variations Within METTL16 and Susceptibility to Sudden Cardiac Death in Chinese Populations With Coronary Artery Disease. The American journal of cardiology 4 37423176
2025 Pan-cancer analysis of Methyltransferase-like 16 (METTL16) and validated in colorectal cancer. Aging 3 40015977
2025 Norcantharidin inhibits the METTL16/MAT2A pathway to induce apoptosis and suppress tumor progression in ovarian cancer. Archives of biochemistry and biophysics 3 40517800
2025 Platycodin D-mediated METTL16 downregulation promotes docetaxel treatment of prostate cancer by regulating ferroptosis. BMC cancer 3 40597047
2025 Nanoformulations Downregulating METTL16 Combined with mRNA Tumor Vaccines Suppress Triple-Negative Breast Cancer and Prevent Metastasis. International journal of nanomedicine 3 40665962
2025 METTL16-dependent GPX4 m6A modification links ferroptosis to NSCLC TKIs resistance. BMC cancer 3 40826028
2025 METTL16 Promotes Lipid Metabolic Reprogramming and Colorectal Cancer Progression. International journal of biological sciences 3 40860196
2025 METTL16-mediated inhibition of MXD4 promotes leukemia through activation of the MYC-MAX axis. Oncogene 3 40946103
2024 METTL16 participates in haemoglobin H disease through m6A modification. PloS one 3 39088431
2026 CDK13 drives clear cell renal carcinoma through METTL16-mediated m6A modification of ACLY mRNA. Experimental & molecular medicine 2 41680470
2025 A novel cinnamic acid derivative for hepatocellular carcinoma therapy by degrading METTL16 protein. Bioorganic & medicinal chemistry 2 40186923
2025 SSB cooperates with METTL16-mediated m6A RNA methylation to promote chemoresistance in colorectal cancer cells. Cell reports 2 40580478
2025 METTL16 emerges as a pivotal epitranscriptomic regulator, linking RNA modification, tumor progression, and immune modulation. Frontiers in immunology 2 41322419
2024 Genetic Variants in METTL16 Affect the Risk of Non-Syndromic Orofacial Clefts. Birth defects research 2 39404474
2026 Loss of UFL1 confers enzalutamide resistance of prostate tumors by regulating METTL16-mediated m6A modification of EEF1A1 mRNA. International journal of biological sciences 1 41608626
2025 METTL16 Contributes to Coronary Heart Disease by Inducing TET2 m6A Modification. Journal of inflammation research 1 40453970
2025 METTL16 promotes progression of clear cell renal cell carcinoma via up-regulating N6-methyladenosine modification of KLK4 mRNA. Molecular and cellular biochemistry 1 40627260
2025 Multi-omics and experimental validation identify methylation-related genes and METTL16 as key regulators in diabetic foot ulcer pathogenesis. Scientific reports 1 41310324
2024 Gene polymorphisms of METTL5 and METTL16 are related to epithelial ovarian cancer risk in South China: A three-center case-control study. Journal of Cancer 1 38370381
2024 Thrombopoietin improves the functions of bone marrow endothelial progenitor cells via METTL16/Akt signalling of haematological patients with chemotherapy-induced thrombocytopenia. British journal of haematology 1 39189039
2025 METTL16 accelerates lung adenocarcinoma progression by inducing N6-methyladenosine modification of GTSE1 to regulate p53 pathway and cell cycle. Cell division 0 40405148
2025 METTL16 promotes corneal nerve regeneration in diabetic corneal neuropathy. Experimental eye research 0 40639767
2025 METTL16 in cancer: Roles and regulatory mechanisms. Genes & diseases 0 41459114

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