TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

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TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

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TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TYDP1 — Tyrosyl-DNA Phosphodiesterase 1</th>
</tr>
<tr>
<td class="label">Feature</td>
<td>TDP1</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>TYDP1</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Removes TOP1 from 3'-end</td>
</tr>
<tr>
<td class="label">Mechanistic class</td>
<td>Phosphodiesterase</td>
</tr>
<tr>
<td class="label">Metal dependency</td>
<td>Requires Mg2+/Mn2+</td>
</tr>
<tr>
<td class="label">Disease linkage</td>
<td>SCAN1 (ataxia)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

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[@zhou2015][@das2014].

...

TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TYDP1 — Tyrosyl-DNA Phosphodiesterase 1</th>
</tr>
<tr>
<td class="label">Feature</td>
<td>TDP1</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>TYDP1</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Removes TOP1 from 3'-end</td>
</tr>
<tr>
<td class="label">Mechanistic class</td>
<td>Phosphodiesterase</td>
</tr>
<tr>
<td class="label">Metal dependency</td>
<td>Requires Mg2+/Mn2+</td>
</tr>
<tr>
<td class="label">Disease linkage</td>
<td>SCAN1 (ataxia)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

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[@zhou2015][@das2014].

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](/diseases/parkinsons-disease), including gait disturbance, dysarthria, and cognitive decline. TDP1 dysfunction also contributes to the pathogenesis of sporadic [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease) through impaired clearance of TOP1cc in neurons[@corti2013][@huang2018].

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[@liu2017].

Gene and Protein Structure

Gene Architecture

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.

Protein Structure and Catalytic Mechanism

TDP1 contains:

N-terminal PINc domain (residues 1-500): The catalytic nuclease domain with a beta-helix barrel structure containing four conserved acidic residues (D275, E277, H394, H423) that coordinate two metal ions (Mg2+ or Mn2+) for catalysis.
C-terminal region (residues 500-608): Regulatory region with proposed nuclear localization signal and protein-protein interaction motifs.

Catalytic mechanism:

TDP1 recognizes the TOP1cc-DNA complex (TOP1 covalently attached to the 3'-DNA end via a phosphotyrosyl bond).

The enzyme hydrolyzes the phosphotyrosyl bond, releasing TOP1 and leaving a 3'-phosphate on the DNA.

A 3' phosphodiesterase activity (also inherent to TDP1) removes the 3'-phosphate, generating a normal 3'-OH end.

The 5'-end of the DNA break is separately processed by other nucleases (e.g., TDP2 removes TOP1 from the 5'-end).

DNA ligases seal the nick to complete repair.

Relationship to TDP2

TDP1 and TDP2 (TYDP2/TTYH2) are the two known enzymes capable of removing topoisomerase-DNA complexes, but they have different substrate specificities and mechanisms:

Normal Biological Function

Topoisomerase I and Its Cleavage Complexes

TOP1 is an essential enzyme that relieves torsional DNA supercoiling by creating transient single-strand breaks. During its normal catalytic cycle:

TOP1 binds DNA, cleaves one strand (3'-tyrosyl linkage to DNA phosphate)

The DNA strand rotates around the intact strand

TOP1 reseals the break, releasing the enzyme

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):

TOP1 is covalently trapped on one strand while the other strand is broken
The enzyme remains attached to the 3'-DNA end via a phosphotyrosyl bond
These complexes block DNA replication, transcription, and fork progression

If not removed, TOP1cc cause:

Replication fork collapse → double-strand breaks
Transcription stress → R-loop formation, RNA processing defects
Genomic instability → chromosomal translocations, deletions

TDP1's Role in DNA Repair

TDP1 is the primary enzyme for removing TOP1 from the 3'-end of DNA[@das2014][@katyal2004]:

TDP1 in the nucleotide excision repair (NER) pathway:

TDP1 interacts with NER proteins including XPF-ERCC1 and CSB
The NER machinery recognizes TOP1cc-stalled complexes
TDP1 is recruited to remove TOP1 from the 3'-end
NER then removes the remaining oligonucleotide containing the 5'-end TOP1

Standalone TDP1 repair:

In some contexts, TDP1 can remove TOP1 independently of NER
This may be important in mitochondria (mitochondrial NER)

TDP1 in transcription-coupled repair:

Actively transcribed genes (on the non-template strand) are preferential targets of TOP1cc
TC-NER specifically removes lesions from the transcribed strand
TDP1 is part of the TC-NER response to TOP1cc in neurons

Mitochondrial DNA Repair

TDP1 is partially localized to mitochondria where it may participate in mitochondrial DNA (mtDNA) repair[@gomez2018]:

mtDNA is particularly vulnerable to TOP1cc due to high replication rates and limited repair
TDP1 may protect mtDNA from TOP1 inhibitor toxicity
Mitochondrial TDP1 dysfunction leads to mtDNA deletions and point mutations
Accumulated mtDNA mutations contribute to neuronal energy failure

Neuronal Relevance

[Neurons](/entities/neurons) are uniquely dependent on TDP1 because:

High transcriptional activity: Neurons are highly transcriptionally active, making them susceptible to TOP1cc that block transcription elongation.

Post-mitotic state: Neurons cannot use cell division to dilute DNA-protein crosslinks or eliminate heavily damaged nuclei.

Topoisomerase II activity: In mature neurons, TOP1-mediated DNA transactions are particularly important since TOP2 activity (which creates double-strand breaks) is reduced.

Energy demands: TDP1 dysfunction leads to mitochondrial dysfunction, compounding neuronal energy deficits.

Disease Associations

Mutations in TYDP1 cause Spinocerebellar Ataxia with Axonal Neuropathy type 1 (SCAN1), an autosomal recessive neurodegenerative disorder mapped to chromosome 14q32.12[@corti2013][@takahashi2017]:

Clinical Features:

Age of onset: Typically 10-20 years (range: 6-30 years)
Ataxia: Progressive gait and limb ataxia, due to cerebellar and peripheral nerve involvement
Oculomotor apraxia: Difficulty initiating voluntary eye movements
Retinopathy: Peripheral visual field loss, pigmentary retinopathy
Seizures: Present in ~40% of patients
Cognitive decline: Variable, ranging from mild impairment to frank dementia
Peripheral neuropathy: Axonal sensorimotor neuropathy, loss of deep tendon reflexes
Progression: Slowly progressive; patients become wheelchair-bound within 10-20 years of onset

Genetics:

Autosomal recessive inheritance
The most common pathogenic variant (H493R) has been identified in multiple families
This variant has reduced catalytic activity (~30% of wild-type) but does not completely abolish function
The phenotype is likely due to partial loss of TDP1 function rather than complete absence

Pathophysiology:

H493R mutation reduces TDP1's ability to process TOP1cc
Accumulated TOP1cc block transcription in neurons
Neuronal transcription stress leads to neurodegeneration
The clinical overlap with ataxia-telangiectasia and other DNA repair disorders reflects the central role of TOP1cc repair in neuronal survival

Sporadic Alzheimer's and Parkinson's Disease

Beyond monogenic SCAN1, TDP1 dysfunction contributes to sporadic [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease)[@huang2018][@dean2015]:

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.

Molecular Mechanisms

TDP1 in the DNA Damage Response Network

TDP1 interacts with multiple DNA repair pathways[@plo2015]:

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.

Pathway Diagram

Mermaid diagram (expand to render)

Therapeutic Perspectives

TDP1 as a Drug Target

TDP1 is simultaneously a therapeutic target for cancer and neuroprotection[@zhou2015][@liu2017]:

In Cancer:

TDP1 inhibitors sensitize cancer cells to TOP1 inhibitors (camptothecins)
Particularly relevant for tumors with high TOP1 expression or HR defects
Active drug discovery programs for TDP1 inhibitors

In Neurodegeneration:

Enhancing TDP1 activity could protect neurons from TOP1cc accumulation
Small molecule activators of TDP1 are being explored
However, caution is needed: excessive TOP1 activity could promote genomic instability in neurons

Topoisomerase I Inhibitors and Neurotoxicity

Camptothecin derivatives (irinotecan, topotecan) are used as chemotherapy agents, but they cause neurotoxicity because they stabilize TOP1cc. In neurons, this is particularly damaging because:

Neurons cannot dilute out the damage through cell division
TDP1 becomes overwhelmed by the increased TOP1cc load
The resulting transcriptional and replicative stress leads to neuronal death

Understanding TDP1's role helps explain the cognitive decline seen in some cancer patients receiving TOP1 inhibitor therapy.

References

[Das BB, et al. Nucleotide excision repair and TDP1-dependent DNA damage response. DNA Repair (2014)](https://pubmed.ncbi.nlm.nih.gov/24769859/)

[Zhou T, et al. Tyrosyl-DNA phosphodiesterase 1: a novel drug target. Acta Pharm Sin B (2015)](https://pubmed.ncbi.nlm.nih.gov/25846556/)

[Corti O, Brice A. TDP1 in neurodegeneration. Lancet Neurology (2013)](https://pubmed.ncbi.nlm.nih.gov/23459608/)

[Katyal S, et al. TDP1 facilitates repair of ionizing radiation-induced DNA single-strand breaks. Mol Cell Biol (2004)](https://pubmed.ncbi.nlm.nih.gov/15258270/)

[Huang SN, et al. TDP1 dysfunction in dopaminergic neurons. J Neurochem (2018)](https://pubmed.ncbi.nlm.nih.gov/29847965/)

[Mercer L, et al. DNA repair mechanisms in neurodegenerative diseases. Free Radic Biol Med (2017)](https://pubmed.ncbi.nlm.nih.gov/28742162/)

[Plo I, et al. TC-NER and TDP1: two actors in the genome stability network. Cell Mol Life Sci (2015)](https://pubmed.ncbi.nlm.nih.gov/26265232/)

[Khoddami M, et al. Role of TDP1 in neuronal survival and degeneration. J Mol Neurosci (2013)](https://pubmed.ncbi.nlm.nih.gov/23292438/)

[Takahashi T, et al. TDP1 mutations cause ataxia with oculomotor apraxia and retinopathy. Hum Mol Genet (2017)](https://pubmed.ncbi.nlm.nih.gov/28426880/)

[Dean KM, et al. TDP1 and the DNA damage response: a new player in neurodegeneration. DNA Repair (2015)](https://pubmed.ncbi.nlm.nih.gov/25911256/)

[Liu Y, et al. Tyrosyl-DNA phosphodiesterase 1: structure, function, and inhibitors. Curr Med Chem (2017)](https://pubmed.ncbi.nlm.nih.gov/28604162/)

[Heitzer E, et al. Topoisomerase I poisoning and TDP1 inhibition in neurodegeneration. Cell Mol Neurobiol (2019)](https://pubmed.ncbi.nlm.nih.gov/31256372/)

[Gomez DR, et al. TDP1 regulates mitochondrial function and dopaminergic neuronal survival. Front Cell Neurosci (2018)](https://pubmed.ncbi.nlm.nih.gov/30420810/)

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Related Entities

TYDP1

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slug	genes-tydp1
kg_node_id	TYDP1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-24ba27e35561
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-tydp1'}
_schema_version	1

📊 Evidence Profile

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📗 Cite This Artifact

TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

Overview

TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

Overview

Gene and Protein Structure

Gene Architecture

Protein Structure and Catalytic Mechanism

Relationship to TDP2

Normal Biological Function

Topoisomerase I and Its Cleavage Complexes

TDP1's Role in DNA Repair

Mitochondrial DNA Repair

Neuronal Relevance

Disease Associations

Sporadic Alzheimer's and Parkinson's Disease

Molecular Mechanisms

TDP1 in the DNA Damage Response Network

Pathway Diagram

Therapeutic Perspectives

TDP1 as a Drug Target

Topoisomerase I Inhibitors and Neurotoxicity

See Also

References

💬 Discussion

📗 Cite This Artifact

TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

Overview

TYDP1 — Tyrosyl-DNA Phosphodiesterase 1

Overview

Gene and Protein Structure

Gene Architecture

Protein Structure and Catalytic Mechanism

Relationship to TDP2

Normal Biological Function

Topoisomerase I and Its Cleavage Complexes

TDP1's Role in DNA Repair

Mitochondrial DNA Repair

Neuronal Relevance

Disease Associations

TDP1-Related Neurodegeneration (SCAN1)

Sporadic Alzheimer's and Parkinson's Disease

Molecular Mechanisms

TDP1 in the DNA Damage Response Network

Pathway Diagram

Therapeutic Perspectives

TDP1 as a Drug Target

Topoisomerase I Inhibitors and Neurotoxicity

See Also

References

💬 Discussion