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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
TDP2
tyrosyl-DNA phosphodiesterase 2
Chromosome 6 Β· 6p22.3
NCBI Gene: 51567Ensembl: ENSG00000111802.15HGNC: HGNC:17768UniProt: A0A384MDM5
89PubMed Papers
21Diseases
0Drugs
13Pathogenic Variants
FUNCTIONAL ROLE
DNA Repair
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
magnesium ion binding5'-tyrosyl-DNA phosphodiesterase activitydouble-strand break repairneuron developmentspinocerebellar ataxia, autosomal recessive 23Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiencyneurodegenerative diseasegenetic disorder
✦AI Summary

TDP2 (tyrosyl-DNA phosphodiesterase 2) is a 5'-tyrosyl-DNA phosphodiesterase that serves dual roles in DNA repair and viral pathogenesis. Primarily, TDP2 excises topoisomerase II-DNA adducts by cleaving covalent protein-DNA crosslinks generated during topoisomerase-mediated DNA metabolism 1. This repair function coordinates with non-homologous end joining (NHEJ) pathway components Ku and ligase IV 1. Additionally, TDP2 contributes to suppressing genomic instability caused by DNA-protein crosslinks through ubiquitylation-dependent mechanisms working alongside SPRTN and PARP1-driven pathways 23. Clinically, TDP2 is essential for picornavirus replication, removing the VPg (viral protein genome-linked) primer from viral RNA 5'-ends 1. Mutations in TDP2 cause spinocerebellar ataxia type 23, suggesting critical roles in neuronal function 4. TDP2 represents a therapeutic target: inhibition synergizes with topoisomerase II inhibitors (etoposide, doxorubicin) in cancer treatment, while TDP2 inhibition may prevent viral replication 15. Post-translational modifications fine-tune TDP2's regulatory networks for optimal repair efficiency 67, positioning TDP2 as a multifunctional enzyme bridging genome stability and host-pathogen interactions.

Sources cited
1
TDP2 excises topoisomerase II-DNA adducts, coordinates with Ku and ligase IV in NHEJ, essential for picornavirus VPg removal, and potential anticancer/antiviral target
PMID: 24856239
2
TDP1/TDP2 deficiency causes sensitivity to DNA-protein crosslinks and chromosomal instability independently of direct DPC removal
PMID: 36282523
3
TDP2 mediates repair of topoisomerase cleavage complexes; TDP2 mutations associated with neurodegenerative disease
PMID: 27649880
4
TDP2 participates in ubiquitylation-driven repair pathway for topoisomerase III-DNA crosslinks alongside PARP1 and SPRTN
PMID: 39028621
5
Post-translational modifications regulate TDP2 function in repairing trapped topoisomerase-DNA covalent complexes
PMID: 35101776
6
TDP2 inhibitors show synergy with topoisomerase II inhibitors in cancer cells, providing therapeutic potential
PMID: 27128689
7
Post-translational modifications orchestrate TDP2-mediated repair of topoisomerase cleavage complexes
PMID: 40581090
8
TDP2 resolves abortive topoisomerase cleavage complexes that threaten genome stability
PMID: 32653827
Disease Associationsβ“˜21
spinocerebellar ataxia, autosomal recessive 23Open Targets
0.71Strong
Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiencyOpen Targets
0.71Strong
neurodegenerative diseaseOpen Targets
0.54Moderate
genetic disorderOpen Targets
0.41Moderate
cerebellar ataxiaOpen Targets
0.34Weak
neoplasmOpen Targets
0.09Suggestive
lung cancerOpen Targets
0.08Suggestive
prostate cancerOpen Targets
0.08Suggestive
non-small cell lung carcinomaOpen Targets
0.06Suggestive
iritisOpen Targets
0.06Suggestive
uveitisOpen Targets
0.06Suggestive
infectionOpen Targets
0.05Suggestive
cancerOpen Targets
0.05Suggestive
colorectal carcinomaOpen Targets
0.04Suggestive
hemorrhageOpen Targets
0.03Suggestive
complicationOpen Targets
0.03Suggestive
poliovirus infectionOpen Targets
0.03Suggestive
lung carcinomaOpen Targets
0.03Suggestive
immunodeficiency 19Open Targets
0.03Suggestive
combined immunodeficiency due to ZAP70 deficiencyOpen Targets
0.03Suggestive
Spinocerebellar ataxia, autosomal recessive, 23UniProt
Pathogenic Variants13
NM_016614.3(TDP2):c.400C>T (p.Arg134Ter)Pathogenic
not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 134
NM_016614.3(TDP2):c.591del (p.Pro198fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 198
NM_016614.3(TDP2):c.580_581del (p.Gln194fs)Pathogenic
Inborn genetic diseases
β˜…β˜†β˜†β˜†2023β†’ Residue 194
NM_016614.3(TDP2):c.949C>T (p.Arg317Ter)Pathogenic
Spinocerebellar ataxia, autosomal recessive 23
β˜…β˜†β˜†β˜†2022β†’ Residue 317
NM_016614.3(TDP2):c.392_395del (p.Glu131fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 131
NM_016614.3(TDP2):c.390dup (p.Glu131fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 131
NM_016614.3(TDP2):c.635_636+2delLikely pathogenic
Spinocerebellar ataxia, autosomal recessive 23
β˜…β˜†β˜†β˜†2021
NM_016614.3(TDP2):c.650del (p.Gly217fs)Pathogenic
Spinocerebellar ataxia, autosomal recessive 23
β˜…β˜†β˜†β˜†2020β†’ Residue 217
NM_016614.3(TDP2):c.4G>T (p.Glu2Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2020β†’ Residue 2
NM_016614.3(TDP2):c.636+3_636+6delPathogenic
Cerebellar ataxia
β˜…β˜†β˜†β˜†2020
NM_016614.3(TDP2):c.389C>G (p.Ser130Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2019β†’ Residue 130
NM_016614.3(TDP2):c.425+1G>APathogenic
Spinocerebellar ataxia, autosomal recessive 23|Sarcoma
β˜†β˜†β˜†β˜†2018
NM_016614.3(TDP2):c.413_414delinsAA (p.Ser138Ter)Pathogenic
Spinocerebellar ataxia, autosomal recessive 23
β˜†β˜†β˜†β˜†2017β†’ Residue 138
View on ClinVar β†—
Related Genes
UBA52Protein interaction100%UBBProtein interaction100%UBCProtein interaction100%TOP2AProtein interaction97%KIAA0319Protein interaction94%DCDC2Protein interaction94%
Tissue Expression6 tissues
Brain
100%
Heart
61%
Liver
59%
Bone Marrow
50%
Lung
47%
Ovary
31%
Gene Interaction Network
Click a node to explore
TDP2UBA52UBBUBCTOP2AKIAA0319DCDC2
PROTEIN STRUCTURE
Preparing viewer…
PDB6Q00 Β· 0.85 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
1.20LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.89 [0.67–1.20]
RankingsWhere TDP2 stands among ~20K protein-coding genes
  • #5,384of 20,598
    Most Researched89
  • #2,591of 5,498
    Most Pathogenic Variants13
  • #12,569of 17,882
    Most Constrained (LOEUF)1.20
Genes detectedTDP2
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2).
PMID: 24856239
DNA Repair (Amst) Β· 2014
1.00
2
SPRTN and TDP1/TDP2 Independently Suppress 5-Aza-2'-deoxycytidine-Induced Genomic Instability in Human TK6 Cell Line.
PMID: 36282523
Chem Res Toxicol Β· 2022
0.90
3
Roles of eukaryotic topoisomerases in transcription, replication and genomic stability.
PMID: 27649880
Nat Rev Mol Cell Biol Β· 2016
0.80
4
PARP1-driven repair of topoisomerase IIIΞ± DNA-protein crosslinks by FEN1.
PMID: 39028621
Cell Rep Β· 2024
0.70
5
Post-translational regulation of Tyrosyl-DNA phosphodiesterase (TDP1 and TDP2) for the repair of the trapped topoisomerase-DNA covalent complex.
PMID: 35101776
DNA Repair (Amst) Β· 2022
0.60