Affinage

TDP1

Tyrosyl-DNA phosphodiesterase 1 · UniProt Q9NUW8

Length
608 aa
Mass
68.4 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TDP1 is a phospholipase D (PLD) superfamily phosphodiesterase that resolves 3′-blocking DNA lesions—including trapped topoisomerase I and II covalent complexes, 3′-phosphoglycolates, chain-terminating nucleoside analogs, and abasic-site–derived DNA–protein crosslinks—through a two-step catalytic mechanism involving a covalent His263–phospho-DNA intermediate (PMID:11572945, PMID:11839309, PMID:16141202, PMID:35349719). TDP1 operates within the XRCC1/Ligase IIIα–dependent single-strand break repair pathway and also participates in canonical NHEJ through interaction with XLF, with its recruitment, stability, and activity regulated by ATM/DNA-PK phosphorylation at Ser81, PARP1-mediated PARylation, SUMOylation at Lys111, PRMT5-catalyzed arginine methylation at Arg361/Arg586, and UCHL3-mediated deubiquitylation (PMID:13679147, PMID:19851285, PMID:22415824, PMID:24493735, PMID:29718323, PMID:29898404, PMID:29078113). TDP1 functions in both nuclear and mitochondrial DNA repair, where it is essential for processing oxidative and topoisomerase-induced damage; its loss causes progressive cerebellar atrophy in mice and, in humans, the homozygous H493R active-site mutation causes spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1), through a neomorphic mechanism in which mutant TDP1 becomes covalently trapped on DNA and additionally blocks TDP2-dependent backup repair (PMID:12244316, PMID:15920477, PMID:17914460, PMID:21041670, PMID:38761375).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    Establishing that TDP1 is a PLD-superfamily enzyme that catalyzes phosphodiester bond cleavage through a covalent phospho-histidine intermediate resolved the fundamental catalytic mechanism by which 3′-phosphotyrosyl bonds are hydrolyzed.

    Evidence Site-directed mutagenesis of HKD motifs and detection of covalent enzyme-DNA intermediate in vitro

    PMID:11572945

    Open questions at the time
    • Structural basis of substrate recognition not yet defined
    • In vivo relevance of covalent intermediate not demonstrated
  2. 2002 High

    High-resolution crystal structures of TDP1 alone and with transition-state analogs identified the two-domain architecture, confirmed His263 as the catalytic nucleophile, and revealed that Top1-DNA substrates require prior proteolytic trimming before TDP1 can access the lesion.

    Evidence X-ray crystallography at 1.69 Å resolution, structures with vanadate/tungstate covalently bound to His263, and a quaternary transition-state mimic with peptide and ssDNA

    PMID:11839309 PMID:12470949 PMID:12618186

    Open questions at the time
    • Structure of full-length TDP1 with intact Top1cc substrate not available
    • Proteolytic processing step not structurally characterized
  3. 2002 High

    Mapping the SCAN1 disease-causing H493R mutation to the TDP1 active site established the first direct link between a DNA repair phosphodiesterase and human neurodegeneration, while yeast genetics revealed that TDP1 and structure-specific endonucleases (Rad1-Rad10, Mus81) function as parallel pathways for Top1 damage repair.

    Evidence Positional cloning and linkage analysis in SCAN1 families; yeast epistasis with camptothecin sensitivity in tdp1/rad1/mus81 mutant combinations

    PMID:12244316 PMID:12368472 PMID:12397185

    Open questions at the time
    • Mechanism by which H493R causes neurodegeneration vs. simple loss of function not resolved
    • Whether endonuclease backup pathways are conserved in mammalian cells unclear
  4. 2003 High

    Discovery that TDP1 physically associates with XRCC1 and that XRCC1-containing complexes possess TDP1 activity placed TDP1 within the single-strand break repair (SSBR) pathway, explaining how TDP1 is coordinated with downstream processing enzymes.

    Evidence Co-immunoprecipitation; enzymatic activity and Top1-SSB repair assays in XRCC1-deficient vs. complemented cells

    PMID:13679147

    Open questions at the time
    • Direct structural interface between TDP1 and XRCC1 not mapped
    • Whether other scaffold proteins are involved not addressed
  5. 2005 High

    Biochemical characterization of the SCAN1 H493R mutant revealed it forms a long-lived covalent TDP1-DNA intermediate (t½ ~13 min), establishing that SCAN1 involves a toxic gain-of-function (covalent trapping) rather than simple loss of activity, and broadened TDP1's substrate repertoire to include 3′-phosphoglycolates, abasic sites, and diverse 3′ adducts.

    Evidence In vitro assays with mutant TDP1 detecting covalent intermediate; 3′-PG processing in SCAN1 vs. normal cell extracts; activity on biotin, abasic, and phosphohistidine substrates

    PMID:15647511 PMID:15920477 PMID:16141202

    Open questions at the time
    • Whether trapped TDP1-DNA complexes are processed by backup pathways in vivo not established
    • Relative contribution of each substrate class to SCAN1 pathology unknown
  6. 2006 High

    Demonstrating that yeast Tdp1 can process Top2-derived 5′-phosphotyrosyl linkages expanded TDP1's role beyond Top1 repair to include topoisomerase II damage, while showing that SCAN1 cells are specifically defective in transcription-coupled Top1cc repair.

    Evidence Yeast tdp1 deletion hypersensitivity to Top2 poisons with in vitro cleavage of 5′-phosphotyrosyl substrate; SCAN1 cell Top1cc reversal assay unaffected by aphidicolin

    PMID:16751265 PMID:16935573

    Open questions at the time
    • Physiological significance of 5′-phosphotyrosyl activity in vertebrates not confirmed
    • Whether transcription-coupled repair is the predominant in vivo function remains unclear
  7. 2007 High

    Tdp1-knockout mice develop progressive cerebellar atrophy with defective SSB repair in neurons, and comparison with SCAN1 mice confirmed that SCAN1 H493R is a recessive neomorphic mutation, as trapped TDP1-DNA complexes were detected in vivo in SCAN1 cells; TDP1 was also shown to repair ionizing radiation-induced SSBs and to be stimulated by XRCC1/Lig3α.

    Evidence Tdp1-/- mouse model with neural SSB repair assays and histology; in vivo detection of trapped H493R TDP1-DNA complexes; IR-induced SSB repair kinetics in SCAN1 cells; in vitro stimulation by XRCC1/Lig3α

    PMID:17600775 PMID:17914460 PMID:17948061

    Open questions at the time
    • Why postmitotic neurons are selectively vulnerable not mechanistically explained
    • Whether other tissues show subclinical phenotypes in Tdp1-/- mice not fully explored
  8. 2009 High

    Identification of ATM/DNA-PK-dependent phosphorylation at Ser81 revealed how DNA damage signaling regulates TDP1: phospho-Ser81 stabilizes TDP1, promotes XRCC1 complex formation, and enhances recruitment to damage foci, while synergistic loss of TDP1 and aprataxin demonstrated overlapping roles in quiescent neural cell SSB repair.

    Evidence Phosphorylation site mapping, kinase inhibitor studies, co-IP with XRCC1, nuclear foci analysis, clonogenic survival; Tdp1-/-/Aptx-/- double-KO mouse astrocytes with SSB repair kinetics

    PMID:19303373 PMID:19851285

    Open questions at the time
    • Phosphatase(s) responsible for Ser81 dephosphorylation unknown
    • Whether Ser81 phosphorylation is cell-cycle regulated not addressed
  9. 2010 High

    Discovery that nuclear-encoded TDP1 localizes to mitochondria and is required for mitochondrial BER of oxidative damage established a dual-compartment repair function, while yeast studies showed TDP1's 3′-nucleosidase activity regulates NHEJ fidelity by restricting polymerase access at DSB ends.

    Evidence Subcellular fractionation, confocal microscopy, and mitochondrial BER assays in TDP1-deficient cells; yeast NHEJ reporter with junction sequencing

    PMID:20160111 PMID:21041670

    Open questions at the time
    • Mitochondrial targeting signal or import mechanism not identified
    • Whether NHEJ fidelity role is conserved in mammalian cells not shown
  10. 2012 High

    SUMOylation at Lys111 was shown to promote TDP1 accumulation at damage sites without affecting catalysis, adding a third regulatory PTM layer; vertebrate DT40 knockout studies confirmed TDP1 processes Top2cc, bleomycin-induced 3′-PG, and abasic-site lesions, and established parallel and epistatic relationships with CtIP.

    Evidence Mass spectrometry identification of K111 SUMOylation, K111R mutant SSB repair assays; DT40 TDP1-KO complementation with drug sensitivity and epistasis analysis

    PMID:22375014 PMID:22415824

    Open questions at the time
    • SUMO E3 ligase(s) targeting TDP1 not identified
    • Whether SUMOylation is damage-type specific unknown
  11. 2013 High

    TDP1 was found to remove chain-terminating nucleoside analogs (ACV, Ara-C, AZT, ddC) from nuclear and mitochondrial DNA, establishing TDP1 as a determinant of therapeutic nucleoside analog cytotoxicity and mtDNA integrity.

    Evidence In vitro cleavage of CTNA-terminated DNA by recombinant TDP1; Tdp1-/- DT40 cell hypersensitivity and mtDNA depletion assays

    PMID:23775789

    Open questions at the time
    • Clinical relevance of TDP1 status to nucleoside analog therapy in patients not established
    • Whether TDP1 is rate-limiting for CTNA removal in vivo uncertain
  12. 2014 High

    Mapping the direct TDP1-PARP1 interaction and demonstrating that PARylation stabilizes TDP1 and recruits XRCC1 established PARP1 as the upstream sensor that channels Top1cc repair through the TDP1-SSBR pathway.

    Evidence Domain-mapped co-IP (TDP1 N-terminus binds PARP1 C-terminus), PARylation assay, recruitment imaging, DT40 TDP1/PARP1 double-KO epistasis

    PMID:24493735

    Open questions at the time
    • Whether PARylation is required for mitochondrial TDP1 function not tested
    • Stoichiometry of the TDP1-PARP1-XRCC1 complex unknown
  13. 2015 Medium

    Discovery of the TDP1-XLF physical interaction and TDP1's ability to stimulate Ku70/80 DNA binding and DNA-PK activity established TDP1 as a participant in the early stages of mammalian NHEJ, extending its role beyond SSBR.

    Evidence Co-IP/pulldown of TDP1-XLF, in vitro activity stimulation on dsDNA, DNA-PK kinase assay

    PMID:25841101

    Open questions at the time
    • In vivo NHEJ contribution not demonstrated with chromosomal assay at this stage
    • Structural basis of TDP1-XLF interaction not resolved
  14. 2017 High

    CRISPR TDP1-KO in human cells confirmed TDP1 is required for efficient NHEJ at cohesive DSBs and showed that Ser81 phosphorylation regulates the TDP1-XLF interaction, linking DNA damage signaling to NHEJ pathway choice.

    Evidence TDP1-KO HEK-293 cells, chromosomal NHEJ reporter, S81A/S81E mutant complementation

    PMID:29078113

    Open questions at the time
    • Whether TDP1-dependent NHEJ operates at IR-induced or physiological DSBs in vivo not shown
    • Phospho-Ser81 effect on other NHEJ factors not assessed
  15. 2018 High

    PRMT5-mediated symmetric arginine dimethylation at R361 and R586 was shown to directly enhance TDP1 catalytic activity and promote XRCC1 association, while UCHL3 was identified as the deubiquitylase stabilizing TDP1, and TDP1-Artemis epistasis within C-NHEJ for 3′-PG DSBs was established with distinct cytogenetic consequences.

    Evidence In vitro methylation and phosphodiesterase assays with R361A/R586A mutants; UCHL3 depletion/overexpression with ubiquitylation and stability assays; TDP1-KO/Artemis-null epistasis with dicentric chromosome and 53BP1 foci analysis

    PMID:29718323 PMID:29898404 PMID:30113698

    Open questions at the time
    • Whether PRMT5-TDP1 axis is regulated by DNA damage signaling not fully established
    • Identity of the E3 ubiquitin ligase targeting TDP1 unknown
  16. 2019 High

    Demonstrating that SCAN1 H493R TDP1 is selectively trapped on mitochondrial regulatory DNA, triggering Drp1-mediated fission and PINK1-dependent mitophagy, provided a mitochondrial mechanism contributing to SCAN1 neurodegeneration.

    Evidence Mito-targeted Top1 poison in SCAN1 cells, ChIP-like detection of TDP1-mtDNA complexes, mitochondrial fission/PINK1 pathway imaging

    PMID:31723605

    Open questions at the time
    • Whether mitochondrial dysfunction is the primary driver of SCAN1 cerebellar atrophy vs. nuclear DNA damage not resolved
    • Tissue-specific factors governing mtDNA trapping not identified
  17. 2022 High

    TDP1 substrate range was extended to 3′-PUA–protein/peptide DPC crosslinks from abasic sites, R586 methylation was linked to ubiquitin-mediated TDP1 turnover by impeding UCHL3 binding, establishing PTM crosstalk between arginine methylation and the ubiquitin-proteasome pathway, and genome-wide screening identified APEX1/2 as synthetic lethal with TDP1 with MUS81 generating excess DSBs in TDP1-KO cells.

    Evidence In vitro kinetic assays with 3′-PUA substrates; co-IP and ubiquitylation assays with methylation-site mutants; genome-wide CRISPR screen with DSB quantification

    PMID:35349719 PMID:35705029 PMID:35869071

    Open questions at the time
    • In vivo relevance of 3′-PUA-DPC processing not demonstrated
    • Whether APEX1/2 synthetic lethality is therapeutically exploitable unknown
  18. 2023 Medium

    TDP1 was shown to suppress chromosomal translocations arising from transcription-associated abortive TOP1 activity, with unrepaired SSBs converting to DSBs processed by error-prone MRN/NHEJ; TDP1 and SPRTN were found to cooperate in histone H3-DPC repair via sequential proteolysis then TDP1-mediated peptide removal.

    Evidence Translocation assays with epistasis in TDP1-deficient cells; TDP1/SPRTN epistasis in RPE1 cells and zebrafish with DPC quantification

    PMID:37788708 PMID:37945566

    Open questions at the time
    • Whether TDP1 loss contributes to translocations in SCAN1 patients unknown
    • SPRTN-TDP1 cooperation not validated in neural cell models
  19. 2024 High

    CRISPR-engineered SCAN1 cells revealed that H493R TDP1 gains a dominant-negative function by blocking TDP2-dependent backup DSB repair, causing accumulation of transcriptional DSBs specifically in G1—establishing that SCAN1 pathogenesis involves both loss of TDP1 activity and active interference with an alternative repair pathway.

    Evidence Isogenic CRISPR SCAN1 human cells, TOP1cc detection, R-loop analysis, γH2AX by cell cycle, TDP2 epistasis

    PMID:38761375

    Open questions at the time
    • Whether pharmacological TDP2 activation could rescue SCAN1 cells not tested
    • Structural basis for H493R blocking TDP2 access not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase(s) targeting TDP1, the structural basis by which the trapped H493R intermediate blocks TDP2, the mechanism of TDP1 mitochondrial import, and whether the APEX1/2 synthetic lethality or SPRTN epistasis can be therapeutically exploited in TOP1 inhibitor-treated cancers.
  • E3 ligase for TDP1 ubiquitylation not identified
  • Structural mechanism of H493R-mediated TDP2 blockade unknown
  • Mitochondrial targeting/import mechanism undefined
  • Therapeutic exploitation of synthetic lethal interactions not validated in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 9 GO:0140096 catalytic activity, acting on a protein 4 GO:0140097 catalytic activity, acting on DNA 3
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 3
Pathway
R-HSA-73894 DNA Repair 17 R-HSA-1643685 Disease 5
Partners
LIG3PARP1PRMT5SPRTNUCHL3XLFXRCC1
Complex memberships
XRCC1/Lig3α SSBR complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TDP1 belongs to the phospholipase D (PLD) superfamily, containing two HKD signature motifs. Mutagenesis of the invariant histidines and lysines confirmed these residues are essential for activity. The reaction proceeds via a covalent phospho-enzyme intermediate, where the cleaved substrate is transiently linked to the enzyme, consistent with phosphoryl transfer chemistry common to PLD superfamily members. Sequence analysis, site-directed mutagenesis of HKD motifs, in vitro enzymatic assay detecting covalent intermediate Proceedings of the National Academy of Sciences of the United States of America High 11572945
2002 Crystal structure of human TDP1 at 1.69 Å resolution reveals a monomer composed of two similar domains related by pseudo-2-fold symmetry, each contributing conserved histidine, lysine, and asparagine residues to form a single active site. Structure confirms membership in the PLD superfamily and provides insights into substrate binding of the protein-DNA substrate. X-ray crystallography Structure (London, England : 1993) High 11839309
2002 A homozygous H493R mutation in TDP1's active site causes SCAN1. His493 is conserved and located in the active site; protein modeling predicts the arginine substitution disrupts the symmetric active site structure, leading to loss of TDP1 function and neurodegeneration in postmitotic neurons. Genome-wide linkage mapping, positional cloning, protein modeling Nature genetics High 12244316
2002 Crystal structures of human TDP1 bound to vanadate and tungstate (phosphate transition state analogs) show the inhibitor covalently bound to His263, confirming this histidine as the nucleophile in the first catalytic step. Vanadate adopts trigonal bipyramidal geometry mimicking the transition state for phosphodiester bond hydrolysis. X-ray crystallography with transition state analog inhibitors Journal of molecular biology High 12470949
2002 In yeast, TDP1 and the structure-specific endonuclease Rad1-Rad10 function as primary alternative pathways for repair of Top1 replicative damage. Genetic epistasis shows both pathways converge on recombination (RAD52, RAD51, RAD50), but Rad1-Rad10 additionally depends on RAD59 and SRS2. Yeast genetic epistasis analysis, camptothecin sensitivity assays, double/triple mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 12368472
2002 In yeast, structure-specific nucleases dependent on RAD1 and MUS81 can contribute independently of TDP1 to repair of Top1 damage, and the MRE11 gene is critical for double-strand break repair of CPT lesions. Apurinic endonucleases do not contribute to Top1 repair in parallel to Tdp1. Yeast genetic analysis, camptothecin sensitivity, double/triple mutant epistasis Proceedings of the National Academy of Sciences of the United States of America High 12397185
2003 A crystal structure of a quaternary transition state mimic assembled from vanadate, single-stranded DNA, and a topoisomerase I-derived tyrosine-containing peptide reveals that the topoisomerase I-DNA complex must undergo extensive modification (proteolytic trimming) before TDP1 can cleave it, and illustrates the substrate conformation at the active site. X-ray crystallography of transition state mimic complex Chemistry & biology High 12618186
2003 XRCC1 physically associates with TDP1 (co-immunoprecipitation) and XRCC1-containing complexes possess TDP1 and PNKP activities. XRCC1-deficient cells show reduced TDP1 activity and slower repair of Top1-induced DNA breaks, placing TDP1 in the XRCC1-dependent single-strand break repair pathway. Co-immunoprecipitation, enzymatic activity assays in XRCC1-deficient vs. complemented cells DNA repair High 13679147
2005 The SCAN1 H493R mutation reduces TDP1 enzyme activity ~25-fold and causes accumulation of a covalent TDP1-DNA reaction intermediate with a half-life of ~13 min, creating a new protein-DNA adduct in addition to the unrepaired Top1-DNA complex. SCAN1 patient-derived cell lines are hypersensitive to camptothecin, confirming TDP1's role in CPT-induced Top1 damage repair in human cells. In vitro enzymatic assay of mutant enzyme, detection of covalent intermediate, camptothecin sensitivity of SCAN1 cell lines The EMBO journal High 15920477
2005 Human TDP1 catalytic cycle involves a covalent phosphoamide intermediate linking a histidine to DNA 3'-phosphate, which can itself be hydrolyzed by wild-type TDP1. TDP1 also possesses 3'-exonuclease activity removing a single nucleoside from 3'-OH ends, and can remove 3'-abasic sites and 3'-biotin adducts, indicating a broad spectrum of 3'-end processing substrates including phosphotyrosine, phosphohistidine, phosphoglycolate, and abasic sites. In vitro enzymatic assay with diverse substrates, detection of covalent intermediate The Journal of biological chemistry High 16141202
2005 Human TDP1 preferentially binds and cleaves single-stranded and blunt-ended duplex substrates over nicked and tailed duplex substrates, suggesting TDP1 acts upon double-strand breaks in vivo rather than nicked DNA. Kinetic and binding assays (in vitro) with diverse DNA substrates The Journal of biological chemistry Medium 15811850
2005 TDP1 is the primary enzyme responsible for removing 3'-phosphoglycolate (PG) termini in human cell extracts. SCAN1 cell extracts (bearing H493R TDP1) completely fail to process 3'-PG termini on single-strand oligomers and 3'-overhangs of DSBs; adding recombinant wild-type TDP1 restores activity, and no alternative enzyme in extracts can process protruding 3'-PG termini. In vitro end-joining assay with 3'-PG substrates using whole-cell extracts from SCAN1 and normal cells, complementation with recombinant TDP1 Nucleic acids research High 15647511
2006 Yeast TDP1 participates in repair of topoisomerase II-mediated DNA damage: tdp1 deletion confers hypersensitivity to Top2-targeting agents, and bacterially expressed yeast Tdp1 can remove a Top2-derived peptide covalently bound to DNA via a 5'-phosphotyrosyl linkage in vitro. Yeast genetic deletion, drug sensitivity assays, in vitro biochemical cleavage assay with Top2-peptide substrate Proceedings of the National Academy of Sciences of the United States of America High 16751265
2006 SCAN1 cells (TDP1 H493R) are defective in reversal of transcription-associated Top1 cleavage complexes. This defect and CPT hypersensitivity are not affected by aphidicolin (replication inhibitor), implicating TDP1 specifically in repair of transcription-coupled Top1 damage. Top1cc reversal assay in SCAN1 vs. normal cells, aphidicolin treatment, CPT sensitivity DNA repair Medium 16935573
2007 Tdp1-/- mice display age-dependent progressive cerebellar atrophy, and Tdp1-deficient cerebellar neurons and astrocytes cannot rapidly repair DNA single-strand breaks from Top1-DNA complexes or oxidative damage. This establishes TDP1 as required for neural homeostasis in vivo. Tdp1 knockout mouse model, in vitro and in vivo SSB repair assays, histological analysis The EMBO journal High 17914460
2007 The SCAN1 H493R TDP1 mutant retains residual activity and becomes covalently trapped on DNA after CPT treatment in SCAN1 cells in vivo, directly demonstrating that TDP1 repairs Top1 covalent lesions in vivo. Tdp1-/- mice are distinguishable from SCAN1 mice, supporting that SCAN1 arises from a recessive neomorphic mutation (gain of toxic function via trapped TDP1-DNA intermediate) rather than simple loss of function. Tdp1-/- mouse phenotyping, in vivo detection of trapped H493R TDP1-DNA complexes in SCAN1 cells The EMBO journal High 17948061
2007 TDP1 is required for repair of ionizing radiation-induced single-strand breaks, not just Top1-induced SSBs. TDP1 activity at abortive Top1 SSBs is stimulated in vitro by XRCC1/Lig3α. Abortive Top1 cleavage complexes are processed by the proteasome prior to TDP1 action in vivo. TDP1 interacts with DNA ligase IIIα. SSB repair kinetics in SCAN1 cells after IR, in vitro stimulation assay with XRCC1/Lig3α, proteasome inhibitor studies DNA repair High 17600775
2009 TDP1 is phosphorylated at Ser81 by ATM and DNA-PK in response to Top1-associated DSBs. Phospho-TDP1 forms nuclear foci colocalizing with γH2AX. Ser81 phosphorylation stabilizes TDP1, promotes formation of TDP1-XRCC1 complexes, enhances TDP1 mobilization to DNA damage sites, and promotes cell survival and DNA repair after CPT treatment. In vivo phosphorylation assays, kinase inhibitor studies, co-immunoprecipitation, nuclear foci analysis (immunofluorescence), clonogenic survival assays The EMBO journal High 19851285
2009 Loss of TDP1 together with aprataxin synergistically decreases chromosomal single-strand break repair rates in quiescent mouse astrocytes, demonstrating functional epistasis between TDP1 (3'-end processing) and aprataxin (5'-end AMP removal) at overlapping SSB substrates. Tdp1-/-/Aptx-/- double knockout mouse model, SSB repair kinetics assays in primary astrocytes DNA repair High 19303373
2010 TDP1 serine 81 promotes interaction with DNA ligase IIIα (Lig3α). Mutation S81A had no effect on TDP1 catalytic activity in vitro, but markedly reduced protein stability and cell survival following genotoxic stress in vivo. Co-immunoprecipitation, in vitro activity assay with S81A mutant, protein stability assays, clonogenic survival Cell cycle (Georgetown, Tex.) Medium 20009512
2010 A fraction of TDP1 encoded by the nuclear TDP1 gene localizes to mitochondria. Mitochondrial base excision repair depends on TDP1 activity, and TDP1 is required for efficient repair of oxidative damage in mitochondrial DNA. Laser confocal microscopy, subcellular fractionation, biochemical mitochondrial BER assays in TDP1-deficient cells Proceedings of the National Academy of Sciences of the United States of America High 21041670
2010 Yeast TDP1 regulates NHEJ fidelity: tdp1 deletion increases insertion errors (2–4 nt) at 5'-overhang DSBs during NHEJ, dependent on Ku80, DNA ligase IV, and polymerase IV. TDP1's 3'-nucleosidase activity generates 3'-phosphate ends that restrict polymerase and other enzyme access, thereby preventing insertions. Yeast NHEJ reporter assay, junction sequencing, epistasis with NHEJ pathway genes Proceedings of the National Academy of Sciences of the United States of America High 20160111
2012 Vertebrate TDP1 (using chicken DT40 knockout cells complemented with human TDP1) is required for repair of Top1cc, bleomycin-induced 3'-phosphoglycolates, etoposide-induced Top2cc (5'-phosphotyrosyl ends processed in vitro), MMS-induced abasic site-derived 3'-deoxyribose phosphates, H2O2, and ionizing radiation. TDP1 and CtIP act in parallel pathways for Top1cc and MMS lesions, but are epistatic for Top2cc. DT40 TDP1 knockout cells, human TDP1 complementation, drug sensitivity assays, in vitro biochemical assay with 5'-phosphotyrosyl substrate, DT40 TDP1/CtIP double knockout epistasis The Journal of biological chemistry High 22375014
2012 TDP1 is SUMOylated at lysine 111 in mammalian cells. SUMOylation does not affect TDP1 catalytic activity but promotes its accumulation at sites of DNA damage. A SUMO-deficient TDP1 mutant (K111R) shows reduced rate of repair of chromosomal SSBs from transcription-associated Top1 activity and oxidative stress. Purification of SUMOylated TDP1, mass spectrometry identification of SUMOylation site K111, K111R mutant analysis, chromosomal SSB repair assays Nature communications High 22415824
2013 TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating nucleoside analogs (acyclovir, cytarabine, AZT, ddC) by removing the incorporated nucleoside from DNA 3'-ends in vitro. Tdp1-/- DT40 cells are hypersensitive to ACV and Ara-C and accumulate more DNA damage; AZT and ddC cause greater mitochondrial DNA depletion in Tdp1-/- cells. In vitro biochemical cleavage assay with CTNA-terminated DNA, Tdp1-/- DT40 cell sensitivity assays, mtDNA copy number analysis Nucleic acids research High 23775789
2014 PARP1 plays a critical role in directing Top1cc repair via TDP1. The N-terminal domain of TDP1 directly binds the C-terminal domain of PARP1 (demonstrated by domain mapping). TDP1 is PARylated by PARP1; PARylation stabilizes TDP1 (together with SUMOylation) and enhances TDP1 recruitment to DNA damage sites without affecting catalytic activity. TDP1-PARP1 complexes in turn recruit XRCC1. TDP1 and PARP1 are epistatic in DT40 double-knockout cells. TDP1/PARP1 double-knockout DT40 cells, co-immunoprecipitation with domain mapping, PARylation assay, TDP1 recruitment to damage foci, epistasis analysis Nucleic acids research High 24493735
2015 Human TDP1 physically interacts with XLF (NHEJ factor) to form TDP1:XLF:DNA complexes. TDP1:XLF interaction preferentially stimulates TDP1 activity on dsDNA over ssDNA. TDP1 also promotes DNA binding by Ku70/80 and stimulates DNA-PK activity, indicating TDP1 participates in the early stages of mammalian NHEJ. Physical interaction (co-IP/pulldown), in vitro activity stimulation assays, DNA-PK activity assay DNA repair Medium 25841101
2017 TDP1 is required for efficient NHEJ of cohesive DSBs in human cells. TDP1-KO HEK-293 cells (CRISPR/Cas9) show 5-fold reduced NHEJ efficiency in a chromosomal reporter. XLF binding by TDP1 is reduced by S81A and markedly reduced by phosphomimetic S81E, suggesting TDP1-XLF interaction and NHEJ are regulated by S81 phosphorylation. CRISPR/Cas9 TDP1-KO human cells, chromosomal NHEJ reporter assay, in vitro NHEJ activity assay, mutant TDP1 complementation DNA repair High 29078113
2018 PRMT5 directly binds TDP1 and catalyzes symmetric arginine dimethylation at R361 and R586. Top1-induced replication-mediated DNA damage triggers TDP1 arginine methylation, which enhances TDP1 3'-phosphodiesterase activity. R361/R586 methylation also increases TDP1-XRCC1 association and XRCC1 recruitment to Top1cc damage foci. PRMT5 knockdown reduces TDP1 activity and elevates CPT-induced damage. Co-immunoprecipitation, in vitro arginine methylation assay, site-directed mutagenesis (R361A, R586A), TDP1 phosphodiesterase activity assay, XRCC1 co-IP, CPT sensitivity Nucleic acids research High 29718323
2018 TDP1 is regulated by ubiquitylation, and UCHL3 is the deubiquitylase controlling TDP1 proteostasis. Depletion of UCHL3 increases TDP1 ubiquitylation and turnover rate, sensitizing cells to TOP1 poisons. Overexpression of catalytically active (but not inactive) UCHL3 suppresses TDP1 ubiquitylation and stabilizes TDP1. Ubiquitylation assays, UCHL3 depletion/overexpression, protein stability assays, TOP1 poison sensitivity, catalytically inactive UCHL3 mutant Cell reports High 29898404
2018 TDP1 and Artemis cooperate in canonical NHEJ for repair of 3'-phosphoglycolate-terminated DSBs (radiomimetic NCS-induced). TDP1 deficiency causes dramatic increase in dicentric chromosomes (mis-joining), while Artemis deficiency causes unrepaired DSBs (53BP1 foci). The two are strictly epistatic for NCS sensitivity, indicating they perform distinct functions within the same C-NHEJ pathway. TDP1 KO and KD cells, Artemis-null cells, DNA-PK inhibitor, 53BP1 foci, dicentric chromosome analysis, clonogenic survival Nucleic acids research High 30113698
2019 SCAN1-TDP1 (H493R) is selectively trapped on mitochondrial DNA in the regulatory non-coding region and promoter sequences. Trapped TDP1H493R-mtDNA complexes accumulate mtDNA damage, trigger Drp1-mediated mitochondrial fission, block mitobiogenesis, and prompt PINK1-dependent mitophagy to eliminate dysfunctional mitochondria. Mitochondria-targeted Top1 poison (mito-SN38 nanoparticles), ChIP-like detection of TDP1-mtDNA complexes, mitochondrial fission/fragmentation imaging, PINK1/Drp1 pathway analysis Science advances High 31723605
2022 Human TDP1 can repair 3'-PUA-protein/peptide DPCs (Schiff base crosslinks at 3'-DNA termini arising from abasic sites) in vitro. TDP1 directly processes 3'-PUA-aminooxylysine-peptide adducts; for larger DPCs (e.g., 3'-PUA-PARP1), proteolysis must precede TDP1 action. TDP1 can also directly repair 3'-PUA-histone H3 DPCs. Chemically synthesized 3'-PUA-peptide substrates, in vitro kinetic assays with recombinant TDP1, comparison of peptide length and DNA structure effects Nucleic acids research Medium 35349719
2022 PRMT5-mediated arginine methylation at R586 promotes TDP1 ubiquitylation, which in turn facilitates ubiquitin/proteasome-dependent TDP1 turnover by impeding UCHL3 (deubiquitylase) binding to TDP1. R361 methylation enhances TDP1 3'-phosphodiesterase activity. Thus, arginine methylation co-regulates TDP1 stability and catalytic activity through crosstalk with ubiquitylation. In vitro phosphodiesterase assays, co-immunoprecipitation, ubiquitylation assays, UCHL3-TDP1 binding assays with methylation-site mutants, structural modeling Cell reports High 35705029
2022 MUS81 mediates generation of excess DSBs in TDP1-KO cells. APEX1/2 are synthetic lethal with TDP1 but APEX1/2 deficiency does not reduce DSB formation in TDP1-KO cells. TOP1cc can be resolved directly by TDP1 or converted to DSBs repaired by homologous recombination. Genome-wide CRISPR screen, co-deficient cell generation, DSB quantification Nature communications Medium 35869071
2023 TDP1 suppresses chromosomal translocations arising from transcription-associated abortive TOP1 activity. DSBs generated at TOP1-induced SSBs during transcription are repaired by an error-prone pathway requiring the MRN complex and canonical NHEJ that produces translocations when TDP1 is absent. TDP1-deficient cells, translocation assay, epistasis with MRN complex and NHEJ factors Nature communications Medium 37945566
2023 TDP1 and SPRTN cooperate in repair of histone H3-DNA crosslinks and TOP1-DNA crosslinks. Resolution of histone H3-DPCs depends on upstream proteolysis by SPRTN followed by TDP1-mediated peptide removal in RPE1 cells and zebrafish embryos. For endogenous TOP1-DPCs, SPRTN and TDP1 function in separate pathways. TDP1/SPRTN deficient human cells and zebrafish embryos, DPC quantification assays (anti-TOP1 and anti-H3 antibodies), genetic epistasis Open biology Medium 37788708
2024 SCAN1 cells (CRISPR-engineered H493R TDP1 human cells) accumulate TOP1ccs, show altered R-loop distribution, and specifically accumulate transcriptional DSBs in G1 cells due to both increased DSB formation and impaired repair. The mutant TDP1 protein (H493R) gains a dominant-negative function by blocking TDP2-dependent backup DSB repair, not just losing TDP1 enzymatic activity. CRISPR-Cas9 SCAN1 human cell models, TOP1cc detection, R-loop analysis, γH2AX/DSB quantification by cell cycle, TDP2 epistasis Cell reports High 38761375

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nature genetics 413 12244316
2014 Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2). DNA repair 265 24856239
2001 The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily. Proceedings of the National Academy of Sciences of the United States of America 237 11572945
2005 Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. The Journal of biological chemistry 193 16141202
2007 TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. The EMBO journal 183 17914460
2002 Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage. Proceedings of the National Academy of Sciences of the United States of America 182 12368472
2014 PARP1-TDP1 coupling for the repair of topoisomerase I-induced DNA damage. Nucleic acids research 178 24493735
2005 SCAN1 mutant Tdp1 accumulates the enzyme--DNA intermediate and causes camptothecin hypersensitivity. The EMBO journal 178 15920477
2003 Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA repair 164 13679147
2012 Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs DNA damage induced by topoisomerases I and II and base alkylation in vertebrate cells. The Journal of biological chemistry 149 22375014
2002 The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1. Structure (London, England : 1993) 143 11839309
2002 Repair of topoisomerase I covalent complexes in the absence of the tyrosyl-DNA phosphodiesterase Tdp1. Proceedings of the National Academy of Sciences of the United States of America 140 12397185
2005 Deficiency in 3'-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1). Nucleic acids research 133 15647511
2009 Optimal function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA-PK. The EMBO journal 129 19851285
2006 Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Proceedings of the National Academy of Sciences of the United States of America 127 16751265
2004 TDP1 overexpression in human cells counteracts DNA damage mediated by topoisomerases I and II. The Journal of biological chemistry 126 15494395
2007 Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? The EMBO journal 121 17948061
2010 Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria. Proceedings of the National Academy of Sciences of the United States of America 115 21041670
2003 Crystal structure of a transition state mimic for Tdp1 assembled from vanadate, DNA, and a topoisomerase I-derived peptide. Chemistry & biology 113 12618186
2002 Insights into substrate binding and catalytic mechanism of human tyrosyl-DNA phosphodiesterase (Tdp1) from vanadate and tungstate-inhibited structures. Journal of molecular biology 105 12470949
2012 TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1. Nucleic acids research 95 22740648
2007 Novel high-throughput electrochemiluminescent assay for identification of human tyrosyl-DNA phosphodiesterase (Tdp1) inhibitors and characterization of furamidine (NSC 305831) as an inhibitor of Tdp1. Nucleic acids research 89 17576665
2006 Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes. DNA repair 84 16935573
2013 TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs. Nucleic acids research 83 23775789
2011 Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) inhibitors. Expert opinion on therapeutic patents 75 21843105
2009 Synergistic decrease of DNA single-strand break repair rates in mouse neural cells lacking both Tdp1 and aprataxin. DNA repair 72 19303373
2012 SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair. Nature communications 71 22415824
2007 TDP1 facilitates repair of ionizing radiation-induced DNA single-strand breaks. DNA repair 66 17600775
2018 PRMT5-mediated arginine methylation of TDP1 for the repair of topoisomerase I covalent complexes. Nucleic acids research 65 29718323
2014 TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA. The EMBO journal 63 25391662
2012 Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase I (Tdp1)-topoisomerase I (Top1) inhibitors. Journal of medicinal chemistry 62 22536944
2014 Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan. Molecular cancer therapeutics 61 25522766
2012 Caenorhabditis elegans RNA-processing protein TDP-1 regulates protein homeostasis and life span. The Journal of biological chemistry 59 22232551
2012 Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase I (Tdp1) and topoisomerase I (Top1). Journal of medicinal chemistry 55 23259865
2010 TDP1 serine 81 promotes interaction with DNA ligase IIIalpha and facilitates cell survival following DNA damage. Cell cycle (Georgetown, Tex.) 55 20009512
2006 Increased expression and activity of repair genes TDP1 and XPF in non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 55 17118488
2006 TDP1-dependent DNA single-strand break repair and neurodegeneration. Mutagenesis 54 16775218
2013 TDP1 deficiency sensitizes human cells to base damage via distinct topoisomerase I and PARP mechanisms with potential applications for cancer therapy. Nucleic acids research 53 24335147
2005 Substrate specificity of tyrosyl-DNA phosphodiesterase I (Tdp1). The Journal of biological chemistry 52 15811850
2018 UCHL3 Regulates Topoisomerase-Induced Chromosomal Break Repair by Controlling TDP1 Proteostasis. Cell reports 51 29898404
2019 SCAN1-TDP1 trapping on mitochondrial DNA promotes mitochondrial dysfunction and mitophagy. Science advances 49 31723605
2013 TDP1 is an HMG chromatin protein facilitating RNA polymerase I transcription in African trypanosomes. Nucleic acids research 49 23361461
2009 Tdp1 protects against oxidative DNA damage in non-dividing fission yeast. The EMBO journal 49 19197239
2009 4-Pregnen-21-ol-3,20-dione-21-(4-bromobenzenesulfonate) (NSC 88915) and related novel steroid derivatives as tyrosyl-DNA phosphodiesterase (Tdp1) inhibitors. Journal of medicinal chemistry 45 19883083
2015 Synthesis and biological evaluation of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines as potential dual topoisomerase I (Top1)-tyrosyl-DNA phosphodiesterase I (TDP1) inhibitors. Journal of medicinal chemistry 44 25811317
2009 In vitro complementation of Tdp1 deficiency indicates a stabilized enzyme-DNA adduct from tyrosyl but not glycolate lesions as a consequence of the SCAN1 mutation. DNA repair 43 19211312
2018 Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents. Journal of medicinal chemistry 42 30336023
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
2022 TDP1-independent pathways in the process and repair of TOP1-induced DNA damage. Nature communications 40 35869071
2014 Identification of a putative Tdp1 inhibitor (CD00509) by in vitro and cell-based assays. Journal of biomolecular screening 38 25117203
2004 The role of TDP1 from budding yeast in the repair of DNA damage. DNA repair 38 15135727
2015 TDP1 promotes assembly of non-homologous end joining protein complexes on DNA. DNA repair 37 25841101
2013 Real-time detection of TDP1 activity using a fluorophore-quencher coupled DNA-biosensor. Biosensors & bioelectronics 36 23693093
2019 New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors. Molecules (Basel, Switzerland) 35 31619021
2017 TDP1 is required for efficient non-homologous end joining in human cells. DNA repair 35 29078113
2019 Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening. Nucleic acids research 34 31199869
2013 TDP1 and PARP1 deficiency are cytotoxic to rhabdomyosarcoma cells. Molecular cancer research : MCR 34 23913164
2015 Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia. Science advances 33 26601161
2010 Yeast Tdp1 regulates the fidelity of nonhomologous end joining. Proceedings of the National Academy of Sciences of the United States of America 32 20160111
2013 Epigenetic and genetic inactivation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in human lung cancer cells from the NCI-60 panel. DNA repair 31 24355542
2017 Subfunctionalization of duplicate MYB genes in Solanum commersonii generated the cold-induced ScAN2 and the anthocyanin regulator ScAN1. Plant, cell & environment 30 28386931
2014 TDP1/TOP1 Ratio as a Promising Indicator for the Response of Small Cell Lung Cancer to Topotecan. Journal of cancer science & therapy 29 25232464
2021 Effect of Pterostilbene, a Natural Derivative of Resveratrol, in the Treatment of Colorectal Cancer through Top1/Tdp1-Mediated DNA Repair Pathway. Cancers 28 34439157
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 28 32460231
2022 Human TDP1, APE1 and TREX1 repair 3'-DNA-peptide/protein cross-links arising from abasic sites in vitro. Nucleic acids research 27 35349719
2018 Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors. Bioorganic & medicinal chemistry 27 30076000
2017 TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors. Molecular cancer therapeutics 27 28802254
2019 The Protease WSS1A, the Endonuclease MUS81, and the Phosphodiesterase TDP1 Are Involved in Independent Pathways of DNA-protein Crosslink Repair in Plants. The Plant cell 26 30760561
2021 Synthesis of Methoxy-, Methylenedioxy-, Hydroxy-, and Halo-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors and Their Biological Activity for Drug-Resistant Cancer. Journal of medicinal chemistry 23 34008967
2020 The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme. International journal of molecular sciences 23 32998385
2018 TDP1 suppresses mis-joining of radiomimetic DNA double-strand breaks and cooperates with Artemis to promote optimal nonhomologous end joining. Nucleic acids research 22 30113698
2018 A polysaccharide from Antrodia cinnamomea mycelia exerts antitumor activity through blocking of TOP1/TDP1-mediated DNA repair pathway. International journal of biological macromolecules 21 30267816
2020 Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1. Molecules (Basel, Switzerland) 20 32751997
2014 Identification of novel PARP inhibitors using a cell-based TDP1 inhibitory assay in a quantitative high-throughput screening platform. DNA repair 20 24794403
2016 Isoeugenol is a selective potentiator of camptothecin cytotoxicity in vertebrate cells lacking TDP1. Scientific reports 19 27220325
2014 Biochemical assays for the discovery of TDP1 inhibitors. Molecular cancer therapeutics 19 25024006
2021 Dysregulation of MicroRNAs and PIWI-Interacting RNAs in a Caenorhabditis elegans Parkinson's Disease Model Overexpressing Human α-Synuclein and Influence of tdp-1. Frontiers in neuroscience 18 33762903
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
2021 Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy Drugs. Oncology and therapy 17 34159519
2017 Identification of Natural Products That Inhibit the Catalytic Function of Human Tyrosyl-DNA Phosphodiesterase (TDP1). SLAS discovery : advancing life sciences R & D 17 28697309
2015 Tyrosyl-DNA-phosphodiesterase I (TDP1) participates in the removal and repair of stabilized-Top2α cleavage complexes in human cells. Mutation research 17 26421495
2022 Interplay between symmetric arginine dimethylation and ubiquitylation regulates TDP1 proteostasis for the repair of topoisomerase I-DNA adducts. Cell reports 16 35705029
2021 Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments. Molecules (Basel, Switzerland) 16 34073771
2019 Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments. Anti-cancer agents in medicinal chemistry 16 30523770
2015 A Theoretical Study of Phosphoryl Transfers of Tyrosyl-DNA Phosphodiesterase I (Tdp1) and the Possibility of a "Dead-End" Phosphohistidine Intermediate. Biochemistry 16 26121557
2014 Neuroprotection and repair of 3'-blocking DNA ends by glaikit (gkt) encoding Drosophila tyrosyl-DNA phosphodiesterase 1 (TDP1). Proceedings of the National Academy of Sciences of the United States of America 16 25331878
2024 TDP1 mutation causing SCAN1 neurodegenerative syndrome hampers the repair of transcriptional DNA double-strand breaks. Cell reports 15 38761375
2017 HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia. Scientific reports 15 28993637
2013 The role of TDP1 and APTX in mitochondrial DNA repair. Biochimie 15 24161509
2021 Tdp1 protects from topoisomerase 1-mediated chromosomal breaks in adult zebrafish but is dispensable during larval development. Science advances 13 33514542
2014 Development of an oligonucleotide-based fluorescence assay for the identification of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors. Analytical biochemistry 13 24637157
2023 TDP-1 and FUST-1 co-inhibit exon inclusion and control fertility together with transcriptional regulation. Nucleic acids research 12 37587694
2017 Synthesis, anti-cancer screening and tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition activity of novel piperidinyl sulfamides. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 12 29037996
2013 Tracking the processing of damaged DNA double-strand break ends by ligation-mediated PCR: increased persistence of 3'-phosphoglycolate termini in SCAN1 cells. Nucleic acids research 11 24371269
2023 Tyrosyl-DNA phosphodiesterase 1 (TDP1) and SPRTN protease repair histone 3 and topoisomerase 1 DNA-protein crosslinks in vivo. Open biology 10 37788708
2023 TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription. Nature communications 10 37945566
2020 Genome-wide study on uveal melanoma patients finds association to DNA repair gene TDP1. Melanoma research 10 31626034
2021 Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors. Molecules (Basel, Switzerland) 9 33808389
2021 Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties. Pharmaceuticals (Basel, Switzerland) 9 34062881