PRIMPOL — DNA Primase/Polymerase
Overview
PRIMPOL (DNA Primase/Polymerase) is a unique bifunctional enzyme belonging to the archaeo-eukaryotic primase (AEP) family. Located on chromosome 9q34.2, the gene encodes a 517-amino acid protein with a molecular weight of approximately 58 kDa. PRIMPOL represents a remarkable fusion of ancient and modern DNA metabolism functions, possessing both DNA primase activity to initiate DNA synthesis and translesion synthesis (TLS) polymerase activity to bypass DNA lesions that would otherwise block replication [1](https://pubmed.ncbi.nlm.nih.gov/23750002/).
PRIMPOL is distinguished among[@garcia-gomez2015] eukaryotic DNA metabolism enzymes by its dual catalytic capabilities. Unlike classical primases that function exclusively in replication initiation or specialized TLS polymerases that only perform lesion bypass, PRIMPOL can perform both functions. This makes it uniquely positioned to contribute to nuclear DNA replication restart following replication stress and to serve as the primase for mitochondrial DNA (mtDNA) replication [3](https://pubmed.ncbi.nlm.nih.gov/26220072/).
The protein localizes to both cellular compartments where it performs essential functions: in mitochondria where it serves as the primase for mtDNA replication, and in the nucleus where it operates at stalled replication forks and contributes to the DNA damage response. Nuclear localization is dynami[@yang2019]c and increases in response to DNA damage, reflecting its role in managing replication stress [9](https://pubmed.ncbi.nlm.nih.gov/31163628/).
<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">PRIMPOL — DNA Primase/Polymerase</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>PRIMPOL</td></tr>
<tr><td><strong>Full Name</strong></td><td>DNA Primase/Polymerase</td></tr>
<tr><td><strong>Chromosome</strong></td><td>9q34.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[84295](https://www.ncbi.nlm.nih.gov/gene/84295)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[616761](https://www.omim.org/entry/616761)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>[ENSG00000146859](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000146859)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q8IY92](https://www.uniprot.org/uniprot/Q8IY92)</td></tr>
<tr><td><strong>Protein Length</strong></td><td>517 amino acids</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>~58 kDa</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Alzheimer's Disease, Parkinson's Disease, ALS, Cancer</td></tr>
</table>
</div>
Gene and Protein Structure
Genomic Organization
The PRIMPOL gene spans approximately 15 kb on chromosome 9q34.2 and consists of 14 exons. The gene is transcribed into a 2.1 kb mRNA that encodes the 517-amino acid protein. The gene is evolutionarily con[@iyer2015]served, with orthologs found in all eukaryotes, reflecting its fundamental importance in DNA metabolism [2](https://pubmed.ncbi.nlm.nih.gov/24889369/).
Protein Architecture
PRIMPOL contains several functional domains:
N-terminal Primase Domain: Contains the active site for primer synthesis, utilizing ATP to create short RNA-DNA primers. This domain retains the catalytic core of the ancient AEP family primases.
C-terminal Polymerase Domain: Belongs to the UB logarithmic (Lyn) family of DNA polymerases. This domain catalyzes translesion DNA synthesis using a template-switching mechanism.
Mitochondrial Targeting Sequence (MTS): An N-terminal signal that directs the protein to mitochondria. This sequence is cleaved upon mitochondrial import.
RPA-Binding Domain: A region that mediates interaction with replication protein A (RPA), enabling recruitment to stalled replication forks.
DNA-Binding Regions: Multiple basic regions that facilitate DNA binding, essential for both primase and polymerase activities.Catalytic Properties
PRIMPOL exhibits remarkable catalytic versatility:
Primase Activity:
- Can initiate DNA synthesis de novo using NTPs
- Prefers to synthesize short primers (8-12 nucleotides)
- Requires DNA templates with single-stranded regions
- Can use both RNA and DNA nucleotides
- Activity is manganese-dependent
Polymerase Activity:
- Can extend primers past DNA lesions
- Low processivity compared to replicative polymerases
- Can incorporate nucleotides opposite damaged bases
- Template-switching mechanism for lesion bypass
- Higher error rate than replicative polymerases
Biological Functions
Mitochondrial DNA Replication
PRIMPOL serves as the primase for human mitochondrial DNA replication [3](https://pubmed.ncbi.nlm.nih.gov/26220072/):
Primer Synthesis: PRIMPOL synthesizes RNA-DNA primers at the origin of mtDNA replication (OH).
Primer Extension: The mitochondrial DNA polymerase γ extends these primers to complete mtDNA replication.
Primase Replacement: In mitochondrial replication, PRIMPOL can replace the classical primase that was lost during evolution.
Maintenance of mtDNA: Proper primer synthesis is essential for maintaining mtDNA copy number and integrity.The importance of PRIMPOL in mtDNA maintenance is highlighted by studies showing that loss of PRIMPOL leads to mtDNA depletion and mitochondrial dysfunction [11](https://pubmed.ncbi.nlm.nih.gov/34028872/).
Nuclear Translesion Synthesis
In the nucleus, PRIMPOL functions as a specialized TLS polymerase [8](https://pubmed.ncbi.nlm.nih.gov/29479641/):
Replication Fork Stalling: When replicative polymerases encounter DNA lesions (8-oxoguanine, UV-induced pyrimidine dimers, base alkylations), the replication fork stalls.
PRIMPOL Recruitment: PRIMPOL is recruited to the stalled fork through interactions with RPA and checkpoint proteins [13](https://pubmed.ncbi.nlm.nih.gov/31293274/).
Primer Synthesis Downstream: PRIMPOL synthesizes a new primer downstream of the lesion.
Lesion Bypass: Using its polymerase activity, PRIMPOL extends the primer past the lesion.
Replication Restart: After lesion bypass, the primer is handed off to replicative polymerases for continued DNA synthesis.This pathway is particularly important in cells with high rates of endogenous DNA damage, such as neurons that are post-mitotic and cannot rely on DNA replication for repair [10](https://pubmed.ncbi.nlm.nih.gov/32803715/).
DNA Damage Response
PRIMPOL contributes to the cellular DNA damage response:
Checkpoint Activation: PRIMPOL recruitment to stalled forks activates ATR/Chk1 checkpoint signaling.
Repair Scaffold Formation: The protein helps organize repair complexes at damaged DNA.
Replication Restart: Facilitates restart of stalled forks, preventing fork collapse and DNA double-strand breaks.
Genome Stability: Through its activities, PRIMPOL helps maintain genomic stability, particularly in dividing cells.Protein Interactions
PRIMPOL interfaces with multiple protein complexes:
Replication Protein A (RPA):
- Primary recruitment factor for nuclear PRIMPOL
- RPA binding domain facilitates fork localization
- Complexes protect single-stranded DNA during stress
Checkpoint Proteins:
- ATR/ATRIP for kinase signaling
- MDC1 (Mediator of DNA Damage Checkpoint 1)
- 53BP1 for downstream repair pathway choice
Mitochondrial Replication:
- TWINKLE helicase for mtDNA unwinding
- mtSSB (mitochondrial single-stranded binding protein)
- DNA polymerase γ for mtDNA synthesis
Role in Neurodegenerative Diseases
Alzheimer's Disease
PRIMPOL has been implicated in Alzheimer's disease pathogenesis through multiple mechanisms [4](https://pubmed.ncbi.nlm.nih.gov/28968465/):
Oxidative Stress Connection:
The brain consumes approximately 20% of total body oxygen while comprising only 2% of body mass. This high metabolic rate, combined with limited antioxidant capacity, results in persistent oxidative stress in neuronal cells. This oxidative stress produces multiple types of DNA lesions:
- 8-oxoguanine: The most common oxidative DNA lesion, resulting from oxidation of guanine bases
- Single-strand breaks: Arising from repair of oxidative damage or direct oxidative attack
- Base alkylations: Modified bases from reactive oxygen species
- Interstrand crosslinks: More complex lesions from chronic oxidative stress
AD brains show dramatically elevated levels of oxidative DNA damage in neurons compared to age-matched controls. This damage accumulates over decades and is thought to contribute to neuronal dysfunction and death.
TLS in Alzheimer's Disease:
PRIMPOL's TLS activity may represent a double-edged sword in AD:
- Neuroprotective Function: PRIMPOL's ability to bypass oxidative DNA lesions may help neurons cope with the heavy burden of oxidative DNA damage, potentially delaying neuronal death.
- Pathogenic Consequences: Chronic activation of TLS pathways can be problematic. Translesion polymerases incorporate mutations at higher rates than replicative polymerases, and persistent TLS may contribute to genomic instability in neurons [7](https://pubmed.ncbi.nlm.nih.gov/34567890/).
- PARP Activation: DNA damage in AD activates PARP (poly ADP-ribose polymerase), which consumes NAD+ and can lead to energy depletion. PRIMPOL-mediated repair may influence this process.
Therapeutic Implications:
Modulating PRIMPOL or associated DNA repair pathways represents a potential therapeutic strategy for AD:
- DNA Repair Enhancement: Small molecules that stabilize PRIMPOL binding to DNA or enhance its catalytic activity could improve neuronal survival
- Antioxidant Approaches: Reducing oxidative DNA damage burden could decrease reliance on TLS
- Combination Therapies: PARP inhibitors combined with DNA repair enhancers may show synergy
Parkinson's Disease
In Parkinson's disease, PRIMPOL intersects with the hallmark mitochondrial dysfunction [5](https://pubmed.ncbi.nlm.nih.gov/30858154/):
Mitochondrial DNA Maintenance:
PRIMPOL's essential role as the mitochondrial DNA primase is critical for maintaining the mitochondrial genome. PD is characterized by:
- mtDNA Mutations: PD neurons show accumulation of mitochondrial DNA mutations that impair energy production
- Complex I Deficiency: Mutations in mtDNA-encoded complex I subunits reduce oxidative phosphorylation
- Dopaminergic Neuron Vulnerability: The high metabolic demands of dopaminergic neurons make them particularly dependent on proper mitochondrial function
PRIMPOL Variants and Risk:
Genetic studies have identified PRIMPOL variants in PD patients:
- Some rare variants may reduce mitochondrial DNA replication fidelity
- These variants could contribute to progressive dopaminergic neuron loss
- The pathogenic significance of most PRIMPOL variants in PD remains under investigation
Therapeutic Potential:
Targeting PRIMPOL in PD:
- Mitochondrial-Targeted Therapies: Improving mtDNA maintenance through PRIMPOL modulation
- Antioxidant Approaches: Reducing oxidative damage to mtDNA
- Gene Therapy: Increasing PRIMPOL expression in dopaminergic neurons
Amyotrophic Lateral Sclerosis (ALS)
DNA repair deficits contribute to ALS pathogenesis [6](https://pubmed.ncbi.nlm.nih.gov/33168716/):
Motor Neuron Vulnerability:
Motor neurons have exceptionally high metabolic demands and limited regenerative capacity:
- High Energy Requirements: Motor neurons require substantial ATP for maintenance of large axonal domains
- Long Axons: The length of motor neuron axons creates significant logistical challenges for cellular maintenance
- Limited Repair Capacity: Post-mitotic neurons cannot replace damaged cells, so DNA damage accumulates over time
- Calcium Homeostasis: Motor neurons rely on calcium handling that can be disrupted by DNA damage
PRIMPOL Variants in ALS:
- Some ALS patients carry PRIMPOL variants
- These variants may impair DNA repair capacity
- Could accelerate motor neuron loss through accumulated DNA damage
Common Mechanisms:
Like AD and PD, ALS involves:
- Oxidative stress
- Mitochondrial dysfunction
- Impaired DNA repair
- Energy metabolism deficits
PRIMPOL sits at the intersection of these pathways, making it a protein of interest in understanding ALS pathogenesis.
Expression Patterns
Tissue Distribution
PRIMPOL exhibits tissue-specific expression:
| Tissue | Expression Level | Notes |
|--------|-----------------|-------|
| Brain | Moderate-High | Neurons and glia |
| Heart | High | Cardiac muscle energy demands |
| Muscle | High | High metabolic activity |
| Liver | Moderate | Hepatocyte metabolism |
| Kidneys | Moderate | Renal cell function |
| Testis | High | Spermatogenesis |
| Ovaries | Moderate | Follicle development |
Brain Region Distribution
In the brain, PRIMPOL shows region-specific expression:
- Cerebral Cortex: High expression in pyramidal neurons
- Hippocampus: High expression in CA1-CA3 regions and dentate gyrus granule cells
- Cerebellum: High expression in Purkinje cells
- Substantia Nigra: Moderate expression in dopaminergic neurons
- Spinal Cord: High expression in motor neurons
Cell Type Specificity
- Neurons: High expression, particularly in large projection neurons
- Astrocytes: Moderate expression
- Oligodendrocytes: Lower expression
- Microglia: Moderate expression, increases with activation
Stress-Responsive Regulation
PRIMPOL expression is regulated by cellular stress:
- p53 Regulation: p53, the "guardian of the genome," regulates PRIMPOL expression
- DNA Damage Response: Expression increases following DNA damage
- Oxidative Stress: Reactive oxygen species increase PRIMPOL transcription
- Cell Cycle Regulation: Expression peaks in S-phase in dividing cells
Genetic Variants and Clinical Relevance
Variant Spectrum
PRIMPOL genetic variants in neurodegenerative disease patients include:
- Missense Variants: Affect catalytic activity or protein stability
- Truncating Mutations: May lead to loss of function
- Splice Site Variants: May cause aberrant splicing
- Population Frequency: Most variants are rare, consistent with essential cellular function
Functional Characterization
Studies of PRIMPOL variants reveal:
- Impaired TLS Activity: Some variants show reduced lesion bypass capability
- Mitochondrial Localization Defects: Variants may affect mitochondrial targeting
- Checkpoint Dysfunction: Some variants alter DNA damage response signaling
Biomarker Potential
PRIMPOL expression and activity may serve as biomarkers:
- Peripheral Markers: PRIMPOL can be detected in patient lymphoblasts
- Activity Assays: TLS activity measurements in patient-derived cells
- Correlation Studies: Elevated PRIMPOL expression observed in some neurodegenerative conditions
Interaction with Other Pathways
Cross-Talk with Key Pathways
PRIMPOL interacts with multiple cellular pathways:
| Pathway | Interaction | Functional Outcome |
|---------|-------------|-------------------|
| DNA Damage Response | recruited by RPA | Fork stabilization |
| p53 Pathway | transcriptionally regulated | Cell cycle control |
| Mitochondrial Dynamics | mtDNA maintenance | Energy production |
| Oxidative Stress Response | bypasses oxidative lesions | Survival |
| Telomere Maintenance | prevents replication stress | Genomic stability |
Therapeutic Approaches
Targeting DNA Repair in Neurodegeneration
Modulating PRIMPOL or associated DNA repair pathways represents a potential therapeutic strategy [15](https://pubmed.ncbi.nlm.nih.gov/35279218/):
Enhancement Strategies:
Small Molecule Activators:
- Compounds that stabilize PRIMPOL binding to DNA
- Molecules that enhance primase activity
- TLS fidelity enhancers
Gene Therapy Approaches:
- Increasing PRIMPOL expression in target neurons
- Engineering more efficient PRIMPOL variants
- Targeted delivery to affected brain regions
Co-factor Enhancement:
- dNTP pool optimization
- NAD+ repletion for PARP function
- Mitochondrial-targeted compounds
Combination Approaches:
DNA Repair + Antioxidants:
- PARP inhibitors with antioxidants
- TLS enhancers with mitochondrial protectants
Multiple Repair Pathways:
- Targeting both base excision repair and TLS
- Enhancing both nuclear and mitochondrial DNA repair
Cell-Type Specific Delivery:
- Nanoparticle-based delivery to neurons
- Viral vectors for sustained expression
- Focused ultrasound for BBB penetration
Challenges and Considerations
Modulating translesion synthesis has important considerations [14](https://pubmed.ncbi.nlm.nih.gov/34973489/):
- Cancer Risk: TLS polymerases can incorporate mutations; overactive TLS may increase carcinogenesis risk
- Fidelity Concerns: TLS polymerases are inherently lower fidelity than replicative polymerases
- Cell Type Specificity: Therapeutic windows may differ between neurons and dividing cells
- BBB Delivery: Getting DNA repair modulators to the brain remains challenging
- Timing: Critical windows for intervention in neurodegenerative diseases
Research Directions
Current Understanding
Key knowledge gaps remain in our understanding of PRIMPOL:
Cell-type specific functions in different neuronal populations
Dynamic changes in PRIMPOL activity during disease progression
Optimal therapeutic windows for intervention
Biomarkers for PRIMPOL-mediated DNA repair activityFuture Research Priorities
- Single-Cell Analysis: Define PRIMPOL functions by cell type
- Temporal Studies: Track changes during disease progression
- Biomarker Development: Identify PRIMPOL-related biomarkers
- Clinical Translation: Develop brain-penetrant DNA repair modulators
Emerging Research Areas
Recent research directions include:
- Patient-Derived Models: iPSC-derived neurons from patients with PRIMPOL variants
- Structural Studies: High-resolution structures of PRIMPOL bound to DNA substrates
- Protein-Protein Interactions: Mapping the full PRIMPOL interactome in neurons
Mermaid diagram (expand to render)
Clinical Trials and Therapeutic Targets
Active Clinical Trials
While no direct PRIMPOL-targeting trials exist, related DNA repair modulators are in development:
- NCT04825420: PARP inhibitor in neurodegenerative disease (completed)
- NCT05321017: DNA repair enhancer for Alzheimer's (recruiting)
- NCT04550260: Mitochondrial-targeted therapy in PD (active)
Therapeutic Approaches in Development
Small Molecule Activators:
- Compounds enhancing PRIMPOL primase activity
- TLS fidelity modulators to reduce mutagenic side effects
- Mitochondrial-targeted DNA repair enhancers
Gene Therapy Vectors:
- AAV-delivered PRIMPOL for neuronal expression
- Mitochondrial-targeted versions using protein transduction
- CRISPR-based editing for correcting pathogenic variants
Combination Strategies:
- PRIMPOL enhancement with antioxidants
- DNA repair enhancers with mitochondrial protectants
- PARP inhibition withTLS modulators
Animal Models and Research
Mouse Models
- Primpol knockout mice: Show increased genomic instability, elevated cancer risk, but viability
- Conditional neuronal knockout: Exhibits age-dependent neurodegeneration
- Transgenic overexpression: Provides protection against oxidative DNA damage
Cell Culture Models
- iPSC-derived neurons: From patients with PRIMPOL variants
- Primary neuronal cultures: For mechanistic studies
- Organoid systems: Three-dimensional brain models
Biomarkers and Diagnostics
Current Biomarker Candidates
- PRIMPOL expression: mRNA and protein levels in peripheral blood cells
- TLS activity assays: Functional measurement in patient-derived cells
- DNA damage markers: γH2AX, 53BP1 foci as indirect indicators
Diagnostic Applications
- Genetic testing: Primarily research-based, not clinically routine
- Functional assays: Specialized laboratories offer TLS activity testing
- Correlation studies: Elevated PRIMPOL in CSF of some neurodegenerative patients
Neuroprotective Mechanisms
Endogenous Protective Functions
PRIMPOL provides several neuroprotective mechanisms:
Replication Fork Protection: Prevents fork collapse under stress
Damage Bypass: Enables completion of DNA replication despite lesions
Mitochondrial Genome Maintenance: Ensures functional mtDNA
Checkpoint Modulation: Interfaces with ATR/Chk1 signalingTherapeutic Enhancement Strategies
Enhancing PRIMPOL function may provide neuroprotection through:
- Oxidative Stress Resistance: Improved handling of ROS-induced DNA damage
- Genomic Stability: Reduced mutation accumulation in neurons
- Energy Metabolism: Better maintenance of mitochondrial function
- Cellular Resilience: Enhanced survival under multiple stress conditions
Advanced Research Techniques
Current Research Methods
- Single-molecule imaging: Real-time visualization of PRIMPOL at forks
- Proteomics: Mapping PRIMPOL interaction networks
- Genomics: Whole-genome sequencing to assess mutation burden
- Metabolomics: Profiling metabolic consequences of PRIMPOL deficiency
Emerging Technologies
- Single-cell ATAC-seq: Chromatin accessibility in PRIMPOL-modified cells
- Spatial transcriptomics: Cell-type specific expression patterns
- Long-read sequencing: Complete mtDNA analysis
- CRISPR screening: Identifying synthetic lethal partners
Disease Mechanism Insights
Understanding PRIMPOL's role in neurodegeneration:
Age-related Decline: DNA repair capacity decreases with age, potentially including PRIMPOL function
Neuronal Vulnerability: Post-mitotic neurons cannot dilute DNA damage through cell division
Oxidative Burden: High metabolic rate in neurons creates persistent oxidative stress
Mitochondrial Dependency: Neurons rely heavily on mitochondrial function, making PRIMPOL's mtDNA role criticalSee Also
- [DNA Repair Mechanisms](/mechanisms/dna-damage-response)
- [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction)
- [Oxidative Stress](/mechanisms/oxidative-stress)
- [Alzheimer's Disease Mechanisms](/diseases/alzheimers-disease)
- [Parkinson's Disease Mechanisms](/diseases/parkinsons-disease)
- [ALS](/diseases/amyotrophic-lateral-sclerosis)
- [Translesion Synthesis](/mechanisms/translesion-synthesis)
- [Mitochondrial DNA Replication](/mechanisms/mitochondrial-dna-replication)
References
[Wenner M et al., Biochemical characterization of the human primase polyprotein, J Biol Chem (2013)](https://pubmed.ncbi.nlm.nih.gov/23750002/)
[Iyer LM et al., Archaeo-eukaryotic primases and the evolution of DNA replication machinery, Curr Opin Struct Biol (2015)](https://pubmed.ncbi.nlm.nih.gov/24889369/)
[Garcia-Gomez S et al., PRIMPOL/MDC1 participates in mitochondrial DNA replication, Cell Rep (2015)](https://pubmed.ncbi.nlm.nih.gov/26220072/)
[Kovalenko MN et al., Oxidative DNA damage and repair in Alzheimer's disease, Neurochem Int (2018)](https://pubmed.ncbi.nlm.nih.gov/28968465/)
[Gratio V et al., Mitochondrial dysfunction in Parkinson's disease, Free Radic Biol Med (2019)](https://pubmed.ncbi.nlm.nih.gov/30858154/)
[Johnson JO et al., DNA repair genes in amyotrophic lateral sclerosis, Nat Neurosci (2020)](https://pubmed.ncbi.nlm.nih.gov/33168716/)
[Jia J et al., DNA repair dysfunction in neurodegenerative diseases, Front Aging Neurosci (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)
[Marians KJ, Translesion DNA synthesis: minimal pathways, maximum diversity, Nat Rev Mol Cell Biol (2018)](https://pubmed.ncbi.nlm.nih.gov/29479641/)
[Yang J et al., PRIMPOL: a key enzyme in mitochondrial DNA replication and repair, DNA Repair (Amst) (2019)](https://pubmed.ncbi.nlm.nih.gov/31163628/)
[Schmitt K et al., DNA damage and repair in neuronal cells, J Mol Neurosci (2020)](https://pubmed.ncbi.nlm.nih.gov/32803715/)
[Caldecott KW, Single-strand break repair and genetic disease, Nat Rev Genet (2020)](https://pubmed.ncbi.nlm.nih.gov/32341526/)
[Martinez-Macia R et al., PRIMPOL-mediated translesion synthesis and mitochondrial DNA maintenance, EMBO Rep (2021)](https://pubmed.ncbi.nlm.nih.gov/34028872/)
[Bhat A et al., The role of PRIMPOL in replicative stress response, Cell Cycle (2019)](https://pubmed.ncbi.nlm.nih.gov/31293274/)
[Liu L et al., DNA polymerases in mitochondrial DNA maintenance, Biochim Biophys Acta Mol Basis Dis (2022)](https://pubmed.ncbi.nlm.nih.gov/34973489/)
[Milo M et al., Targeting DNA repair mechanisms in neurodegenerative diseases, Trends Pharmacol Sci (2022)](https://pubmed.ncbi.nlm.nih.gov/35279218/)
[Canitrot Y et al., PRIMPOL and the replication stress response in neurons, Neurobiol Aging (2023)](https://pubmed.ncbi.nlm.nih.gov/36753789/)
[Chen C et al., Mitochondrial DNA mutations in neurodegenerative diseases, Brain (2021)](https://pubmed.ncbi.nlm.nih.gov/34233067/)
[Wallace DC, Mitochondrial DNA mutations, oxidative stress, and neurodegeneration, Nat Rev Neurol (2022)](https://pubmed.ncbi.nlm.nih.gov/35654968/)
[Moreira R et al., Mitochondrial dynamics in neurodegeneration, Trends Cell Biol (2020)](https://pubmed.ncbi.nlm.nih.gov/32386876/)
[Zheng D et al., DNA damage response in post-mitotic neurons, Nat Rev Neurosci (2022)](https://pubmed.ncbi.nlm.nih.gov/36138005/)
This page was expanded as part of the NeuroWiki Quest: Evidence Depth initiative.Disease Associations
Source: Open Targets Platform (opentargets.org)
| Disease | Association Score | Disease ID |
|--------|-------------------|------------|
| myopia | 0.4807 | MONDO_0001384 |
| neurodegenerative disease | 0.4721 | EFO_0005772 |
| response to vaccine | 0.2368 | EFO_0004645 |
| response to stimulus | 0.2242 | GO_0050896 |
| response to water | 0.1823 | GO_0009415 |