Affinage

TDP2

Tyrosyl-DNA phosphodiesterase 2 · UniProt O95551

Length
362 aa
Mass
40.9 kDa
Annotated
2026-06-10
71 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TDP2 (TTRAP/EAPII) is the major vertebrate 5'-tyrosyl-DNA phosphodiesterase, hydrolyzing the covalent phosphotyrosyl bond that links trapped topoisomerase II to double-strand break ends and thereby enabling error-free repair (PMID:21030584, PMID:22822062). Originally identified as a TRAF-interacting protein that restrains NF-κB activation upstream of NIK/IKKα and modulates TGF-β/Nodal-Smad3 signaling (PMID:10764746, PMID:18039968, PMID:21980489), TDP2 was subsequently established biochemically as a Mg²⁺/Mn²⁺-dependent phosphodiesterase of the APE1-related superfamily whose activity depends on a defined active-site (Asn120, Glu152, Asp262, His351) operating through a single-Mg²⁺ mechanism assisted by a phosphotyrosyl-arginine cation-π interface, acting preferentially on single-stranded 5'-phosphotyrosyl termini (PMID:22822062, PMID:27060144). Crystallographic work defined a deep basic substrate trench with a dynamic lid that selectively accommodates stretched 5'-DNA ends and can also bind RNA in a strained conformation (PMID:23104058, PMID:24808172, PMID:27060144). TDP2 acts within NHEJ to liberate ligatable 5'-phosphotyrosyl DSB termini, but only after the trapped TOP2 is first proteolytically processed, since TDP2 cannot act on intact TOP2-DNA complexes (PMID:23505375, PMID:30011940). Its catalytic activity is allosterically controlled: K63/K27-polyubiquitin chains bind its N-terminal UBA domain to relieve an autoinhibitory state and stimulate phosphodiesterase activity, and ERK3 phosphorylates TDP2 at Ser60 to regulate activity (PMID:27543075, PMID:32356875, PMID:26701725). TDP2 is required for TOP2-dependent gene transcription and for normal neuronal gene expression and interneuron density, and biallelic loss-of-function mutations cause spinocerebellar ataxia (SCAR23) (PMID:24658003). Beyond TOP2, TDP2 contributes to repair of TOP1-mediated and 3'-blocking lesions in the absence of TDP1 (PMID:22740648, PMID:32460231, PMID:37392847), suppresses TOP2-induced and androgen-induced chromosomal breaks and translocations (PMID:28794467, PMID:32277721), functions in mitochondria via a short mitochondrial-targeted isoform (TDP2S) to protect mtDNA (PMID:29438979), and is hijacked by viruses, serving as the VPg unlinkase required for picornavirus replication and as a host factor in HBV cccDNA biogenesis (PMID:32023921, PMID:25201958).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2000 Medium

    Before any catalytic role was known, TDP2 was placed in receptor signaling, answering whether it had a defined cellular function by linking it to TRAF-dependent NF-κB control.

    Evidence Yeast two-hybrid, Co-IP, and reporter assays mapping TRAF binding and NF-κB inhibition upstream of NIK/IKKα

    PMID:10764746

    Open questions at the time
    • No biochemical activity assigned
    • Mechanism of NF-κB inhibition not resolved at the molecular level
  2. 2001 Low

    A bioinformatic prediction first hinted that TDP2 was an enzyme, classifying it within the Mg²⁺/Mn²⁺-dependent phosphodiesterase superfamily related to APE1.

    Evidence Sequence alignment and computational structure prediction

    PMID:11478795

    Open questions at the time
    • Computational only; no experimental enzymatic validation
    • No substrate identified
  3. 2007 Medium

    Loss-of-function in vivo connected TDP2 to developmental signaling, showing it negatively modulates Nodal/Smad3 signaling.

    Evidence Co-IP of Alk4/Smad3 plus morpholino knockdown with transcriptional and morphogenetic phenotypes in zebrafish

    PMID:18039968

    Open questions at the time
    • Direct enzymatic versus scaffolding contribution unresolved
    • Mammalian relevance not established
  4. 2008 Low

    Interaction screens placed TDP2 in PML nuclear bodies and linked it to Parkinson-associated DJ-1, raising a cytoprotective and stress-response role.

    Evidence Y2H, Co-IP, co-localization with PML/DAXX/Sp100, fractionation, and apoptosis assays

    PMID:18706885 PMID:19023331

    Open questions at the time
    • Single-lab co-localization without functional dissection (PML body study)
    • Mechanism linking DJ-1 mutants to TDP2 protective activity unclear
  5. 2009 Medium

    TDP2 was implicated as a host factor for HIV-1 integration, an early hint of viral exploitation predating mechanistic understanding.

    Evidence Y2H, Co-IP, GST-pulldown with HIV-1 integrase plus knockdown/overexpression integration assays

    PMID:19580783

    Open questions at the time
    • Whether catalytic activity is required not tested
    • Direct versus indirect effect on integration unresolved
  6. 2010 High

    Genetic deletion established TDP2 as the dominant cellular 5'-tyrosyl-DNA phosphodiesterase and pinned its function to TOP2-poison resistance.

    Evidence DT40 gene deletion with etoposide/camptothecin/MMS survival and biochemical 5'-TDP activity assays

    PMID:21030584

    Open questions at the time
    • Catalytic residues and structural basis not yet defined
    • Pathway placement within NHEJ not established
  7. 2012 High

    Reconstitution and crystallography defined the catalytic machinery and substrate selectivity, converting the bioinformatic prediction into a validated enzyme mechanism.

    Evidence Recombinant enzyme kinetics with active-site mutagenesis (Asn120/Glu152/Asp262/His351) plus zebrafish and C. elegans crystal structures bound to DNA/peptide

    PMID:22822062 PMID:23104058

    Open questions at the time
    • Metal stoichiometry debated (two-metal vs single-metal)
    • Regulation in cells not addressed
  8. 2012 High

    Genetic epistasis revealed a backup role beyond TOP2, showing TDP2 also processes TOP1-mediated breaks when TDP1 is absent.

    Evidence Single/double/rescue deletions in DT40 and MEFs plus in vivo mouse Top1-poison sensitivity

    PMID:22740648

    Open questions at the time
    • Relative physiological contribution to TOP1 repair unclear
    • Mechanism of 3'-lesion processing not yet biochemically defined
  9. 2013 High

    Cell and mouse studies placed TDP2 functionally within NHEJ, demonstrating it generates ligatable termini and protects against TOP2-induced genome instability in vivo.

    Evidence TDP2 KO DT40 cells and mice with NHEJ end-ligation, γ-H2AX, chromosome instability, and etoposide challenge

    PMID:23505375

    Open questions at the time
    • Requirement for prior TOP2 processing not yet shown
    • Identity of upstream proteolytic factors unknown
  10. 2014 High

    Human genetics defined a disease role and a transcription function, showing TDP2 loss causes ataxia and is required for TOP2-dependent gene transcription in neurons.

    Evidence Homozygous patient mutations, patient-cell hypersensitivity, TOP2-dependent transcription assays, and mouse cerebellar gene-expression/interneuron analysis

    PMID:24658003

    Open questions at the time
    • Molecular link between repair defect and transcriptional loss incomplete
    • Neuron-specific vulnerability mechanism unclear
  11. 2014 High

    Structural and biochemical work showed TDP2 acts only after TOP2 processing and broadened its substrate scope to ribonucleotide-linked tyrosyl adducts.

    Evidence In vitro cleavage of suicidal substrates plus 1.6-Å crystal structure of a TDP2-RNA complex

    PMID:24808172

    Open questions at the time
    • Identity of in vivo processing protease not defined
    • Physiological role of RNA-adduct cleavage unclear
  12. 2014 High

    TDP2 was identified as a host factor for HBV cccDNA formation, generalizing its tyrosyl-phosphodiesterase activity to viral protein-DNA linkages.

    Evidence In vitro cleavage of HBV/DHBV RC-DNA substrates plus RNAi knockdown and rescue with cccDNA Southern quantification

    PMID:25201958

    Open questions at the time
    • Whether TDP2 acts on RC-DNA in vivo without proteolysis not fully resolved
    • Contribution relative to other host factors unquantified
  13. 2016 High

    Discovery of UBA-domain ubiquitin binding and ERK3 phosphorylation revealed how TDP2 activity and recruitment are regulated.

    Evidence Crystal structure of UBA-monoUb, ITC, and mutagenesis with repair readout; separate in vitro kinase mapping of S60 with activity and survival assays

    PMID:26701725 PMID:27543075

    Open questions at the time
    • Physiological ubiquitin ligase/source of polyUb not identified
    • ERK3-TDP2 regulation single-lab (Medium)
  14. 2016 High

    Higher-resolution structures with damaged DNA refined the catalytic model to a single-Mg²  mechanism with a cation-π interface, and tied a human SNP to enzymatic and repair failure.

    Evidence X-ray structures of ligand-free and DNA-bound TDP2, active-site mutagenesis, NHEJ end-joining, and survival assays

    PMID:27060144

    Open questions at the time
    • Population frequency and clinical impact of catalytic SNPs unaddressed
  15. 2017 High

    TDP2 was shown to suppress TOP2-induced chromosomal translocations while paradoxically contributing to a rare leukemogenic translocation subclass through its NHEJ activity.

    Evidence ChIP at TOP2/MLL sites, translocation frequency, and junction sequencing in TDP2-proficient/-deficient cells

    PMID:28794467

    Open questions at the time
    • Determinants directing protective versus mutagenic outcomes unclear
  16. 2018 High

    Identification of the mitochondrial TDP2S isoform extended TDP2's repair role to mtDNA, answering where TDP2 acts outside the nucleus.

    Evidence TSS mapping, fractionation, import assays, KO/rescue, mtDNA quantification, and mitochondrial transcription assays

    PMID:29438979

    Open questions at the time
    • Mitochondrial topoisomerase substrate not directly defined
    • Regulation of isoform choice unknown
  17. 2018 Medium

    A negative-result study established the order of events, demonstrating TDP2 requires prior proteasomal processing of TOP2-DNA complexes before it can act.

    Evidence In vitro cleavage of genomic DNA and TARDIS-based TOP2-DNA complex quantification under TDP2 knockdown and proteasome inhibition

    PMID:30011940

    Open questions at the time
    • Identity and regulation of upstream proteases not resolved
    • Single-lab cellular assay
  18. 2019 Medium

    An ortholog study uncovered a non-canonical activity, showing TDP2/TDPT-1 promotes SUMOylation of an ETS transcription factor to restrain axon regeneration.

    Evidence C. elegans genetic epistasis, Co-IP, and SUMOylation assays

    PMID:31393064

    Open questions at the time
    • Whether mammalian TDP2 has analogous SUMO-related activity untested
    • Mechanism by which TDP2 promotes SUMOylation unclear
  19. 2020 High

    Structural and biochemical work defined an allosteric switch, showing K63-polyubiquitin binding to the UBA domain relieves TDP2 autoinhibition and stimulates catalysis.

    Evidence Co-purification of polyubiquitinated proteins, in vitro stimulation assays, and crystal/SAXS structures of TDP2-Ub3 complexes

    PMID:32356875

    Open questions at the time
    • In vivo trigger and ligase generating the activating chains unidentified
  20. 2020 Medium

    Functional studies extended TDP2's repair scope to 3'-blocking lesions and chain-terminating nucleoside analogs, and demonstrated catalytic requirement for picornavirus replication and androgen-damage suppression.

    Evidence TDP1/TDP2 KO TK6 survival and TOP1cc kinetics; catalytic-mutant rescue of poliovirus/CVB3 in RPE-1 KO; KO cell/mouse androgen-induced break assays

    PMID:32023921 PMID:32277721 PMID:32460231

    Open questions at the time
    • Mechanistic basis of 3'-lesion versus 5'-lesion specificity not fully resolved
    • Each result single-lab
  21. 2023 Medium

    Biochemical dissection confirmed a unified Mg²⁺-dependent mechanism for TDP2 across TOP1- and TOP2-induced and 3'-blocking lesions.

    Evidence In vitro phosphodiesterase assays with metal chelation and Mg²⁺-site mutagenesis plus survival in TDP1/TDP2 KO TK6 cells

    PMID:37392847

    Open questions at the time
    • No structural validation of 3'-lesion engagement
    • Single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The in vivo signals and enzymes that govern TDP2 recruitment and activation remain undefined: the proteases that process trapped TOP2, the ligases generating activating polyubiquitin chains, and how its repair, transcription, signaling, and viral roles are coordinated are unresolved.
  • Upstream protease for TOP2cc processing unidentified
  • Physiological ubiquitin source for UBA activation unknown
  • Integration of catalytic and signaling/scaffolding functions unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 6 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 3 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 2 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-73894 DNA Repair 6 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
DJ-1 (PARK7)ERK3PMLSMAD3TRAF6

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TTRAP (TDP2) associates with CD40 cytoplasmic domain, TNF-R75, CD30, and TNF receptor-associated factors (TRAFs), with highest affinity for TRAF6; it inhibits NF-κB transcriptional activation downstream of CD40, TNF-R75, and PMA, but not downstream of NIK, IKKα, or P65/RelA, placing it upstream of these kinases Yeast two-hybrid, co-immunoprecipitation, dose-dependent reporter assay in transfected cells The Journal of biological chemistry Medium 10764746
2001 Bioinformatic sequence and structure analysis identified TTRAP (TDP2) as a member of the Mg²⁺/Mn²⁺-dependent phosphodiesterase superfamily related to the human APE1 endonuclease Sequence alignment and computational structure prediction Biochemical and biophysical research communications Low 11478795
2007 Ttrap (TDP2) interacts with Alk4 and Smad3 receptors; morpholino knockdown in zebrafish increases Smad3 activity, causing ectopic snail1a expression and apparent repression of e-cadherin, perturbing convergent extension, epiboly and node formation, identifying Ttrap as a negative modulator of Nodal/Smad3 signaling Co-immunoprecipitation (Alk4/Smad3 interaction), morpholino knockdown in zebrafish, in situ hybridization, RT-PCR for target genes Development (Cambridge, England) Medium 18039968
2008 TTRAP (TDP2) is a PML nuclear body-associated protein that co-localizes with PML, DAXX, and Sp100; it interacts with these proteins in yeast mating assays and its expression is induced by IFN-γ Co-localization imaging, yeast mating assay, RT-PCR/Western blot for IFN-γ induction Biochemical and biophysical research communications Low 18706885
2008 TTRAP (TDP2) interacts with PD-associated DJ-1 mutants M26I and L166P more strongly than wild-type DJ-1; upon proteasome impairment TTRAP relocalizes to a detergent-insoluble fraction and forms cytoplasmic aggresome-like structures; DJ-1 mutants block TTRAP's protective activity, unmasking JNK- and p38-MAPK-mediated apoptosis Yeast two-hybrid screen, co-immunoprecipitation, subcellular fractionation, fluorescence imaging, caspase/apoptosis assays Cell death and differentiation Medium 19023331
2009 TTRAP (TDP2) interacts with HIV-1 integrase via its N-terminal 180 residues; stable TTRAP knockdown decreases lentiviral integration, while TTRAP overexpression increases it, demonstrating a facilitating role in HIV-1 integration Yeast two-hybrid, co-immunoprecipitation, GST pulldown, intracellular co-localization, stable knockdown and overexpression integration assays Biochemical and biophysical research communications Medium 19580783
2010 TDP2/TTRAP is the major (if not the only) 5'-tyrosyl DNA phosphodiesterase activity in vertebrate cells; TDP2-deleted DT40 cells are highly sensitive to etoposide (Top2 poison) but not to camptothecin (Top1 poison) or MMS Gene deletion in DT40 cells, cell survival assays, biochemical 5'-TDP activity assays in cell extracts The Journal of biological chemistry High 21030584
2011 TTRAP (TDP2) accumulates in nucleolar cavities upon proteasome inhibition in a PML-dependent manner; within the nucleolus, TTRAP controls levels of ribosomal RNA precursor and processing intermediates through a mechanism independent of its 5'-tyrosyl DNA phosphodiesterase activity Fluorescence microscopy, RNA analysis, proteasome inhibitor treatment, PML knockdown, TDP2 catalytic mutant complementation Cell death and differentiation Medium 21921940
2011 TTRAP (TDP2) associates with TGF-β receptors and components of the TRAF6-TAK1 signaling module; modulation of TTRAP levels differentially regulates TGF-β-activated p38 and NF-κB responses, and affects cell viability in the presence of TGF-β Co-immunoprecipitation, TTRAP knockdown/overexpression, reporter assays, cell viability assays PloS one Medium 21980489
2012 Crystal structure of zebrafish TDP2 bound to DNA reveals a deep, narrow basic groove that selectively accommodates the 5' end of single-stranded DNA in a stretched conformation; C. elegans TDP2 structure shows this groove can also accommodate an acidic peptide in vitro, suggesting molecular mimicry as a potential autoregulation and signaling mechanism X-ray crystallography, in vitro binding assays Nature structural & molecular biology High 23104058
2012 Human TDP2 is a Mg²⁺/Mn²⁺-dependent phosphodiesterase; preferred substrate is single-stranded or 4-bp overhang duplex DNA bearing a 5'-phosphotyrosyl bond; kcat/Km is ~4×10⁵ s⁻¹M⁻¹; catalytic residues Asn-120, Glu-152, Asp-262, and His-351 are essential for activity; a two-metal mechanism is proposed In vitro enzyme assays with recombinant TDP2, site-directed mutagenesis of active-site residues, metal titration, kinetic parameter determination The Journal of biological chemistry High 22822062
2012 TDP2 promotes repair of Top1-mediated DNA breaks in the absence of TDP1; double deletion of Tdp1 and Tdp2 reduces strand break repair and cell survival below Tdp1-/- alone; TDP2 overexpression in Tdp1-/-/Tdp2-/-/- cells partially rescues the Tdp1-/- defect; Tdp1/Tdp2 double KO mice are more sensitive to Top1 poisons than Tdp1 KO alone Gene deletion in DT40 cells and mouse embryonic fibroblasts, DNA strand break repair assays, cell survival assays, mouse in vivo sensitivity experiments Nucleic acids research High 22740648
2012 DJ-1 L166P mutation alters rRNA biogenesis by sequestering TTRAP (TDP2) from the nucleolus into cytoplasmic aggregates via a TRAF6-dependent mechanism; TTRAP is found associated with nucleolus and Lewy bodies in post-mortem sporadic PD brain Subcellular fractionation, fluorescence imaging, RNA analysis, TRAF6 inhibition, immunohistochemistry of PD brain tissue PloS one Medium 22532838
2013 TDP2 functions in NHEJ to liberate 5'-phosphotyrosyl DSB termini competent for ligation; Tdp2-deleted mice are sensitive to TOP2-induced damage with lymphoid toxicity, intestinal damage, and increased bone marrow genome instability TDP2 KO DT40 cells and mice, NHEJ end-ligation assays, γ-H2AX foci, chromosome instability assays, in vivo etoposide treatment PLoS genetics High 23505375
2014 TDP2 is required for TOP2-dependent gene transcription in human cells and mouse post-mitotic neurons; loss of TDP2 inhibits transcription following abortive TOP2 activity, and TDP2 is required for normal levels of many neuronal gene transcripts and normal interneuron density in mouse cerebellum Homozygous TDP2 mutations identified in patients; patient cell hypersensitivity assays; TOP2-dependent transcription assays in cultured cells and mouse neurons; gene expression analysis in developing mouse brain; immunohistochemistry for interneuron density Nature genetics High 24658003
2014 TDP2 requires prior proteolytic processing or denaturation of irreversible Top2 cleavage complexes before it can act; TDP2 is most efficient on single-stranded DNA substrates; TDP2 can remove tyrosine linked to a single misincorporated ribonucleotide or to polyribonucleotides; crystal structure at 1.6-Å defines how RNA is accommodated in the TDP2 active site in a strained conformation In vitro TDP2 cleavage assays with suicidal substrates, X-ray crystallography at 1.6 Å of TDP2–RNA substrate complex The Journal of biological chemistry High 24808172
2014 Human and chicken TDP2 (but not human TDP1) can specifically cleave the Tyr-DNA bond in HBV and DHBV RC-DNA substrates and release viral P protein in vitro without prior proteolysis; RNAi-mediated TDP2 depletion in human cells slows conversion of RC-DNA to cccDNA, and ectopic TDP2 expression restores faster conversion, establishing TDP2 as a host factor in HBV cccDNA biogenesis In vitro cleavage assays with virus-adapted substrates, RNAi knockdown, ectopic expression, Southern blot quantification of cccDNA Proceedings of the National Academy of Sciences of the United States of America High 25201958
2016 ERK3 (an atypical MAPK) phosphorylates TDP2 at serine 60 and regulates its 5'-phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against TOP2 inhibitor-induced DNA damage and growth inhibition In vitro kinase assay, phosphorylation site mapping (S60), phosphodiesterase activity assays, cell survival assays with TOP2 inhibitors Oncotarget Medium 26701725
2016 X-ray crystal structures of ligand-free Tdp2 and Tdp2-DNA complexes with alkylated and abasic DNA reveal a dynamic active site lid and deep substrate binding trench; mutagenesis and biochemical studies support a single Mg²⁺-ion mechanism assisted by a phosphotyrosyl-arginine cation-π interface; a Tdp2 active site SNP ablates Mg²⁺ binding and catalytic activity, impairs NHEJ of tyrosine-blocked termini, and renders cells etoposide-sensitive X-ray crystallography, active-site mutagenesis, biochemical phosphodiesterase assays, NHEJ end-joining assay, cell survival assay Nucleic acids research High 27060144
2016 TDP2 N-terminal region contains a ubiquitin-associated (UBA) domain that binds multiple ubiquitin forms, preferring K48- or K63-linked polyUbs over monoUb; crystal structure of TDP2 UBA bound to monoUb reveals a canonical UBA-Ub interaction lacking the conserved MGF motif; mutations in the UBA-Ub binding interface do not affect nuclear import of TDP2 but severely compromise repair of Top2-mediated DNA damage X-ray crystallography of UBA-Ub complex, isothermal titration calorimetry, mutagenesis, nuclear import assays, DNA damage repair assays Nucleic acids research High 27543075
2017 TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity at the MLL translocation hotspot; TDP2 suppresses TOP2-induced chromosome rearrangements; however, TDP2-dependent NHEJ contributes to a rare subclass of translocations with 4-bp perfect homology junctions associated with therapy-related leukemia ChIP for TDP2 at TOP2 sites/MLL locus, chromosome translocation assays, NHEJ junction sequencing in TDP2-proficient and -deficient breast cancer cells Nature communications High 28794467
2018 TDP2 does not remove intact TOP2-DNA complexes from genomic DNA in vitro and TDP2 depletion in cells does not slow removal of TOP2-DNA complexes by itself, indicating that prior processing steps (proteasomal degradation) are required before TDP2 can act on the remaining 5'-tyrosine adduct; SUMOylated TOP2-DNA complex levels and DSB levels are unaffected by TDP2 knockdown in K562 cells after etoposide and proteasome inhibition In vitro TDP2 cleavage assays on genomic DNA, TARDIS assay for TOP2-DNA complexes in cells, TDP2 knockdown, SUMOylated TOP2 TARDIS assay International journal of molecular sciences Medium 30011940
2018 TDP2 exists as two isoforms: full-length TDP2 with a nuclear localization signal and UBA domain (N-terminus), and a short isoform TDP2S that contains a mitochondrial targeting sequence and localizes to mitochondria and cytosol; both isoforms are active in mitochondria; TDP2 KO cells are hypersensitive to mitochondrial-targeted doxorubicin and show selective mitochondrial DNA depletion; TDP2S alone can protect against mitochondrial doxorubicin; loss of TDP2 reduces mitochondrial transcription levels Alternative TSS mapping, subcellular fractionation, mitochondrial import assays, TDP2 KO and rescue experiments, cell survival assays, mtDNA quantification, mitochondrial transcription assays, CRISPR engineering EMBO reports High 29438979
2019 C. elegans TDP2 ortholog TDPT-1 induces SUMOylation of the ETS transcription factor ETS-4, inhibiting ETS-4 transcriptional activity and negatively regulating axon regeneration; MXL-1 (Max-like transcription factor) binds and inhibits TDPT-1, counteracting ETS-4 SUMOylation; tdpt-1 deletion suppresses mxl-1 but not ets-4 axon regeneration defects Genetic epistasis (deletion analysis in C. elegans), co-immunoprecipitation, SUMOylation assays, axon regeneration assays EMBO reports Medium 31393064
2020 TDP2 co-purifies with K63- and K27-poly-ubiquitinated cellular proteins; poly-ubiquitin chains of ≥Ub3 stimulate TDP2 catalytic activity in nuclear extracts and enhance TDP2 binding of DNA-protein crosslinks in vitro; crystal structures and SAXS of TDP2-Ub complexes show the TDP2 UBA domain binds K63-Ub3 in a 1:1 complex that relieves an autoinhibitory state; TDP2 SNPs can disrupt the TDP2-Ubiquitin interface Affinity purification/co-purification, in vitro phosphodiesterase stimulation assays with nuclear extracts, X-ray crystallography, small-angle X-ray scattering (SAXS), SNP analysis Nucleic acids research High 32356875
2020 TDP2 promotes the second step (peptide removal) of TOP1cc repair in the absence of TDP1; TDP1-/-TDP2-/- cells are more sensitive than TDP1-/- or TDP2-/- cells to agents producing 3'-blocking lesions (AZT, cytarabine, abacavir, gemcitabine, trifluridine), confirming TDP2's role in repairing 3'-blocking lesions Antibody-based TOP1cc repair kinetics assay, TDP1 and TDP2 single/double KO TK6 cells, cell survival assays DNA repair Medium 32460231
2020 Catalytically inactive TDP2 does not rescue the picornavirus (poliovirus/CVB3) growth defect in TDP2 KO human RPE-1 cells, confirming that TDP2 5'-phosphodiesterase (VPg unlinkase) activity is required for efficient enterovirus replication; VPg removal is required for steps downstream of translation, including negative- and positive-strand RNA synthesis CRISPR/Cas9 TDP2 KO, catalytic mutant complementation, virus growth kinetics, viral protein and RNA assays, polysome assembly, dsRNA detection Viruses Medium 32023921
2020 TDP2 suppresses androgen-induced DNA double-strand breaks in human prostate cancer cells during G1 phase; loss of TDP2 causes five times more androgen-induced chromosome breaks in mitotic spreads; TDP2-deficient mice accumulate DSBs in prostate epithelial cells after androgen injection, demonstrating a physiological role for TDP2 in repairing stalled TOP2ccs induced by androgens γ-H2AX foci, chromosome break assays in mitotic spreads, TDP2 KO cells and mice, in vivo androgen injection Genes to cells Medium 32277721
2023 TDP2 repairs TOP1-induced 3'-blocking lesions via a Mg²⁺-dependent catalytic mechanism similar to TOP2-damage repair; Mg²⁺-TDP2 binding is required for repair of both TOP1- and TOP2-induced DNA damage, as well as for repair of incorporated chain-terminating nucleoside analogs at 3' ends In vitro phosphodiesterase assays with metal chelation, mutagenesis of Mg²⁺ binding residues, cell survival assays in TDP1/TDP2 KO TK6 cells The Journal of biological chemistry Medium 37392847

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2). DNA repair 271 24856239
2014 Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses. Proceedings of the National Academy of Sciences of the United States of America 190 25201958
2013 TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. PLoS genetics 132 23505375
2010 TDP2/TTRAP is the major 5'-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage. The Journal of biological chemistry 127 21030584
2012 Genetic variants of FOXP2 and KIAA0319/TTRAP/THEM2 locus are associated with altered brain activation in distinct language-related regions. The Journal of neuroscience : the official journal of the Society for Neuroscience 126 22262880
2014 TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nature genetics 118 24658003
2000 TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation. The Journal of biological chemistry 117 10764746
2014 Proteolytic degradation of topoisomerase II (Top2) enables the processing of Top2·DNA and Top2·RNA covalent complexes by tyrosyl-DNA-phosphodiesterase 2 (TDP2). The Journal of biological chemistry 101 24808172
2012 TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1. Nucleic acids research 95 22740648
2007 A haplotype spanning KIAA0319 and TTRAP is associated with normal variation in reading and spelling ability. Biological psychiatry 74 17597587
2012 Structural basis for recognition of 5'-phosphotyrosine adducts by Tdp2. Nature structural & molecular biology 57 23104058
2012 Biochemical characterization of human tyrosyl-DNA phosphodiesterase 2 (TDP2/TTRAP): a Mg(2+)/Mn(2+)-dependent phosphodiesterase specific for the repair of topoisomerase cleavage complexes. The Journal of biological chemistry 55 22822062
2017 TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription. Nature communications 50 28794467
2008 Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations. Cell death and differentiation 48 19023331
2012 Parkinson's disease DJ-1 L166P alters rRNA biogenesis by exclusion of TTRAP from the nucleolus and sequestration into cytoplasmic aggregates via TRAF6. PloS one 45 22532838
2017 Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl-DNA Phosphodiesterase 2 (Tdp2). Journal of medicinal chemistry 41 28418653
2007 Ttrap is an essential modulator of Smad3-dependent Nodal signaling during zebrafish gastrulation and left-right axis determination. Development (Cambridge, England) 38 18039968
2016 Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2). Journal of medicinal chemistry 35 26910725
2016 Reversal of DNA damage induced Topoisomerase 2 DNA-protein crosslinks by Tdp2. Nucleic acids research 34 27060144
2018 Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23). Neurology. Genetics 33 30109272
2016 ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells. Oncotarget 31 26701725
2020 Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase 1 DNA-protein crosslinks and 3'-blocking lesions in the absence of tyrosyl-DNA phosphodiesterase 1 (TDP1). DNA repair 29 32460231
2016 Deazaflavin Inhibitors of Tyrosyl-DNA Phosphodiesterase 2 (TDP2) Specific for the Human Enzyme and Active against Cellular TDP2. ACS chemical biology 26 27128689
2011 Pleiotropic functions of EAPII/TTRAP/TDP2: cancer development, chemoresistance and beyond. Cell cycle (Georgetown, Tex.) 26 21926483
2001 Sequence analysis identifies TTRAP, a protein that associates with CD40 and TNF receptor-associated factors, as a member of a superfamily of divalent cation-dependent phosphodiesterases. Biochemical and biophysical research communications 26 11478795
2018 Effect of TDP2 on the Level of TOP2-DNA Complexes and SUMOylated TOP2-DNA Complexes. International journal of molecular sciences 23 30011940
2011 The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition. Cell death and differentiation 23 21921940
2016 Novel TDP2-ubiquitin interactions and their importance for the repair of topoisomerase II-mediated DNA damage. Nucleic acids research 22 27543075
2018 Mitochondrial tyrosyl-DNA phosphodiesterase 2 and its TDP2S short isoform. EMBO reports 20 29438979
2017 TDP2, TOP2, and SUMO: what is ZATT about? Cell research 20 29160298
2009 Cellular protein TTRAP interacts with HIV-1 integrase to facilitate viral integration. Biochemical and biophysical research communications 19 19580783
2021 New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1. International journal of molecular sciences 18 34768766
2022 Post-translational regulation of Tyrosyl-DNA phosphodiesterase (TDP1 and TDP2) for the repair of the trapped topoisomerase-DNA covalent complex. DNA repair 17 35101776
2020 Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2. Nucleic acids research 15 32356875
2011 A TRAF and TNF receptor-associated protein (TTRAP) in mollusk with endonuclease activity. Developmental and comparative immunology 15 21440568
2019 Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide. Journal of medicinal chemistry 14 30998359
2008 TTRAP is a novel PML nuclear bodies-associated protein. Biochemical and biophysical research communications 14 18706885
2019 Consolidating the Role of TDP2 Mutations in Recessive Spinocerebellar Ataxia Associated with Pediatric Onset Drug Resistant Epilepsy and Intellectual Disability (SCAR23). Cerebellum (London, England) 13 31410782
2019 Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors. DNA repair 13 31775111
2018 Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2). European journal of medicinal chemistry 12 29677635
2018 Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors. Bioorganic & medicinal chemistry letters 12 30522956
2013 Overexpression of TTRAP inhibits cell growth and induces apoptosis in osteosarcoma cells. BMB reports 12 23433115
2011 TTRAP is a novel component of the non-canonical TRAF6-TAK1 TGF-β signaling pathway. PloS one 12 21980489
2009 PhiC31 integrase interacts with TTRAP and inhibits NFkappaB activation. Molecular biology reports 12 19757154
2023 Repair of topoisomerase 1-induced DNA damage by tyrosyl-DNA phosphodiesterase 2 (TDP2) is dependent on its magnesium binding. The Journal of biological chemistry 11 37392847
2018 New fluorescence-based high-throughput screening assay for small molecule inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2). European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 11 29574079
2020 Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23). Journal of human genetics 9 32651480
2021 A novel non-sense mutation in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by bilateral upward gaze; report of a case and review of the literature. European journal of medical genetics 8 34606976
2020 Effects of TDP2/VPg Unlinkase Activity on Picornavirus Infections Downstream of Virus Translation. Viruses 8 32023921
2023 Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia. Human genetics 7 37558815
2020 TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands. Genes to cells : devoted to molecular & cellular mechanisms 7 32277721
2020 4-Benzylideneisoquinoline-1,3(2H,4H)-diones as tyrosyl DNA phosphodiesterase 2 (TDP2) inhibitors. Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents 6 33776385
2019 TDP2 negatively regulates axon regeneration by inducing SUMOylation of an Ets transcription factor. EMBO reports 6 31393064
2023 Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway. International journal of molecular sciences 5 37047518
2021 The synthesis of furoquinolinedione and isoxazoloquinolinedione derivatives as selective Tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors. Bioorganic chemistry 5 33839584
2019 Deazaflavin Inhibitors of TDP2 with Cellular Activity Can Affect Etoposide Influx and/or Efflux. ACS chemical biology 5 31091068
2018 VPg unlinkase/TDP2 in cardiovirus infected cells: Re-localization and proteolytic cleavage. Virology 5 29353210
2015 TTRAP is a critical factor in grouper immune response to virus infection. Fish & shellfish immunology 5 26172204
1992 Immunomodulatory effects of fusarochromanones TDP-1 and TDP-2. Natural toxins 5 1344894
2009 Essential validation of gene trap mouse ES cell lines: a test case with the gene Ttrap. The International journal of developmental biology 4 19598121
2007 [Effect of TTRAP expression on apoptosis induced by hydroquinone in HL-60 cells in vitro.]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 4 18226367
2022 SPRTN and TDP1/TDP2 Independently Suppress 5-Aza-2'-deoxycytidine-Induced Genomic Instability in Human TK6 Cell Line. Chemical research in toxicology 3 36282523
2025 Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin. Genes and environment : the official journal of the Japanese Environmental Mutagen Society 2 40155951
2024 A novel pathogenic variant in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by pituitary tumor and hyperhidrosis: a case report. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2 38433132
2024 Tyrosyl-DNA phosphodiesterase 2 (Tdp2) repairs DNA-protein crosslinks and protects against double strand breaks in vivo. Frontiers in cell and developmental biology 2 39228401
2025 Post-Translational Modifications Orchestrate Repair of Trapped Topoisomerase-Induced DNA Breaks via TDP1 and TDP2. Journal of molecular biology 1 40581090
2018 Erratum: Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23). Neurology. Genetics 1 30588497
2026 TDP2 drives immune evasion and metastatic progression in prostate cancer. PloS one 0 41481587
2025 Design, synthesis, and evaluation of dehydroabietyl imidazolidine-2,4-diones, 2,4,5-triones, and 2-thioxoimidazolidine-4,5-diones as TDP1 inhibitors and dual TDP1/TDP2 inhibitors. Archiv der Pharmazie 0 39801260
2025 Spinocerebellar ataxia, autosomal recessive type 23 (SCAR23) with compound TDP2 variants: clinical, molecular, and quantitative follow-up. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 0 41457191
2025 The effect of dimeric bisbenzimidazoles on the activity of DNA repair enzymes TDP1, TDP2, PARP1 and PARP2. Vavilovskii zhurnal genetiki i selektsii 0 41541557

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