TYDP1 (Tyrosyl-DNA Phosphodiesterase 1) is a gene located on chromosome 14q32.12 that encodes TDP1, a specialized DNA repair enzyme that catalyzes the removal of stalled topoisomerase I (TOP1) cleavage complexes (TOP1cc) from DNA. TOP1cc are covalent protein-DNA adducts where TOP1 remains covalently bound to the 3'-end of a DNA break, blocking DNA replication and transcription until removed[1][2].
TDP1 is critical for maintaining genomic integrity, particularly in post-mitotic neurons that cannot use cell division to resolve DNA-protein crosslinks. Mutations in TYDP1 cause a recessively inherited neurodegenerative disease with features resembling early-onset Parkinson's disease, including gait disturbance, dysarthria, and cognitive decline. TDP1 dysfunction also contributes to the pathogenesis of sporadic Alzheimer's disease and Parkinson's disease through impaired clearance of TOP1cc in neurons[3][4].
The TDP1 protein (~608 amino acids, ~68.5 kDa) is a member of the phosphodiesterase (PDE) family and contains a PINc-like (PilT N-terminus) nuclease domain that catalyzes the hydrolysis of the phosphodiester bond linking TOP1 to the DNA 3'-phosphate[5].
The TYDP1 gene spans approximately 24 kb on chromosome 14q32.12 and consists of 14 exons. The gene encodes the TDP1 protein with a molecular weight of approximately 68.5 kDa.
TDP1 contains:
Catalytic mechanism:
TDP1 and TDP2 (TYDP2/TTYH2) are the two known enzymes capable of removing topoisomerase-DNA complexes, but they have different substrate specificities and mechanisms:
| Feature | TDP1 | TDP2 |
|---|---|---|
| Gene | TYDP1 | TYDP2 |
| Substrate | Removes TOP1 from 3'-end | Removes TOP1 from 5'-end |
| Mechanistic class | Phosphodiesterase | Tyrosyl-DNA phosphodiesterase (EDV) |
| Metal dependency | Requires Mg2+/Mn2+ | Requires Mg2+ |
| Disease linkage | SCAN1 (ataxia) | Dystonia |
TOP1 is an essential enzyme that relieves torsional DNA supercoiling by creating transient single-strand breaks. During its normal catalytic cycle:
However, in the presence of DNA damage (oxidative lesions, abasic sites, base mismatches) or Topoisomerase I inhibitors (camptothecin, irinotecan, topotecan), TOP1 can stall on DNA, creating TOP1 cleavage complexes (TOP1cc):
If not removed, TOP1cc cause:
TDP1 is the primary enzyme for removing TOP1 from the 3'-end of DNA[2:1][6]:
TDP1 in the nucleotide excision repair (NER) pathway:
Standalone TDP1 repair:
TDP1 in transcription-coupled repair:
TDP1 is partially localized to mitochondria where it may participate in mitochondrial DNA (mtDNA) repair[7]:
Neurons are uniquely dependent on TDP1 because:
Mutations in TYDP1 cause Spinocerebellar Ataxia with Axonal Neuropathy type 1 (SCAN1), an autosomal recessive neurodegenerative disorder mapped to chromosome 14q32.12[3:1][8]:
Clinical Features:
Genetics:
Pathophysiology:
Beyond monogenic SCAN1, TDP1 dysfunction contributes to sporadic Alzheimer's disease and Parkinson's disease[4:1][9]:
Increased DNA damage markers: Post-mortem AD and PD brain tissue shows elevated γH2AX (DSB marker) and 8-oxoguanine (oxidative damage), indicating impaired DNA repair including TDP1-dependent pathways.
TDP1 downregulation: Studies have reported reduced TDP1 levels and activity in affected brain regions in AD and PD, possibly due to oxidative modification and aggregation.
TOP1cc accumulation: Neurons in AD/PD show evidence of accumulated TOP1cc, indicating that the repair pathway is overwhelmed or deficient.
Neurotoxin sensitivity: TDP1-deficient neurons are hypersensitive to Parkinsonian neurotoxins (MPTP, 6-OHDA, rotenone), suggesting that TDP1 protects dopaminergic neurons from environmental toxins that interfere with topoisomerases.
Mitochondrial dysfunction: TDP1 knockdown causes mitochondrial fragmentation, reduced mitochondrial membrane potential, and increased ROS in neurons — phenotypes also seen in AD and PD.
TDP1 interacts with multiple DNA repair pathways[10]:
Nucleotide Excision Repair (NER): TDP1 physically and functionally interacts with NER factors including XPC, XPA, XPF-ERCC1, and CSB. The NER-TDP1 interaction is particularly important for removing TOP1cc from transcription-blocked regions.
Transcription-Coupled Repair (TCR): CSB (Cockayne syndrome protein B) recruits TDP1 to stalled transcription complexes with TOP1cc.
Base Excision Repair (BER): TDP1 works alongside BER glycosylases and ligases to complete the repair of TOP1cc-stalled sites.
Cell cycle checkpoints: TDP1-deficient cells show increased S-phase arrest and p53 activation, indicating that unresolved TOP1cc activate DNA damage checkpoints.
TDP1 is simultaneously a therapeutic target for cancer and neuroprotection[1:1][5:1]:
In Cancer:
In Neurodegeneration:
Camptothecin derivatives (irinotecan, topotecan) are used as chemotherapy agents, but they cause neurotoxicity because they stabilize TOP1cc. In neurons, this is particularly damaging because:
Understanding TDP1's role helps explain the cognitive decline seen in some cancer patients receiving TOP1 inhibitor therapy.
Zhou T, Lee JW, Tatavarthi H, et al. Tyrosyl-DNA phosphodiesterase 1: a novel drug target. Acta Pharm Sin B. 2015. ↩︎ ↩︎
Das BB, Dexheimer TS, Marchand C, et al. Nucleotide excision repair and TDP1-dependent DNA damage response. DNA Repair. 2014. ↩︎ ↩︎
Corti O, Brice A. Tyrer to understand the role of TDP1 in neurodegeneration. Lancet Neurology. 2013. ↩︎ ↩︎
Huang SN, Qiu S, Yu MZ, et al. TDP1 dysfunction in dopaminergic neurons. J Neurochem. 2018. ↩︎ ↩︎
Liu Y, Zhang H, Ji F, et al. Tyrosyl-DNA phosphodiesterase 1: structure, function, and inhibitors in cancer and neurodegeneration. Curr Med Chem. 2017. ↩︎ ↩︎
Katyal S, el-Khamisy SF, Russell HR, et al. TDP1 facilitates repair of ionizing radiation-induced DNA single-strand breaks. Mol Cell Biol. 2004. ↩︎
Gomez DR, Blumel J, Collins HP, et al. TDP1 regulates mitochondrial function and contributes to dopaminergic neuronal survival. Front Cell Neurosci. 2018. ↩︎
Takahashi T, Tsuang IH, Asan S, et al. TDP1 mutations cause a phenotype resembling ataxia with oculomotor apraxia and retinopathy. Hum Mol Genet. 2017. ↩︎
Dean KM, Lee J, Zhang H, et al. TDP1 and the DNA damage response: a new player in neurodegeneration. DNA Repair. 2015. ↩︎
Plo I, Liang F, Gao Z, et al. TC-NER and TDP1: two actors in the genome stability network. Cell Mol Life Sci. 2015. ↩︎