Affinage

TRDMT1

tRNA (cytosine(38)-C(5))-methyltransferase · UniProt O14717

Length
391 aa
Mass
44.6 kDa
Annotated
2026-06-10
92 papers in source corpus 34 papers cited in narrative 34 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

TRDMT1/DNMT2 is a cytosine-5 methyltransferase that, despite a fold and catalytic machinery shared with bacterial DNA m5C MTases, acts on RNA rather than DNA, installing m5C at cytosine 38 in the anticodon loop of tRNA(Asp), tRNA(Gly), and tRNA(Val) (PMID:16424344, PMID:18567810, PMID:20679393). Methyl transfer uses a DNA-methyltransferase-type chemistry through catalytic motifs IV, VI, VIII and the conserved CFT-motif cysteine C292, forming a transient covalent enzyme–tRNA complex (PMID:18567810, PMID:23877245), with substrate recognition dictated by the anticodon loop sequence, position-34 identity, the variable loop, and the T-arm (PMID:22591353, PMID:34871455, PMID:24711368, PMID:34110975). This C38 modification stabilizes target tRNAs against stress-induced ribonuclease cleavage and promotes tRNA aminoacylation and accurate near-cognate codon decoding, thereby sustaining protein synthesis (PMID:20679393, PMID:26271101, PMID:27462411); loss of activity in mice causes haematopoietic and developmental defects and codon-level mistranslation, and is synthetically lethal with the complementary methyltransferase NSun2 (PMID:22885326, PMID:26271101). The enzyme dynamically shuttles between the nucleus and cytoplasmic stress granules/P-bodies in response to stress (PMID:20679393, PMID:20864816), and its catalytic output is gated by allosteric and redox inputs, including enolase binding antagonized by 2-phosphoglycerate, cysteine S-nitrosylation, intermolecular disulfide bonds, and stimulation by queuosine pre-modification of the substrate (PMID:20174608, PMID:24562908, PMID:26424849, PMID:37579906). Through control of tRNA fragmentation, TRDMT1/DNMT2 feeds into broader processes: it limits inhibitory tRNA fragments to enable Dicer-2-dependent siRNA antiviral responses (PMID:24012760), and is required for sperm small-noncoding-RNA-mediated intergenerational epigenetic inheritance (PMID:29695786). Pharmacologically, its tRNA methylation is inhibited by the ribonucleoside analogue azacytidine and by allosteric small molecules that synergize with chemotherapeutics in cancer cells (PMID:19808971, PMID:40894903).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Before any catalytic substrate was known, the structure established that DNMT2 possesses a bona fide m5C methyltransferase fold and cofactor pocket, framing the puzzle of an apparently inactive 'DNA' methyltransferase.

    Evidence X-ray crystallography at 1.8 Å with AdoHcy bound and in vitro DNA-binding assay

    PMID:11139614

    Open questions at the time
    • Did not identify the physiological substrate
    • DNA binding in vitro did not establish DNA as the catalytic target
  2. 2006 High

    Resolved the long-standing identity crisis by showing the enzyme methylates tRNA(Asp) at C38 rather than DNA, redefining DNMT2 as an RNA methyltransferase.

    Evidence Mass spectrometry, in vitro methylation, and cross-species genetic complementation

    PMID:16424344

    Open questions at the time
    • Did not define the catalytic mechanism
    • Full substrate repertoire beyond tRNA(Asp) unknown
    • Biological consequence of the modification unaddressed
  3. 2008 High

    Demonstrated that an RNA substrate is methylated by a DNA-methyltransferase-type catalytic mechanism, unifying the structural fold with its unexpected RNA activity.

    Evidence Site-directed mutagenesis of motif IV/VI/VIII residues and C292 with in vitro tRNA methylation assays

    PMID:18567810

    Open questions at the time
    • Did not map the tRNA-binding surface
    • Covalent intermediate not directly observed in this study
  4. 2010 High

    Expanded the substrate set to tRNA(Val) and tRNA(Gly) and assigned a biological purpose: protecting tRNAs from stress-induced cleavage, linking the modification to stress physiology.

    Evidence RNA bisulfite sequencing, Drosophila mutants, stress-granule localization, and RNase protection assays

    PMID:20679393

    Open questions at the time
    • Mechanism of stress-granule recruitment unresolved
    • Downstream physiological readout of fragment accumulation not yet defined
  5. 2012 High

    Established the in vivo importance of the modification for translation, showing tRNA stability, protein synthesis, and differentiation depend on DNMT2 acting together with NSun2.

    Evidence Mouse Dnmt2/NSun2 double-knockout genetics with polysome profiling

    PMID:22885326

    Open questions at the time
    • Did not separate direct translational effects from indirect developmental effects
    • Mechanism by which unmethylated tRNAs are destabilized not biochemically dissected here
  6. 2012 High

    Mapped the tRNA-binding cleft adjacent to the SAM pocket and showed methylation involves induced tRNA conformational change, providing a structural basis for substrate engagement.

    Evidence Systematic surface alanine mutagenesis of 20 residues with in vitro catalytic and binding assays plus modeling, complemented by ortholog crystal structure and EMSA

    PMID:22591353 PMID:22737219

    Open questions at the time
    • No co-crystal of human DNMT2 with full tRNA
    • Precise base-flipping geometry not visualized
  7. 2015 High

    Connected the molecular modification to physiology and translational fidelity, showing C38 methylation prevents fragmentation, supports aminoacylation, and prevents codon mistranslation, with defined developmental and haematopoietic phenotypes.

    Evidence Mouse knockouts with bisulfite-seq, flow cytometry, quantitative proteomics, and in vitro aminoacylation and reporter assays

    PMID:26271101 PMID:27462411

    Open questions at the time
    • Quantitative contribution of each target tRNA to phenotypes not separated
    • Direct demonstration that mistranslation drives the haematopoietic defect incomplete
  8. 2015 Medium

    Defined the substrate specificity logic, showing the variable loop, anticodon-loop motif, and prior queuosine modification act as positive determinants for methylation.

    Evidence In vitro methylation with mutant tRNAs across homologs, plus in vivo queuine feeding and transglycosylase knockout

    PMID:23877245 PMID:24711368 PMID:26424849

    Open questions at the time
    • Hierarchy of determinants in vivo not fully resolved
    • Whether queuosine coupling operates in human cells not directly tested in these studies
  9. 2013 Medium

    Extended DNMT2 function beyond translation, showing that by limiting tRNA fragments it enables Dicer-2-dependent siRNA biogenesis and innate antiviral defense.

    Evidence Drosophila small-RNA sequencing, genetic mutants, in vitro Dcr-2 assays, and viral titration with RNA Co-IP

    PMID:23370384 PMID:24012760

    Open questions at the time
    • Whether DNMT2 directly methylates viral RNA versus acting through tRNA fragments unresolved
    • Relevance to mammalian antiviral immunity not established
  10. 2013 Medium

    Implicated DNMT2 in heritable RNA-based epigenetic phenomena, showing it is required for paramutation transmission.

    Evidence Mouse genetics, sperm tRNA bisulfite sequencing, and microinjection

    PMID:23717211

    Open questions at the time
    • mRNA methylation claim not rigorously confirmed biochemically
    • Molecular link between tRNA methylation and paramutation indirect
  11. 2018 High

    Provided a mechanistic basis for intergenerational inheritance, showing Dnmt2-dependent m5C on sperm sncRNAs shapes their structure and transmits diet-induced metabolic phenotypes.

    Evidence Mouse knockout with RNA modification mass spectrometry, small-RNA-seq, and embryo injection

    PMID:29695786

    Open questions at the time
    • Identity of the causal sncRNA species not fully defined
    • How m5C-altered structure changes recipient embryo gene expression unresolved
  12. 2010 Medium

    Revealed allosteric and metabolic regulation, showing glycolytic enolase binds and inhibits Dnmt2 in a manner antagonized by 2-phosphoglycerate, and that cysteine S-nitrosylation relieves this inhibition.

    Evidence Yeast two-hybrid, Co-IP, in vitro methylation, and cysteine mutagenesis/S-nitrosylation assays in Entamoeba

    PMID:20174608 PMID:24562908

    Open questions at the time
    • Whether the enolase regulatory axis operates in human cells untested
    • Quantitative impact on cellular tRNA methylation in vivo unclear
  13. 2021 Medium

    Identified post-translational control of human TRDMT1, showing TRIM28-mediated K251 polyubiquitination removes it from DNA damage sites to allow homologous recombination, with a cancer mutation disrupting this balance.

    Evidence Co-IP, ubiquitination and HR reporter assays, mutagenesis, and cisplatin sensitivity

    PMID:33778494

    Open questions at the time
    • Mechanistic link between an RNA methyltransferase and HR not biochemically defined
    • Single-lab Co-IP without reciprocal validation across systems
  14. 2023 Medium

    Defined redox gating of the human enzyme, showing intermolecular disulfide bonds constrain activity and that glutathione redox state and dimerization modulate tRNA methylation.

    Evidence LC-MS/MS of recombinant protein, in vitro methylation with redox manipulation, and western blotting

    PMID:37579906

    Open questions at the time
    • Physiological redox conditions driving this switch in cells not established
    • Functional consequence of dimerization for substrate engagement unclear
  15. 2025 Medium

    Opened a tractable therapeutic route by discovering a non-cofactor allosteric pocket and small-molecule inhibitors that lower tRNA m5C and synergize with chemotherapy.

    Evidence DNA-encoded library screening, X-ray crystallography, microscale thermophoresis, bisulfite-seq, and cell viability assays; with prior azacytidine specificity and cancer-mutation catalytic studies

    PMID:19808971 PMID:25747896 PMID:40894903

    Open questions at the time
    • In vivo efficacy and selectivity of allosteric inhibitors not established
    • On-target tRNA methylation as the driver of the chemotherapy synergy not fully isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether TRDMT1 has a genuine, sequence-specific mRNA m5C activity and direct nuclear DNA-repair function in human cells distinct from its tRNA role remains unresolved.
  • mRNA methylation claims rest on low-confidence single-method studies
  • Direct DNA-repair mechanism not biochemically defined
  • Causal contribution of tRNA versus putative mRNA targets to cancer phenotypes unseparated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0003723 RNA binding 3 GO:0016740 transferase activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
ADAT2/3ENOLASENSUN2TRIM28

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Human DNMT2 (TRDMT1) does not methylate DNA but instead methylates tRNA(Asp), specifically at cytosine 38 in the anticodon loop, as shown by mass spectrometry and genetic/biochemical approaches. Human DNMT2 restored methylation in vitro to tRNA(Asp) from Dnmt2-deficient mouse, Arabidopsis, and Drosophila, in a manner dependent on preexisting patterns of modified nucleosides. Mass spectrometry, in vitro methylation assay, genetic complementation across species Science High 16424344
2001 Crystal structure of human DNMT2 in complex with S-adenosyl-L-homocysteine determined at 1.8 Å resolution. The large domain containing catalytic motifs is structurally similar to bacterial m5C MTase M.HhaI. DNMT2 binds AdoHcy in the same conformation as confirmed m5C MTases. DNMT2 binds DNA to form a denaturant-resistant complex in vitro. X-ray crystallography, in vitro DNA-binding assay Nucleic Acids Research High 11139614
2008 Human DNMT2 methylates tRNA(Asp) using a DNA methyltransferase-like catalytic mechanism. Site-directed mutagenesis of residues from motifs IV, VI, and VIII (analogous to DNA MTase catalytic residues) abolished activity, as did exchange of C292 in the conserved CFT motif. DNMT2 is the first RNA methyltransferase demonstrated to use a DNA methyltransferase-type mechanism. In vitro tRNA methylation assay, site-directed mutagenesis RNA High 18567810
2010 In addition to tRNA(Asp-GTC), Dnmt2 also methylates tRNA(Val-AAC) and tRNA(Gly-GCC). Drosophila Dnmt2 mutants showed reduced viability under stress conditions, and Dnmt2 relocalized to stress granules following heat shock. Dnmt2-mediated methylation protected these tRNAs against stress-induced ribonuclease cleavage. RNA bisulfite sequencing, genetic mutant analysis, immunofluorescence/localization, RNase protection assay Genes & Development High 20679393
2012 Cytosine-C5 tRNA methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis in mice. Double-knockout of both enzymes showed synthetic lethality with underdeveloped phenotype and impaired cellular differentiation. Loss of Dnmt2 and NSun2 caused substantially reduced steady-state levels of unmethylated tRNAs and reduced rates of overall protein synthesis. Dnmt2 and NSun2 have complementary, non-overlapping target-site specificities. Mouse double-knockout genetics, RNA methylation analysis, polysome profiling/protein synthesis assay Nature Structural & Molecular Biology High 22885326
2007 Dnmt2 functions in the cytoplasm (not nucleus) to promote liver, brain, and retina development in zebrafish. Morpholino knockdown conferred differentiation defects in specific organs. Cytoplasmic localization was required for proper organ differentiation. Zebrafish Dnmt2 methylates an RNA species of ~80 bases consistent with tRNA. Morpholino knockdown in zebrafish, subcellular localization rescue experiments, RNA methylation assay Genes & Development High 17289917
2015 Dnmt2 methylates C38 of tRNA(Asp(GTC)), tRNA(Gly(GCC)), and tRNA(Val(AAC)), preventing their fragmentation. Loss of Dnmt2 in mice causes delayed endochondral ossification in newborns, reduced haematopoietic stem and progenitor cell population, and cell-autonomous differentiation defects. C38 methylation by Dnmt2 enables accurate discrimination of near-cognate codons, ensuring translational fidelity; Dnmt2 KO bone marrow cells show systematic codon mistranslation. RNA bisulfite sequencing, mouse knockout, flow cytometry, quantitative proteomics EMBO Journal High 26271101
2015 Mouse aspartyl-tRNA synthetase shows a 4–5-fold preference for C38-methylated tRNA(Asp) over unmethylated tRNA(Asp). Dnmt2 KO murine embryonic fibroblasts exhibit ~30% reduced charging of tRNA(Asp). Protein synthesis of reporters fused to poly-Asp sequences was reduced in Dnmt2 KO cells, as was expression of endogenous proteins containing poly-Asp sequences. In vitro aminoacylation assay, reporter gene assay, western blotting in Dnmt2 KO cells Cell Discovery High 27462411
2013 Dnmt2 is required for efficient Dicer-2 (Dcr-2) function in Drosophila. Dnmt2 limits tRNA fragmentation during heat shock; tRNA fragments serve as Dcr-2 substrates and inhibit Dcr-2 activity on long dsRNAs. Heat-shocked Dnmt2 mutants accumulate dsRNAs, produce fewer siRNAs, and show misregulation of siRNA pathway-dependent genes. Small RNA sequencing, genetic mutant analysis, in vitro Dcr-2 activity assay Cell Reports High 24012760
2013 Dnmt2 expression is required for RNA-mediated epigenetic heredity (paramutation) in mice. Kit paramutant phenotype was not transmitted to progeny of Dnmt2−/− mice, and Sox9 paramutation was not established in Dnmt2−/− embryos. RNA bisulfite sequencing confirmed Dnmt2-dependent tRNA methylation in mouse sperm and indicated Dnmt2-dependent cytosine methylation in Kit RNA in paramutant embryos. Mouse genetics, RNA bisulfite sequencing, microinjection experiments PLoS Genetics Medium 23717211
2018 Deletion of mouse Dnmt2 abolished sperm sncRNA-mediated intergenerational transmission of high-fat-diet-induced metabolic disorders. Dnmt2 deletion prevented elevation of RNA modifications (m5C, m2G) in sperm 30–40 nt RNA fractions induced by a high-fat diet. Dnmt2-mediated m5C contributes to the secondary structure and biological properties of sperm sncRNAs. Mouse knockout, RNA modification mass spectrometry, small RNA sequencing, embryo injection Nature Cell Biology High 29695786
2011 Dnmt2 undergoes nucleo-cytoplasmic shuttling in response to cellular stress, relocalizing from the nucleus to cytoplasmic stress granules (SGs) and RNA processing bodies (P-bodies). Dnmt2 interacts with proteins involved in RNA processing and cellular stress response. Immunofluorescence, subcellular fractionation, co-immunoprecipitation Epigenetics Medium 20864816
2008 Drosophila Dnmt2 is both a cytoplasmic and nuclear protein, with a significant amount bound to the nuclear matrix. Dnmt2 localization is highly dynamic during the cell cycle: it enters prophase nuclei and shows a spindle-like, microtubule-dependent localization during mitotic divisions, and can access DNA during mitosis. Subcellular fractionation, live imaging of Dnmt2-EGFP, microtubule disruption experiments PloS One Medium 18183295
2012 The tRNA-binding site of human DNMT2 was mapped to a surface cleft adjacent to the SAM-binding pocket. Systematic alanine mutagenesis of 20 surface lysine/arginine residues identified 8 residues whose mutation caused >4-fold decreases in catalytic activity. These cluster in a cleft large enough to accommodate the tRNA anticodon loop/stem. DNMT2 induces conformational changes in tRNA during methyl transfer. Systematic surface mutagenesis, in vitro tRNA methylation assay, tRNA binding assay, structural modeling Biochemistry High 22591353
2010 In Entamoeba histolytica, the glycolytic enzyme enolase binds Dnmt2 (Ehmeth) and acts as its inhibitor. This interaction is antagonized by the glycolytic intermediate 2-phosphoglycerate (2-PG), linking glucose metabolism to Dnmt2 activity. Glucose starvation drives enolase into the nucleus, increasing enolase-Ehmeth complex formation and reducing tRNA(Asp) methylation. Yeast two-hybrid screen, co-immunoprecipitation, in vitro methylation assay, nuclear localization analysis PLoS Pathogens Medium 20174608
2014 The E. histolytica Dnmt2 homolog (Ehmeth) confers resistance to nitrosative stress by maintaining tRNA(Asp) methylation. Cysteine residues C228 and C229 of Ehmeth are susceptible to S-nitrosylation and are crucial for Ehmeth-enolase binding; S-nitrosylation of these residues disrupts the inhibitory enolase-Ehmeth complex, increasing tRNA methylation. This defines a mechanism by which NO regulates Dnmt2 activity. Site-directed mutagenesis, in vitro methylation assay, S-nitrosylation assay, co-immunoprecipitation Eukaryotic Cell Medium 24562908
2015 Dnmt2-dependent tRNA methylation in S. pombe (Pmt1) and Dictyostelium (DnmA) is strongly stimulated by prior queuosine (Q) modification of the substrate tRNA. In vivo tRNA methylation levels were induced by queuine-containing medium, and in vitro Pmt1 activity was enhanced on Q-containing RNA. This was abrogated by loss of the tRNA-guanine transglycosylase that inserts queuine. In vitro methylation assay, in vivo tRNA methylation analysis, genetic knockout of transglycosylase Nucleic Acids Research High 26424849
2021 Position 34 of the tRNA anticodon is a discriminative element for m5C38 modification by human DNMT2. For tRNA(Asp(GUC)) and tRNA(Gly(GCC)), G34 is the discriminator; for tRNA(Val(AAC)), inosine modification at position 34 (formed by ADAT2/3) is a prerequisite for hDNMT2 recognition. The C32U33(G/I)34N35(C/U)36A37C38 motif in the anticodon loop, U11:A24 in the D stem, and correct variable loop size are required for substrate recognition. In vitro methylation assay with mutant tRNAs, RNA bisulfite sequencing Nucleic Acids Research High 34871455
2009 Azacytidine (a ribonucleoside analogue), but not decitabine (a deoxyribonucleoside analogue), inhibits DNMT2-dependent cytosine 38 methylation of tRNA(Asp) in human cancer cell lines. Drug-induced loss of RNA methylation was specific for DNMT2 target sites and not other RNA methyltransferase sites. Azacytidine caused stronger metabolic effects than decitabine. RNA bisulfite sequencing, cell viability/metabolic assays in cancer cell lines Cancer Research Medium 19808971
2016 Dnmt2-deficiency in mice causes cardiac hypertrophy with preserved function. Mechanistically, Dnmt2 deficiency leads to increased dissociation of the 7SK/Rn7sk non-coding RNA component from the P-TEFb complex, activating P-TEFb (a critical step for cardiac growth) and increasing RNA Pol II transcriptional elongation. Mouse knockout, echocardiography, P-TEFb complex analysis, Rn7sk RNA interaction assay PLoS One Medium 27270731
2021 TRDMT1 is poly-ubiquitinated at lysine 251 by the E3 ubiquitin ligase TRIM28, which removes TRDMT1 from DNA damage sites and allows completion of homologous recombination (HR). The cancer-associated G155V mutation causes hyper-ubiquitination of TRDMT1, reduced TRDMT1 levels, and impaired HR. TRDMT1 is a key regulator of HR in transcribed genomic regions. Co-immunoprecipitation, ubiquitination assay, HR reporter assay, mutagenesis, in vitro and in vivo cisplatin sensitivity NAR Cancer Medium 33778494
2017 DNMT2 binds and methylates mRNA species in a sequence-independent manner and is re-localized to stress granules in a phosphorylation-dependent manner. DNMT2 methylates HIV-1 RNA, providing post-transcriptional stability to the viral RNA; DNMT2 overexpression increased HIV-1 viral titre. RNA immunoprecipitation, m5C methylation assay, co-localization, viral titre measurement The Biochemical Journal Low 28476776
2013 Dnmt2 is required for efficient innate antiviral immune responses in Drosophila against Drosophila C virus (DCV). Dnmt2 mutant flies accumulate increasing DCV levels. Dnmt2 binds DCV RNA, suggesting direct contribution to virus control possibly through RNA methylation. Genetic mutant analysis, viral titration, RNA co-immunoprecipitation EMBO Reports Medium 23370384
2016 Dnmt2 can methylate DNA fragments when presented as covalent DNA-RNA hybrids in the structural context of a tRNA molecule, more efficiently than the natural tRNA substrate. The 5'-half of tRNA(Asp) can guide methylation toward single-stranded tRNA fragments in vitro. In an engineered system, guide RNAs can direct Dnmt2 to perform cytidine methylation on single-stranded DNA in vitro. In vitro methylation assay using composite nucleic acid substrates, engineered guide RNA system RNA Biology Medium 27819523
2014 The variable loop of tRNA functions as a specificity determinant for Dnmt2 substrate recognition. Exchange of two nucleotides in the variable loop of murine tRNA(Asp) to match tRNA(Glu) strongly reduced activity of the Geobacter Dnmt2 and also human DNMT2, indicating the variable loop is a conserved specificity element. In vitro methylation assay with tRNA mutants, comparative analysis across Dnmt2 homologs Nucleic Acids Research Medium 24711368
2021 Human DNMT2/TRDMT1 preferred tRNA(Gly-GCC) as substrate in vitro. The T-arm is indispensable for DNMT2/TRDMT1 activity. G19, U20, and A21 in the D-loop and G53, C56, A58, and C61 in the T-loop are critical base determinants. The conserved CUXXCAC sequence in the anticodon loop is the most critical determinant, stabilizing C38-flipping to promote methylation. New substrates tRNA(Val-CAC) and tRNA(Gln-CUG) were identified in vitro; U32C substitution converts non-substrate tRNA(Ala-AGC) into a substrate. In vitro methylation assay with truncation and point mutants, circular dichroism RNA Biology Medium 34110975
2023 Intermolecular disulfide bonds (C292-C292, C292-C287, C79-C24, C222-C24) restrict DNMT2/TRDMT1 tRNA methylation activity. DTT (a reductant) is required for full enzyme catalysis. DNMT2/TRDMT1 exists primarily as dimers via intermolecular disulfide bonds in HEK293T cells. GSSG stress enhanced tRNA methylation in early stress; GSH stress downregulated DNMT2/TRDMT1 expression and promoted tRNA methylation by breaking disulfide bonds. LC-MS/MS of recombinant protein, in vitro methylation assay with redox manipulation, western blotting International Journal of Biological Macromolecules Medium 37579906
2015 Somatic cancer mutations in DNMT2 alter catalytic properties: E63K caused ~2-fold increase in tRNA methylation activity; G155S and L257V caused >4-fold decrease; R371H and G155V rendered the enzyme nearly inactive. All mutant proteins were properly folded as confirmed by circular dichroism, indicating direct effects on catalytic mechanism rather than protein misfolding. Site-directed mutagenesis, in vitro tRNA methylation assay, circular dichroism spectroscopy Biochimie Medium 25747896
2012 The Dictyostelium Dnmt2 homolog DnmA methylates C38 in tRNA(Asp(GUC)) in vitro and in vivo. CLIP identified specific tRNA fragments bound by DnmA and revealed tRNA(Glu(CUC/UUC)) and tRNA(Gly(GCC)) as weaker substrates for both human Dnmt2 and DnmA in vitro. Dnmt2 enzymes form transient covalent complexes with their substrates; the dynamics of complex formation and resolution correlate with methylation efficiency in vitro. In vitro methylation assay, UV-crosslinking immunoprecipitation (CLIP), in vivo bisulfite sequencing Nucleic Acids Research Medium 23877245
2012 Crystal structure of E. histolytica Dnmt2 homolog EhMeth at 2.15 Å resolution in complex with S-adenosyl-L-homocysteine was determined, revealing the complete active site loop. Mobility shift assays showed that the full-length tRNA is required for stable complex formation with EhMeth in vitro. X-ray crystallography, electrophoretic mobility shift assay (EMSA) PloS One Medium 22737219
2025 X-ray crystallography of DNMT2 revealed a previously unknown allosteric binding pocket formed via active site loop rearrangement. DNA-encoded library screening identified non-SAH-like inhibitors binding this pocket. A lead compound with KD of 3.04 µM reduces m5C levels in MOLM-13 tRNA and synergizes with doxorubicin to impair cell viability, demonstrating functional allosteric inhibition of DNMT2. DNA-encoded library screening, X-ray crystallography, microscale thermophoresis, tRNA bisulfite sequencing, cell viability assay iScience Medium 40894903
2019 TRDMT1 knockdown in HEK293 cells inhibited cell proliferation and migration, effects reversible by re-expression of TRDMT1. RNA bisulfite sequencing showed that TRDMT1 knockdown changes mRNA methylation (m5C) levels, implicating TRDMT1 in mRNA m5C modification in addition to tRNA methylation. CRISPR-based knockdown, RNA bisulfite sequencing, cell proliferation/migration assays Biochemical and Biophysical Research Communications Low 31570165
2021 TRDMT1 participates in DNA damage repair in granulosa cells. Reactive oxygen species induced nuclear shuttling of TRDMT1 and increased DNA damage and apoptosis. Overexpression of TRDMT1 prevented ROS-induced apoptosis, while TRDMT1 mutants with reduced RNA m5C methylation activity showed impaired DNA repair following ROS induction. Overexpression/mutant analysis in granulosa cells, DNA damage assays, apoptosis assays Aging Low 34100772
2030 In anaplastic thyroid cancer, DNMT2 catalyzes m5C38 methylation on tRNA-Asp-GUC, tRNA-Gly-GCC, and tRNA-Val-AAC. Loss of DNMT2 leads to increased production of 5'tiRNAGly-GCC through ANG-mediated cleavage of hypomethylated tRNA-Gly-GCC. This 5'tiRNAGly-GCC directly binds hnRNPH1, reducing hnRNPH1 protein levels and promoting cancer progression. DNMT2 knockdown, RNA bisulfite sequencing, RNA immunoprecipitation with hnRNPH1, in vivo tumor model Cell Death & Disease Medium 41723159

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science (New York, N.Y.) 822 16424344
2010 RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes & development 592 20679393
2012 RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nature structural & molecular biology 493 22885326
2018 Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nature cell biology 362 29695786
1998 Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic acids research 294 9592134
2001 Structure of human DNMT2, an enigmatic DNA methyltransferase homolog that displays denaturant-resistant binding to DNA. Nucleic acids research 190 11139614
2013 Dnmt2-dependent methylomes lack defined DNA methylation patterns. Proceedings of the National Academy of Sciences of the United States of America 185 23641003
2003 A Dnmt2-like protein mediates DNA methylation in Drosophila. Development (Cambridge, England) 176 12944428
2009 Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. Cancer research 172 19808971
2003 The human Dnmt2 has residual DNA-(cytosine-C5) methyltransferase activity. The Journal of biological chemistry 171 12794065
2015 The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis. The EMBO journal 170 26271101
2007 Dnmt2 functions in the cytoplasm to promote liver, brain, and retina development in zebrafish. Genes & development 170 17289917
2009 Retrotransposon silencing and telomere integrity in somatic cells of Drosophila depends on the cytosine-5 methyltransferase DNMT2. Nature genetics 151 19412177
2016 Mechanism and biological role of Dnmt2 in Nucleic Acid Methylation. RNA biology 147 27232191
2008 Human DNMT2 methylates tRNA(Asp) molecules using a DNA methyltransferase-like catalytic mechanism. RNA (New York, N.Y.) 141 18567810
2013 RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2. PLoS genetics 140 23717211
2010 Solving the Dnmt2 enigma. Chromosoma 124 19730874
2003 Endogenous assays of DNA methyltransferases: Evidence for differential activities of DNMT1, DNMT2, and DNMT3 in mammalian cells in vivo. Molecular and cellular biology 116 12665573
2013 The RNA methyltransferase Dnmt2 is required for efficient Dicer-2-dependent siRNA pathway activity in Drosophila. Cell reports 106 24012760
2014 Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity. Genome research 95 24558263
2011 On the evolutionary origin of eukaryotic DNA methyltransferases and Dnmt2. PloS one 93 22140515
2015 Dynamic modulation of Dnmt2-dependent tRNA methylation by the micronutrient queuine. Nucleic acids research 85 26424849
2006 Two substrates are better than one: dual specificities for Dnmt2 methyltransferases. Trends in biochemical sciences 83 16679017
2013 Efficient RNA virus control in Drosophila requires the RNA methyltransferase Dnmt2. EMBO reports 78 23370384
2017 Reduced levels of methyltransferase DNMT2 sensitize human fibroblasts to oxidative stress and DNA damage that is accompanied by changes in proliferation-related miRNA expression. Redox biology 77 28843151
2015 Cytosine methylation of tRNA-Asp by DNMT2 has a role in translation of proteins containing poly-Asp sequences. Cell discovery 73 27462411
2019 Depletion of TRDMT1 affects 5-methylcytosine modification of mRNA and inhibits HEK293 cell proliferation and migration. Biochemical and biophysical research communications 68 31570165
2012 Pmt1, a Dnmt2 homolog in Schizosaccharomyces pombe, mediates tRNA methylation in response to nutrient signaling. Nucleic acids research 62 23074192
2011 The DNA methyltranferase Dnmt2 participates in RNA processing during cellular stress. Epigenetics 62 20864816
2009 An association study of 45 folate-related genes in spina bifida: Involvement of cubilin (CUBN) and tRNA aspartic acid methyltransferase 1 (TRDMT1). Birth defects research. Part A, Clinical and molecular teratology 62 19161160
2017 Cross-Talk between Dnmt2-Dependent tRNA Methylation and Queuosine Modification. Biomolecules 60 28208632
2010 A new nuclear function of the Entamoeba histolytica glycolytic enzyme enolase: the metabolic regulation of cytosine-5 methyltransferase 2 (Dnmt2) activity. PLoS pathogens 60 20174608
2003 The eukaryotic DNMT2 genes encode a new class of cytosine-5 DNA methyltransferases. The Journal of biological chemistry 57 12819212
2017 Cytosine methylation by DNMT2 facilitates stability and survival of HIV-1 RNA in the host cell during infection. The Biochemical journal 54 28476776
2016 The RNA methyltransferase Dnmt2 methylates DNA in the structural context of a tRNA. RNA biology 47 27819523
2013 Target recognition, RNA methylation activity and transcriptional regulation of the Dictyostelium discoideum Dnmt2-homologue (DnmA). Nucleic acids research 46 23877245
2015 Somatic cancer mutations in the DNMT2 tRNA methyltransferase alter its catalytic properties. Biochimie 45 25747896
2014 Nanodiamond-mediated impairment of nucleolar activity is accompanied by oxidative stress and DNMT2 upregulation in human cervical carcinoma cells. Chemico-biological interactions 45 24928743
2021 The lack of functional DNMT2/TRDMT1 gene modulates cancer cell responses during drug-induced senescence. Aging 42 34139673
2021 Position 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2. Nucleic acids research 41 34871455
2021 Malaria Parasite Stress Tolerance Is Regulated by DNMT2-Mediated tRNA Cytosine Methylation. mBio 39 34724812
2017 Downregulation of methyltransferase Dnmt2 results in condition-dependent telomere shortening and senescence or apoptosis in mouse fibroblasts. Journal of cellular physiology 39 28177119
2004 Evolution of dnmt-2 and mbd-2-like genes in the free-living nematodes Pristionchus pacificus, Caenorhabditis elegans and Caenorhabditis briggsae. Nucleic acids research 39 15576683
2016 Dnmt2/Trdmt1 as Mediator of RNA Polymerase II Transcriptional Activity in Cardiac Growth. PloS one 38 27270731
2022 DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis. Apoptosis : an international journal on programmed cell death 34 36273376
2014 The Dnmt2 RNA methyltransferase homolog of Geobacter sulfurreducens specifically methylates tRNA-Glu. Nucleic acids research 33 24711368
2022 Selenium Supplementation Improved Cardiac Functions by Suppressing DNMT2-Mediated GPX1 Promoter DNA Methylation in AGE-Induced Heart Failure. Oxidative medicine and cellular longevity 32 35432721
2014 The Entamoeba histolytica Dnmt2 homolog (Ehmeth) confers resistance to nitrosative stress. Eukaryotic cell 32 24562908
2008 The Drosophila cytosine-5 methyltransferase Dnmt2 is associated with the nuclear matrix and can access DNA during mitosis. PloS one 31 18183295
2021 TRDMT1 participates in the DNA damage repair of granulosa cells in premature ovarian failure. Aging 29 34100772
2014 The relative importance of DNA methylation and Dnmt2-mediated epigenetic regulation on Wolbachia densities and cytoplasmic incompatibility. PeerJ 29 25538866
2021 New substrates and determinants for tRNA recognition of RNA methyltransferase DNMT2/TRDMT1. RNA biology 26 34110975
2017 DNA methyltransferase homologue TRDMT1 in Plasmodium falciparum specifically methylates endogenous aspartic acid tRNA. Biochimica et biophysica acta. Gene regulatory mechanisms 23 28847733
2024 Biological function molecular pathways and druggability of DNMT2/TRDMT1. Pharmacological research 22 38782147
2022 TRDMT1 exhibited protective effects against LPS-induced inflammation in rats through TLR4-NF-κB/MAPK-TNF-α pathway. Animal models and experimental medicine 22 35474613
2023 TRDMT1-mediated RNA C-5 methylation as a novel target in anticancer therapy. Biochimica et biophysica acta. Reviews on cancer 20 37625528
2012 Mapping the tRNA binding site on the surface of human DNMT2 methyltransferase. Biochemistry 20 22591353
2022 5-Azacytidine Inhibits the Activation of Senescence Program and Promotes Cytotoxic Autophagy during Trdmt1-Mediated Oxidative Stress Response in Insulinoma β-TC-6 Cells. Cells 19 35406777
2023 Chemical Space Virtual Screening against Hard-to-Drug RNA Methyltransferases DNMT2 and NSUN6. International journal of molecular sciences 17 37047081
2010 In vitro tRNA methylation assay with the Entamoeba histolytica DNA and tRNA methyltransferase Dnmt2 (Ehmeth) enzyme. Journal of visualized experiments : JoVE 17 21048666
2021 Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response. NAR cancer 16 33778494
2016 [Dnmt2 is the Most Evolutionary Conserved and Enigmatic Cytosine DNA Methyltransferase in Eukaryotes]. Genetika 16 27281847
2012 Structure analysis of Entamoeba histolytica DNMT2 (EhMeth). PloS one 16 22737219
2021 Evidence of Adaptive Evolution in Wolbachia-Regulated Gene DNMT2 and Its Role in the Dipteran Immune Response and Pathogen Blocking. Viruses 15 34452330
2022 Paternal knockdown of tRNA(cytosine-5-)-methyltransferase (Dnmt2) increases offspring susceptibility to infection in red flour beetles. Insect molecular biology 12 35790040
2024 tRNA methyltransferase DNMT2 promotes hepatocellular carcinoma progression and enhances Bortezomib resistance through inhibiting TNFSF10. Cellular signalling 9 39617358
2022 Deficiency of TRDMT1 impairs exogenous RNA-based response and promotes retrotransposon activity during long-term culture of osteosarcoma cells. Toxicology in vitro : an international journal published in association with BIBRA 9 35104602
2020 Integrative Analysis of the Doxorubicin-Associated LncRNA-mRNA Network Identifies Chemoresistance-Associated lnc-TRDMT1-5 as a Biomarker of Breast Cancer Progression. Frontiers in genetics 9 32547604
2017 Linking epigenetic function to electrostatics: The DNMT2 structural model example. PloS one 9 28575027
2013 Dnmt2 methyltransferases and immunity: an ancient overlooked connection between nucleotide modification and host defense? BioEssays : news and reviews in molecular, cellular and developmental biology 9 24019003
2020 Transcriptome Analysis of ppdnmt2 and Identification of Superoxide Dismutase as a Novel Interactor of DNMT2 in the Moss Physcomitrella patens. Frontiers in plant science 8 32849734
2023 Restricted tRNA methylation by intermolecular disulfide bonds in DNMT2/TRDMT1. International journal of biological macromolecules 6 37579906
2023 Determinants of DNMT2/TRDMT1 preference for substrates tRNA and DNA during the evolution. RNA biology 6 37966982
2022 RNA 5-methylcytosine status is associated with DNMT2/TRDMT1 nuclear localization in osteosarcoma cell lines. Journal of bone oncology 6 35942470
2018 Evolution of DNMT2 in drosophilids: Evidence for positive and purifying selection and insights into new protein (pathways) interactions. Genetics and molecular biology 6 29668012
2023 Knockout of TRDMT1 methyltransferase affects DNA methylome in glioblastoma cells. Journal of neuro-oncology 5 37169948
2023 Juvenile hormone inhibits adult cuticle formation in Drosophila melanogaster through Kr-h1/Dnmt2-mediated DNA methylation of Acp65A promoter. Insect molecular biology 5 37916965
2025 A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors. Communications chemistry 3 39900960
2024 The mechanism of sevoflurane affecting ovarian cancer cell proliferation and migration by regulating RNA methylase TRDMT1 to activate the β-catenin pathway. Cell biology and toxicology 3 39630363
2023 Role of TRDMT1/DNMT2 in stress adaptation and its influence on transcriptome and proteome dynamics under osmotic stress in Physcomitrium patens. Physiologia plantarum 3 37882266
2025 DNA-encoded library screening uncovers potent DNMT2 inhibitors targeting a cryptic allosteric binding site. iScience 2 40894903
2021 Detection of genetic variation and activity analysis of the promoter region of the cattle tRNA-modified gene TRDMT1. Archives animal breeding 2 34084913
2021 Expression of different genotypes of bovine TRDMT1 gene and its polymorphisms association with body measures in Qinchuan cattle (Bos Taurus). Animal biotechnology 2 34629027
2025 Association of TRDMT1 Gene Polymorphisms With Neuroblastoma Susceptibility: Insights From a Case-Control Study. Journal of cellular and molecular medicine 1 40984038
2020 Trdmt1 3'-untranslated region functions as a competing endogenous RNA in leukemia HL-60 cell differentiation. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 1 33331537
2014 No detectable effect of the DNA methyltransferase DNMT2 on Drosophila meiotic recombination. G3 (Bethesda, Md.) 1 25168011
2001 Novel nucleotide substitutions within the coding region of DNMT2 are in strong linkage disequilibrium in Caucasians and Japanese. Human heredity 1 11713417
2026 DNMT2 inhibits anaplastic thyroid cancer progression by downregulating 5'tiRNAGly-GCC production. Cell death & disease 0 41723159
2025 Dissecting the function of the DNMT2-homolog (DNMA) in Dictyostelium discoideum. G3 (Bethesda, Md.) 0 40611661
2025 TRDMT1 methyltransferase gene knockout attenuates STING-based cell death signaling during self-extracellular RNA-mediated response in drug-induced senescent osteosarcoma cells. Cellular and molecular life sciences : CMLS 0 40801921
2025 DNMT2-m5C-ACLY Axis Promotes Lenvatinib Resistance in Hepatocellular Carcinoma Through Histone Acetylation-Mediated Notch Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41417568
2023 Suppression of DNMT2/3 by proinflammatory cytokines inhibits CtBP1/2-dependent genes to promote the occurrence of atrophic nonunion. Cytokine 0 37979214

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