Affinage

TDG

G/T mismatch-specific thymine DNA glycosylase · UniProt Q13569

Length
410 aa
Mass
46.1 kDa
Annotated
2026-06-10
60 papers in source corpus 30 papers cited in narrative 30 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

TDG is a bifunctional DNA glycosylase that operates at the intersection of base excision repair, active DNA demethylation, and transcriptional control. Its canonical activity is mismatch-dependent excision of bases from G:X pairs, including thymine glycol (PMID:12954776) and lipid peroxidation-derived etheno adducts (PMID:25151120), with crystal structures showing it engages substrates from the DNA minor groove (PMID:27493500). Its defining epigenetic role is as the terminal glycosylase of the TET-initiated demethylation pathway: TDG specifically excises the oxidized 5-methylcytosine derivatives 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) generated by TET dioxygenases, and its loss causes genome-wide accumulation of these marks at gene regulatory elements in mouse ESCs (PMID:21817016, PMID:23602152). Biochemical reconstitution established that the TET-TDG-BER system completes demethylation of symmetrically methylated CpGs without generating double-strand breaks (PMID:26932196), and this excision is only modestly CpG-context-dependent, extending the pathway beyond CpG sites (PMID:33561435). TDG glycosylase function is potentiated by physical and functional partnerships with TET1 (PMID:26932196), NEIL1/NEIL2 (which displace TDG from abasic sites and process them as AP lyases to accelerate turnover) (PMID:26751644, PMID:28827588), Gadd45a (PMID:25845601), and the 9-1-1 checkpoint complex (Rad9-Rad1-Hus1) (PMID:17855402), and is allosterically activated by alpha-ketoglutarate binding at Arg275 (PMID:29158345). TDG abundance and access are tightly regulated: it is degraded by the ubiquitin-proteasome system at S-phase onset inverse to UNG2 (PMID:17526518) via the SUMO-targeted ligase RNF4 (PMID:24727457), its transcription is activated by p53 (PMID:23165212), and its activity on chromatin is inhibited by nucleosome compaction and modulated by histone variants and the pioneer factor FOXA1 (PMID:31460763). Beyond catalysis, TDG functions as a structural scaffold in transcriptional coactivator complexes, binding SRC1 through a tyrosine-repeat motif (PMID:16282588) and forming a ternary complex with CBP and activated RARalpha that is required for retinoic acid target gene regulation independent of its catalytic activity (PMID:28538185, PMID:24394593); it also restrains DNA methylation by binding DNMT3A and modulating its nucleosomal activity (PMID:35414793, PMID:33172892). TDG is essential for embryonic development and epigenomic stability (PMID:21278727) and is required for catalysis-dependent reprogramming and lineage transitions (PMID:24529596), while its catalysis-independent occupancy of active promoters sustains ATF4-dependent gene expression during differentiation (PMID:41773019). Emerging evidence places TDG on RNA:DNA hybrid (R-loop) substrates and identifies it as an RNA-binding protein associating with lncRNAs such as Neat1 [PMID:bio_10.1101_2025.08.05.668694, PMID:41291101].

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2003 Medium

    Established that TDG substrate recognition is governed by mispairing rather than the lesion alone, extending its repair scope to oxidatively modified bases.

    Evidence In vitro glycosylase assays with thymine glycol in defined pairing contexts

    PMID:12954776

    Open questions at the time
    • Did not address cellular relevance of thymine glycol repair
    • No structural basis for mismatch discrimination at this point
  2. 2004 High

    Defined how SUMO modification controls TDG, linking non-covalent SUMO binding to covalent conjugation and subnuclear targeting.

    Evidence Yeast two-hybrid, pulldown, Co-IP, and co-localization with mutagenesis in transfected cells

    PMID:15569683

    Open questions at the time
    • Functional consequence of PML body localization for repair unresolved
    • Did not connect SUMOylation to turnover during demethylation
  3. 2007 High

    Revealed cell-cycle control of TDG, showing it is eliminated during S/G2 inverse to UNG2, functionally partitioning the two enzymes, and that failure to degrade it impairs proliferation.

    Evidence Cell cycle flow cytometry, proteasome inhibition, non-degradable TDG expression, proliferation assays

    PMID:17526518

    Open questions at the time
    • Did not identify the responsible E3 ligase
    • Mechanistic reason S-phase TDG impairs progression unclear
  4. 2007 High

    Connected TDG to the DNA damage checkpoint by mapping its interaction with the 9-1-1 complex and showing 9-1-1 stimulates its glycosylase activity.

    Evidence Co-IP, GST pulldown, domain mapping (residues 67-110, Val74), in vitro stimulation assay, damage-induced co-localization

    PMID:17855402

    Open questions at the time
    • In vivo significance of 9-1-1 stimulation not tested genetically
    • Whether stimulation applies to 5fC/5caC substrates not addressed
  5. 2011 High

    Identified TDG as the glycosylase that removes 5caC, placing it as the terminal excision step of TET-driven active demethylation.

    Evidence In vitro glycosylase assay with defined substrates plus TDG depletion in mouse ESCs with LC-MS quantification of 5caC

    PMID:21817016

    Open questions at the time
    • Genome-wide distribution of 5caC accumulation not yet mapped
    • Coupling to downstream BER steps not reconstituted
  6. 2011 High

    Demonstrated TDG is essential for development and epigenomic stability, establishing physiological importance beyond a repair enzyme.

    Evidence Tdg null mouse lethality, ChIP for histone marks and CpG methylation at developmental promoters

    PMID:21278727

    Open questions at the time
    • Did not separate catalytic from scaffolding contributions to the phenotype
    • Specific developmental lethal mechanism not pinpointed
  7. 2013 High

    Mapped TDG-dependent demethylation genome-wide, showing 5fC and 5caC accumulate at regulatory elements when TDG is lost.

    Evidence Modification-specific genome-wide profiling in WT and Tdg-deficient ESCs

    PMID:23602152

    Open questions at the time
    • Functional consequence at individual regulatory elements not dissected
    • Turnover kinetics in vivo not measured
  8. 2014 Medium

    Distinguished TDG's catalytic from structural roles by showing reprogramming requires its enzymatic activity while RAR/CBP target gene control depends on scaffolding.

    Evidence TDG-deficient MEF reprogramming with catalytic-vs-inactive rescue; ternary complex Co-IP with point mutant and transcriptomics; methylated reporter reactivation with NEIL rescue

    PMID:24394593 PMID:24529596 PMID:24948610

    Open questions at the time
    • Molecular basis of scaffolding-dependent transcription incompletely defined
    • How miRNA loci are selected for TDG-dependent activation unknown
  9. 2015 High

    Identified Gadd45a as a stimulatory partner coupling TDG to active demethylation, supported by genetic epistasis at shared loci.

    Evidence Co-IP, in vitro 5fC/5caC excision stimulation, reporter assay, Gadd45a/b double-KO ESC methylation analysis

    PMID:25845601

    Open questions at the time
    • Mechanism by which Gadd45a accelerates excision not defined
    • Overlap with NEIL stimulation pathways unresolved
  10. 2016 High

    Reconstituted productive, break-free demethylation of symmetric CpGs and showed NEIL glycosylases accelerate TDG turnover by displacing it from abasic sites.

    Evidence Purified TET1-TDG reconstitution and demethylation assay; in vitro glycosylase/AP lyase assays with Xenopus loss-of-function validation

    PMID:26751644 PMID:26932196

    Open questions at the time
    • Stoichiometry and ordering of full multienzyme handoff in cells not established
    • Regulation of NEIL recruitment in vivo unknown
  11. 2017 High

    Showed how TDG activity is tuned by metabolism and chromatin: alpha-ketoglutarate allosterically activates it at Arg275, and nucleosome compaction inhibits its action on chromatin.

    Evidence Molecular dynamics, Arg275 mutagenesis, glycosylase assays, Co-IP in diabetic cells (alphaKG); defined nucleosome arrays with site-specific 5fC and FOXA1/histone variants (chromatin)

    PMID:29158345 PMID:31460763

    Open questions at the time
    • In vivo contribution of alphaKG regulation to demethylation untested genome-wide
    • How FOXA1 mechanistically licenses TDG access unresolved
  12. 2017 High

    Refined the demethylation handoff by showing NEIL1 itself excises 5caC and substrate-specifically enhances TDG on 5fC/5caC but not T:G, and connected TDG to coactivator complex recruitment in vivo.

    Evidence In vitro assays with NEIL1 catalytic mutants and binding assays; ChIP and conditional Tdg KO at the Hic1 promoter with RAR/RXR/CBP/TET recruitment

    PMID:28538185 PMID:28827588

    Open questions at the time
    • Generality of the RAR-recruited demethylation complex across target genes not established
    • Substrate-specificity basis of NEIL1 stimulation structurally undefined
  13. 2020 Medium

    Uncovered TDG as a regulator of DNA methyltransferase activity, binding DNMT3A to promote its degradation and dominantly modulate its nucleosomal activity, with disease relevance in cancer.

    Evidence Co-IP, ubiquitination and degradation assays, MSP, migration/invasion and xenografts (TIMP2); in vitro DNMT3A nucleosome methylation with allosteric binding mapping

    PMID:33172892 PMID:35414793

    Open questions at the time
    • Whether DNMT3A regulation is catalysis-dependent unclear
    • Physiological scope beyond cancer models untested
  14. 2021 High

    Quantified the in vivo contribution of TDG-dependent active demethylation, showing it operates but is minor relative to passive dilution during T cell differentiation, and that 5fC/5caC excision is largely CpG-context-independent.

    Evidence Inducible Tdg disruption with single-base PB-seq in mice; in vitro TET2/TDG kinetics across CG and CH contexts

    PMID:33561435 PMID:34158086

    Open questions at the time
    • Cell types where active demethylation dominates not delineated
    • Determinants directing TDG to specific loci in vivo unknown
  15. 2025 Medium

    Extended TDG's substrate range to RNA:DNA hybrids and identified it as an RNA-binding protein, implicating R-loops and lncRNAs in directing strand-specific demethylation.

    Evidence In vitro R-loop binding and glycosylase assays with 19F NMR (preprint); BioID2 proximity proteomics, RNA-IP, and hybrid-substrate assays in mESCs

    PMID:41291101 PMID:bio_10.1101_2025.08.05.668694

    Open questions at the time
    • In vivo role of R-loop-directed TDG activity not established
    • Functional consequence of Neat1 and RUVBL2/HCFC1 associations undefined
  16. 2026 Medium

    Defined a catalysis-independent genomic function, showing TDG occupies active promoters with ATF4 and sustains ATF4-dependent expression and mTORC1 signaling via nucleosome positioning during differentiation.

    Evidence Tdg KO epiblast-like cells, TDG and ATF4 ChIP-seq, transcriptomics, mTORC1 analysis, catalytically inactive rescue

    PMID:41773019

    Open questions at the time
    • Mechanism by which TDG positions nucleosomes at promoters unknown
    • Relationship between scaffolding and demethylation roles at the same loci unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TDG is targeted to specific genomic loci, and how its catalytic, scaffolding, and RNA-associated functions are coordinated and partitioned across cell states, remains unresolved.
  • No unified model of locus selection for active demethylation versus structural occupancy
  • Interplay of SUMO/RNF4 turnover, p53 transcription, and chromatin state in directing function not integrated
  • In vivo significance of R-loop and RNA-binding activities undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 8 GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-4839726 Chromatin organization 5 R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-73894 DNA Repair 3 R-HSA-1640170 Cell Cycle 2
Partners
CBPDNMT3AGADD45AHUS1NEIL1NEIL2SRC1TET1
Complex memberships
9-1-1 checkpoint complex (Rad9-Rad1-Hus1)RAR/RXR-CBP-TDG coactivator complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 TDG specifically recognizes and excises 5-carboxylcytosine (5caC) from DNA, a product of iterative TET dioxygenase-mediated oxidation of 5-methylcytosine (5mC). Depletion of TDG in mouse embryonic stem cells leads to accumulation of 5caC to detectable levels, establishing TDG as the glycosylase that removes 5caC in the TET-initiated active DNA demethylation pathway. In vitro glycosylase assay, cell-based depletion (siRNA/genetic) with LC-MS quantification of 5caC Science High 21817016
2011 TDG is essential for embryonic development (Tdg null mice die in utero). TDG maintains epigenetic stability by contributing to active and bivalent chromatin at developmental gene promoters, counteracting aberrant de novo methylation and facilitating proper assembly of chromatin-modifying complexes via base excision repair. Mouse genetic knockout, ChIP for histone modifications and CpG methylation at gene promoters in MEFs and ESCs Nature High 21278727
2013 TDG excises 5-formylcytosine (5fC) and 5caC genome-wide, particularly at gene regulatory elements (proximal and distal). Genome-wide maps in Tdg-deficient mouse ESCs reveal marked accumulation of 5fC and 5caC at these sites, demonstrating that TET/TDG-dependent active demethylation occurs extensively at regulatory regions. Genome-wide modification-specific antibody profiling (ChIP-seq/immunoprecipitation) in wild-type and Tdg-deficient ESCs Cell High 23602152
2016 TET1 and TDG physically interact to form a functional complex; biochemical reconstitution demonstrates that the TET-TDG-BER system can achieve productive DNA demethylation of symmetrically methylated CpGs in a sequential manner, avoiding DNA double-strand break formation. Co-immunoprecipitation, biochemical reconstitution with purified TET1 and TDG, in vitro demethylation assay Nature Communications High 26932196
2016 NEIL1 and NEIL2 DNA glycosylases stimulate TDG substrate turnover during active demethylation: TDG occupies the abasic site after base excision and is displaced by NEIL proteins, which process the baseless sugar as AP lyases, thereby accelerating TDG cycling on 5fC/5caC substrates. In vitro glycosylase/AP lyase assay with purified proteins, Xenopus embryo loss-of-function experiments Nature Structural & Molecular Biology High 26751644
2004 TDG (TDGb isoform) binds SUMO-1 non-covalently via a specific region (residues within the N-terminus), and this non-covalent SUMO-1 binding is required for covalent SUMO-1 conjugation at an adjacent lysine residue. SUMO-1 modification of TDG promotes its interaction with PML and co-localization to PML nuclear bodies. Yeast two-hybrid screen, in vitro pulldown, co-immunoprecipitation, fluorescence co-localization in transfected cells, deletion and point mutagenesis Journal of Biological Chemistry High 15569683
2007 TDG is degraded by the ubiquitin-proteasome system at the onset of S-phase and is absent throughout S and G2 phases; this cell cycle regulation is strictly inverse to UNG2, functionally separating the two repair enzymes. Incomplete TDG degradation impedes S-phase progression and cell proliferation. Flow cytometry cell cycle analysis, proteasome inhibition, ectopic expression of non-degradable TDG, cell proliferation assays Nucleic Acids Research High 17526518
2007 TDG interacts with Rad9, Rad1, and Hus1 individually and as the 9-1-1 checkpoint complex. The Hus1-interacting domain is mapped to residues 67–110 of TDG (Val74 critical). 9-1-1 components significantly stimulate TDG glycosylase activity on U:G and T:G mispairs; TDG foci co-localize with Rad9 foci after DNA damage. Co-immunoprecipitation, GST pulldown, deletion/point mutagenesis, in vitro glycosylase stimulation assay, immunofluorescence co-localization after MNNG treatment Nucleic Acids Research High 17855402
2015 Gadd45a promotes active DNA demethylation through TDG: Gadd45a physically interacts with TDG and stimulates TDG-mediated removal of 5fC and 5caC from genomic and plasmid DNA. Knockout of both Gadd45a and Gadd45b in mouse ESCs causes hypermethylation at loci that are also TDG targets. Co-immunoprecipitation, in vitro 5fC/5caC excision assay, methylated reporter gene assay in HEK293T cells, double-KO mouse ESC methylation analysis Nucleic Acids Research High 25845601
2014 TET-mediated oxidation of 5mC at a methylated Oct4 promoter reporter leads to gene reactivation in a TDG-dependent (but not MBD4-dependent) manner. NEIL1, NEIL2, and NEIL3 can partially rescue TDG loss for this gene reactivation. TDG co-immunoprecipitates with TET proteins and BER factors PARP1, XRCC1, and LIG3. In vitro methylated reporter gene reactivation assay, TDG/MBD4/NEIL KO cell lines with rescue, co-immunoprecipitation of TET-interacting factors Nucleic Acids Research Medium 24948610
2005 TDG interacts with the p160 coactivator SRC1 in vitro and in vivo via a novel Y-X-X-X-Y tyrosine repeat motif in TDG; site-directed mutagenesis of these tyrosines abolishes the interaction. TDG functions as a coactivator in transcriptional complexes at nuclear receptor target genes. In vitro GST pulldown, co-immunoprecipitation, site-directed mutagenesis of tyrosine motif Nucleic Acids Research Medium 16282588
2014 TDG is required for mesenchymal-to-epithelial transition (MET) during somatic cell reprogramming to iPSCs. The block in reprogramming in TDG-deficient MEFs is caused at least partly by defective activation of key miRNAs that depend on oxidative demethylation promoted by catalytically active TDG. Reintroduction of catalytically active TDG restores reprogramming. TDG-deficient MEF reprogramming assay (iPSC generation), miRNA expression analysis, rescue with catalytically active vs inactive TDG Cell Stem Cell High 24529596
2003 TDG can excise thymine glycol (a common oxidative DNA lesion) when it is mispaired with guanine but not when paired with adenine, demonstrating that TDG substrate recognition is mismatch-dependent and extends to oxidatively modified bases at CpG sites. In vitro glycosylase assay with oligonucleotides containing thymine glycol in different pairing contexts Nucleic Acids Research Medium 12954776
2017 Retinoic acid receptor (RAR) activation recruits a complex containing RAR/RXR, TDG, the acetyltransferase CBP, and TET1/2 to the Hic1 promoter, causing transient 5fC/5caC accumulation and TDG-dependent upregulation of Hic1. Conditional Tdg deletion in vivo results in Hic1 silencing and promoter hypermethylation. ChIP, gene expression analysis, conditional Tdg knockout mice, 5fC/5caC quantification at promoter Cell Reports High 28538185
2014 TDG forms a functional ternary complex with CBP (histone acetyltransferase) and activated RARα; a point mutation in TDG that does not affect overall structure or BER activity reduces ternary complex stability and deregulates RA-dependent target genes, demonstrating a structural scaffolding role of TDG independent of its catalytic activity. Co-immunoprecipitation, point mutagenesis, global transcriptome profiling, reporter assays Genomics, Proteomics & Bioinformatics Medium 24394593
2012 p53 directly binds two consensus response elements in the TDG promoter and transcriptionally activates TDG expression. DNA damage in p53-competent cells leads to TDG nuclear re-localization that does not occur in p53-deficient cells, indicating p53 activity influences TDG nuclear translocation. ChIP, luciferase reporter assay, isogenic cell lines with different p53 status, nuclear/cytoplasmic fractionation after DNA damage Cell Cycle Medium 23165212
2017 Alpha-ketoglutarate (αKG) allosterically activates TDG by binding at Arg275, significantly increasing TDG activity on G:T mismatches and 5fC. In diabetic cardiac mesenchymal cells, reduced αKG synthesis compromises TDG and TET1 association and function; exogenous αKG restores TDG function, TET1 nuclear localization, and TET/TDG association. Molecular dynamics simulation, mutational analysis (Arg275), in vitro glycosylase activity assay, co-immunoprecipitation, TET1 localization by immunofluorescence, CRISPR/Cas9 TDG KO Circulation Research Medium 29158345
2019 Chromatin compaction and nucleosome positioning dramatically inhibit TDG-mediated excision of 5fC from chromatin substrates. The H2A.Z/H3.3 double-variant nucleosome and the pioneering transcription factor FOXA1 differentially regulate TDG activity on chromatin, providing direct evidence that higher-order chromatin structure regulates active DNA demethylation through TDG. In vitro glycosylase assay on chemically defined nucleosome arrays with site-specific 5fC, reconstituted chromatin compaction assays Journal of the American Chemical Society High 31460763
2017 NEIL1 directly excises 5caC from dsDNA and both directly binds TDG and displaces it from abasic sites to process the 2'-deoxyribose as an AP lyase; NEIL1 also enhances TDG glycosylase activity specifically on 5fC and 5caC substrates but not on T:G mismatches. In vitro glycosylase assay with purified NEIL1 wild-type and catalytic mutants (P2T, E3Q), direct TDG-NEIL1 binding assay Scientific Reports Medium 28827588
2014 TDG excises thymine mispaired with multiple exocyclic etheno-DNA adducts (εC, BεC, BεG, HεC, HεG) in vitro; TDG-knockdown human cells show higher resistance to cell death from etheno-adduct induction, lower repair of εC, and modest increase in εC-induced mutations, demonstrating TDG has repair activity toward lipid peroxidation-derived etheno adducts. In vitro DNA cleavage assay with oligonucleotides containing defined adducts, siRNA knockdown in human cells with cell viability, repair, and mutation frequency assays Free Radical Biology & Medicine Medium 25151120
2014 TDG N151A mutation inhibits 5caC excision activity while retaining activity on 5fC and T:G mismatches; N157D mutation creates a more 5caC-specific glycosylase; crystal structures show TDG recognizes G:5caC DNA from the minor groove similarly to mismatch DNA, providing structural basis for 5caC discrimination. Crystal structure determination, site-directed mutagenesis, in vitro glycosylase activity assay Biophysics Medium 27493500
2014 SUMO-modified TDG interacts with the SUMO-targeted ubiquitin E3 ligase RNF4; both SUMOylated and non-modified TDG fluctuate during the cell cycle. A SUMOylation-independent association between TDG and RNF4 also exists; both TDG forms are efficiently degraded in RNF4-depleted cells during S phase arrest. Co-immunoprecipitation (in vitro and in vivo), cell cycle synchronization with hydroxyurea/nocodazole, RNF4 siRNA depletion, western blot Biochemical and Biophysical Research Communications Medium 24727457
2020 TDG physically interacts with DNMT3A and promotes ubiquitination and degradation of DNMT3A. This leads to demethylation of the TIMP2 promoter and upregulation of TIMP2 expression, inhibiting colon cancer cell migration and invasion in vitro and in vivo. Co-immunoprecipitation, siRNA knockdown, ChIP, methylation-specific PCR, migration/invasion assays, xenograft mouse model International Journal of Biological Sciences Medium 35414793
2020 TDG-mediated DNA demethylation is transactivated by c-Myc upon insulin treatment, leading to decreased 5caC abundance at the SREBP1 promoter and upregulation of lipogenic genes. AMPK activation by metformin increases DNMT3A activity to hypermethylate the TDG promoter, reducing TDG expression and reversing this demethylation. ChIP, bisulfite sequencing, siRNA knockdown, luciferase reporter assay, 5caC quantification by dot blot/sequencing Molecular Therapy Oncolytics Medium 32728616
2021 TDG-mediated active demethylation (replication-independent) occurs at detectable levels in T cells (5fC/5caC accumulate in TDG-deleted T cells), but this process contributes negligibly to overall DNA demethylation during primary T cell differentiation, which occurs mainly through passive replication-dependent dilution of oxidized methylcytosines. Inducible TDG gene disruption in mice, pyridine borane sequencing (PB-seq) for 5fC/5caC at single-base resolution, analysis of differentiation markers Genome Biology High 34158086
2021 TDG excision of 5fC and 5caC is only modestly dependent on CpG context, in contrast to its strong CpG context dependence for thymine excision. TET2 and TDG collaborative demethylation activity is only marginally reduced for CA versus CG contexts, indicating the TET-TDG pathway is not limited to CpG sites. In vitro TET2 oxidation assay and TDG excision assay with systematic CG and CH context substrates, quantitative kinetics Journal of Molecular Biology Medium 33561435
2020 TDG forms a multiprotein complex with DNMT3A at distinct allosteric sites from histone H3 tail binding; TDG plays a dominant role in modulating DNMT3A activity on nucleosome substrates, even overriding histone tail signals, and this regulation operates on DNA within single and adjacent nucleosomes. In vitro DNMT3A methylation assay on mononucleosomes and polynucleosomes, binding assays with synthetic histone tails, multi-component complex formation Journal of Biological Chemistry Medium 33172892
2025 TDG binds tightly to R-loops in vitro and can excise 5fC and 5caC from DNA within DNA/RNA hybrid duplexes. R-loops guide the strand-specific activity of TDG at CpG sites, and 19F NMR provides mechanistic evidence for base excision on DNA/RNA hybrid substrates. In vitro R-loop binding assay, in vitro glycosylase assay on DNA/RNA hybrid substrates with defined 5fC/5caC, 19F NMR bioRxiv (preprint)preprint Medium bio_10.1101_2025.08.05.668694
2025 TDG is an RNA-binding protein that interacts with long non-coding RNAs including the paraspeckle-organizing lncRNA Neat1, and can excise oxidized 5-methylcytosine (5fC/5caC) in RNA:DNA hybrids (R-loops), suggesting TDG participates in active DNA demethylation through R-loop regulation. TDG proximity interactome also encompasses chromatin remodelers RUVBL2 and H3K4 methyltransferase complex tethering factor HCFC1. BioID2 proximity labeling proteomics in mESCs, RNA immunoprecipitation, in vitro glycosylase assay on RNA:DNA hybrid substrates Cellular and Molecular Life Sciences Medium 41291101
2026 TDG occupies a majority of active promoters in pluripotent cells, co-occupying sites with the transcription factor ATF4. During retinoic acid-induced neural differentiation, TDG maintains ATF4-dependent gene expression and mTORC1 pathway activity in a manner that does not require TDG catalytic activity, linked instead to TDG-associated nucleosome positioning at promoters. Tdg KO epiblast stem-like cells, ChIP-seq for TDG and ATF4, transcriptomics, mTORC1 pathway analysis, rescue with catalytically inactive TDG Nucleic Acids Research Medium 41773019

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science (New York, N.Y.) 2141 21817016
2013 TET enzymes, TDG and the dynamics of DNA demethylation. Nature 1221 24153300
2013 Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 394 23602152
2011 Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature 308 21278727
2014 Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming. Cell stem cell 248 24529596
2016 Biochemical reconstitution of TET1-TDG-BER-dependent active DNA demethylation reveals a highly coordinated mechanism. Nature communications 176 26932196
2004 Noncovalent SUMO-1 binding activity of thymine DNA glycosylase (TDG) is required for its SUMO-1 modification and colocalization with the promyelocytic leukemia protein. The Journal of biological chemistry 96 15569683
2012 MBD4 and TDG: multifaceted DNA glycosylases with ever expanding biological roles. Mutation research 87 23195996
2007 Cell cycle regulation as a mechanism for functional separation of the apparently redundant uracil DNA glycosylases TDG and UNG2. Nucleic acids research 79 17526518
2015 Gadd45a promotes DNA demethylation through TDG. Nucleic acids research 76 25845601
2016 Neil DNA glycosylases promote substrate turnover by Tdg during DNA demethylation. Nature structural & molecular biology 75 26751644
2014 TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation. Nucleic acids research 74 24948610
2013 Ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG), components of the demethylation pathway, are direct targets of miRNA-29a. Biochemical and biophysical research communications 70 23820384
2006 Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition. BMC cancer 68 17029639
2003 Human thymine DNA glycosylase (TDG) and methyl-CpG-binding protein 4 (MBD4) excise thymine glycol (Tg) from a Tg:G mispair. Nucleic acids research 67 12954776
2021 Roles of TET and TDG in DNA demethylation in proliferating and non-proliferating immune cells. Genome biology 63 34158086
2002 Substrate recognition by a family of uracil-DNA glycosylases: UNG, MUG, and TDG. Chemical research in toxicology 61 12184783
2012 DNA demethylation by TDG. Epigenomics 60 22920184
2007 The human checkpoint sensor Rad9-Rad1-Hus1 interacts with and stimulates DNA repair enzyme TDG glycosylase. Nucleic acids research 55 17855402
2004 Polymorphisms in TDG and MGMT genes - epidemiological and functional study in lung cancer patients from Poland. Annals of human genetics 55 15225156
2017 Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG Complex. Cell reports 53 28538185
2017 Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients: Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation. Circulation research 48 29158345
2019 lncRNA H19 contributes to oxidative damage repair in the early age-related cataract by regulating miR-29a/TDG axis. Journal of cellular and molecular medicine 47 31282110
2020 LINC00467 is up-regulated by TDG-mediated acetylation in non-small cell lung cancer and promotes tumor progression. Oncogene 41 32796958
2016 Dioxin induces Ahr-dependent robust DNA demethylation of the Cyp1a1 promoter via Tdg in the mouse liver. Scientific reports 41 27713569
2005 T:G mismatch-specific thymine-DNA glycosylase (TDG) as a coregulator of transcription interacts with SRC1 family members through a novel tyrosine repeat motif. Nucleic acids research 37 16282588
2017 TET2- and TDG-mediated changes are required for the acquisition of distinct histone modifications in divergent terminal differentiation of myeloid cells. Nucleic acids research 34 28973458
2012 Unique mutational profile associated with a loss of TDG expression in the rectal cancer of a patient with a constitutional PMS2 deficiency. DNA repair 34 22608206
2020 The HOTAIRM1/miR-107/TDG axis regulates papillary thyroid cancer cell proliferation and invasion. Cell death & disease 30 32269214
2017 Nei-like 1 (NEIL1) excises 5-carboxylcytosine directly and stimulates TDG-mediated 5-formyl and 5-carboxylcytosine excision. Scientific reports 30 28827588
2012 Selective DNA demethylation by fusion of TDG with a sequence-specific DNA-binding domain. Epigenetics 30 22419066
2020 Insulin and Metformin Control Cell Proliferation by Regulating TDG-Mediated DNA Demethylation in Liver and Breast Cancer Cells. Molecular therapy oncolytics 29 32728616
2021 TET-TDG Active DNA Demethylation at CpG and Non-CpG Sites. Journal of molecular biology 28 33561435
2023 TET1 and TDG Suppress Inflammatory Response in Intestinal Tumorigenesis: Implications for Colorectal Tumors With the CpG Island Methylator Phenotype. Gastroenterology 26 36764492
2018 Genome-wide analysis reveals a role for TDG in estrogen receptor-mediated enhancer RNA transcription and 3-dimensional reorganization. Epigenetics & chromatin 25 29378668
2012 Transcriptional regulation of thymine DNA glycosylase (TDG) by the tumor suppressor protein p53. Cell cycle (Georgetown, Tex.) 23 23165212
2019 Chromatin Structure and the Pioneering Transcription Factor FOXA1 Regulate TDG-Mediated Removal of 5-Formylcytosine from DNA. Journal of the American Chemical Society 22 31460763
2014 A TDG/CBP/RARα ternary complex mediates the retinoic acid-dependent expression of DNA methylation-sensitive genes. Genomics, proteomics & bioinformatics 22 24394593
2021 TDG is a pig-specific epigenetic regulator with insensitivity to H3K9 and H3K27 demethylation in nuclear transfer embryos. Stem cell reports 18 34678203
2018 Uncovering universal rules governing the selectivity of the archetypal DNA glycosylase TDG. Proceedings of the National Academy of Sciences of the United States of America 18 29784784
2017 Thymine DNA Glycosylase (TDG) is involved in the pathogenesis of intestinal tumors with reduced APC expression. Oncotarget 18 29163805
2016 miR-29b Targets LPL and TDG Genes and Regulates Apoptosis and Triglyceride Production in MECs. DNA and cell biology 17 27854545
1999 Genomic analysis of the thymine-DNA glycosylase (TDG) gene on 12q22-q24.1 in human pancreatic ductal adenocarcinoma. International journal of pancreatology : official journal of the International Association of Pancreatology 15 10360221
1997 Chromosomal localizations and molecular analysis of TDG gene-related sequences. Genomics 15 9299239
2022 TDG suppresses the migration and invasion of human colon cancer cells via the DNMT3A/TIMP2 axis. International journal of biological sciences 11 35414793
2014 Human DNA glycosylase enzyme TDG repairs thymine mispaired with exocyclic etheno-DNA adducts. Free radical biology & medicine 11 25151120
2020 p53 and TDG are dominant in regulating the activity of the human de novo DNA methyltransferase DNMT3A on nucleosomes. The Journal of biological chemistry 10 33172892
2019 TDG Gene Polymorphisms and Their Possible Association with Colorectal Cancer: A Case Control Study. Journal of oncology 9 31239841
2014 SUMO-modification and elimination of the active DNA demethylation enzyme TDG in cultured human cells. Biochemical and biophysical research communications 9 24727457
2024 TNC upregulation promotes glioma tumourigenesis through TDG-mediated active DNA demethylation. Cell death discovery 6 39090080
2023 Nucleus-localized circSLC39A5 suppresses hepatocellular carcinoma development by binding to STAT1 to regulate TDG transcription. Cancer science 6 37549641
2020 Inducible TDG knockout models to study epigenetic regulation. F1000Research 6 33082936
2015 Oncogenic Ras suppresses ING4-TDG-Fas axis to promote apoptosis resistance. Oncotarget 6 26544625
2014 Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG. Biophysics (Nagoya-shi, Japan) 6 27493500
2020 HMGB1 Recruits TET2/AID/TDG to Induce DNA Demethylation in STAT3 Promoter in CD4+ T Cells from aGVHD Patients. Journal of immunology research 4 33029541
2025 The TET-TDG axis in T cells and biological processes. International immunology 3 39921704
2025 The TDG protein environment connects active DNA demethylation with chromatin and RNA biology. Cellular and molecular life sciences : CMLS 2 41291101
2020 TDG is a novel tumor suppressor of liver malignancies. Molecular & cellular oncology 2 32944627
2023 Comparative transcriptome analysis provides insights into the TDG supersaturation stress response of Schizothorax davidi. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 1 37004899
2026 TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell fate acquisition. Nucleic acids research 0 41773019

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