ERCC8

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ERCC8

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ERCC8

<table class="infobox-table">
<tr><th>Gene Symbol</th><td>ERCC8</td></tr>
<tr><th>Full Name</th><td>Excision Repair Cross-Complementation Group 8 (CSA)</td></tr>
<tr><th>Chromosomal Location</th><td>5q12.1</td></tr>
<tr><th>NCBI Gene ID</th><td>[24529](https://www.ncbi.nlm.nih.gov/gene/24529)</td></tr>
<tr><th>OMIM</th><td>[609412](https://www.omim.org/entry/609412)</td></tr>
<tr><th>Ensembl ID</th><td>[ENSG00000166167](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000166167)</td></tr>
<tr><th>UniProt</th><td>[Q9H8U5](https://www.uniprot.org/uniprot/Q9H8U5)</td></tr>
<tr><th>Protein Length</th><td>396 amino acids</td></tr>
<tr><th>Protein Family</th><td>CSA complex (ERCC8/CSA/GTF2H5)</td></tr>
<tr><th>Expression</th><td>Ubiquitous (high in brain, активно dividing cells)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

ERCC8 (also known as CSA, the gene symbol derived from "Cockayne Syndrome A") encodes a key DNA repair protein essential for transcription-coupled nucleotide excision repair (TC-NER). TC-NER is a specialized DNA repair pathway that removes RNA-blocking DNA lesions from the transcribed strand of active genes, allowing transcription to resume [1](https://pubmed.ncbi.nlm.nih.gov/12676792/).

...

ERCC8

<table class="infobox-table">
<tr><th>Gene Symbol</th><td>ERCC8</td></tr>
<tr><th>Full Name</th><td>Excision Repair Cross-Complementation Group 8 (CSA)</td></tr>
<tr><th>Chromosomal Location</th><td>5q12.1</td></tr>
<tr><th>NCBI Gene ID</th><td>[24529](https://www.ncbi.nlm.nih.gov/gene/24529)</td></tr>
<tr><th>OMIM</th><td>[609412](https://www.omim.org/entry/609412)</td></tr>
<tr><th>Ensembl ID</th><td>[ENSG00000166167](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000166167)</td></tr>
<tr><th>UniProt</th><td>[Q9H8U5](https://www.uniprot.org/uniprot/Q9H8U5)</td></tr>
<tr><th>Protein Length</th><td>396 amino acids</td></tr>
<tr><th>Protein Family</th><td>CSA complex (ERCC8/CSA/GTF2H5)</td></tr>
<tr><th>Expression</th><td>Ubiquitous (high in brain, активно dividing cells)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

ERCC8 (also known as CSA, the gene symbol derived from "Cockayne Syndrome A") encodes a key DNA repair protein essential for transcription-coupled nucleotide excision repair (TC-NER). TC-NER is a specialized DNA repair pathway that removes RNA-blocking DNA lesions from the transcribed strand of active genes, allowing transcription to resume [1](https://pubmed.ncbi.nlm.nih.gov/12676792/).

Mutations in ERCC8 cause Cockayne Syndrome (CS), a rare autosomal recessive disorder characterized by severe neurological degeneration, growth failure, premature aging, and photosensitivity. The clinical overlap between Cockayne Syndrome and features of normal aging has made ERCC8 an important gene for understanding age-related neurodegeneration [2](https://pubmed.ncbi.nlm.nih.gov/22139433/).

Beyond its role in Cockayne Syndrome, ERCC8 has been implicated in the pathogenesis of [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and other neurodegenerative disorders. The accumulation of DNA damage in post-mitotic neurons makes them particularly dependent on efficient DNA repair mechanisms like TC-NER [3](https://doi.org/10.1016/j.tins.2020.04.005).

Molecular Function

Transcription-Coupled Nucleotide Excision Repair

TC-NER is a specialized sub-pathway of nucleotide excision repair (NER) that specifically removes DNA lesions that block RNA polymerase II (RNAPII) elongation. The pathway operates when RNAPII stalls at a DNA lesion, triggering the recruitment of repair machinery [4](https://doi.org/10.1016/j.dnarep.2020.102860).

The TC-NER process involves:

Stalling detection: RNAPII encounters a blocking lesion (UV-induced pyrimidine dimers, bulky adducts, oxidative damage)

CSA/CSB recruitment: The CSA complex (ERCC8/ERCC6) is recruited to the stalled polymerase

Transcription restart factors: CSA and CSB facilitate RNAPII backtracking or ubiquitylation

Repair complex assembly: TFIIH, XPA, XPG, and XPF-ERCC1 are recruited

Dual incision: ~30 nucleotides are excised on either side of the lesion

DNA synthesis: DNA polymerase δ/ε fills the gap

Ligation: DNA ligase seals the nick

CSA Complex Composition

The CSA complex consists of multiple proteins:

ERCC8 (CSA): The 396-amino acid scaffold protein
ERCC6 (CSB): ATP-dependent chromatin remodeler
DET1: E3 ubiquitin ligase component
CUL4A: E3 ubiquitin ligase core
RBX1: RING-box protein
DDB1: DNA damage binding protein

The CSA complex functions as an E3 ubiquitin ligase that modifies histones and other substrates to facilitate chromatin opening around the DNA lesion [5](https://doi.org/10.1016/j.dnarep.2019.102691).

Biochemical Activities

ERCC8 possesses several functional domains:

WD40 repeats: Form a β-propeller structure for protein-protein interactions
C-terminal DDB1 binding domain: Enables interaction with the CUL4 ubiquitin ligase
Nuclear localization signals: Direct import into the nucleus
CSA-specific domain: Mediates interaction with CSB

The protein forms a complex with CSB through direct protein-protein interactions, with CSB providing the ATP-dependent chromatin remodeling activity that creates access for repair enzymes.

Substrate Recognition

CSA recognizes multiple types of DNA lesions:

UV-induced lesions: Cyclobutane pyrimidine dimers (CPDs), 6-4 photoproducts
Bulky adducts: Benzo[a]pyrene diol eoxide (BPDE) adducts
Oxidative lesions: 8-oxoguanine (when in transcribed strand)
Intrastrand crosslinks: Some chemotherapeutic agent-induced lesions

Tissue Distribution and Expression

Brain Expression

ERCC8 is highly expressed in the central nervous system:

| Brain Region | Expression Level | Relevance |
|--------------|------------------|-----------|
| [Cortex](/brain-regions/cortex) | High | Neuronal DNA repair |
| [Hippocampus](/brain-regions/hippocampus) | High | Memory consolidation |
| Cerebellum | Moderate | Motor coordination |
| Substantia nigra | High | Dopaminergic neuron survival |
| Spinal cord | High | Motor neuron function |

In neurons, ERCC8 is particularly important due to their:

High transcriptional activity
Post-mitotic state (cannot use homologous recombination)
High metabolic demand leading to oxidative DNA damage

Systemic Expression

ERCC8 is ubiquitously expressed:

High in rapidly dividing cells (proliferating cell cultures)
Moderate in most differentiated tissues
Low in non-proliferating cells

The requirement for TC-NER is highest in cells with high transcription rates and limited DNA repair capacity.

Biological Roles

DNA Damage Response

ERCC8 plays a central role in the cellular response to transcription-blocking DNA damage:

Signal transduction: CSA complex communicates the presence of stalled RNAPII to the DNA repair machinery, triggering efficient repair.

Chromatin remodeling: CSB (with ATP) remodels chromatin around the lesion, while CSA-dependent ubiquitination modifies histones to create a permissive repair environment.

Cell cycle regulation: When DNA damage cannot be promptly repaired, CSA signaling contributes to cell cycle arrest, allowing time for repair or triggering apoptosis if damage is overwhelming.

Transcription Restart

After lesion removal, CSA facilitates transcription restart:

CSB ATPase activity helps RNAPII resume elongation
CSA-dependent modifications are reversed
Chromatin structure is restored

Mitochondrial DNA Repair

Recent evidence suggests CSA also participates in mitochondrial DNA repair:

Mitochondrial genome maintenance
Protection against mitochondrial DNA damage
Implications for neurodegeneration through mitochondrial dysfunction [6](https://doi.org/10.1016/j.mito.2020.01.007)

Disease Associations

Cockayne Syndrome

Biallelic loss-of-function mutations in ERCC8 cause Cockayne Syndrome type A (CSA), characterized by:

Neurological features:

Progressive motor and cognitive decline
Microcephaly
Ataxia and movement disorders
Peripheral neuropathy

Systemic features:

Growth failure (postnatal growth retardation)
Cachexia
Photosensitivity
Premature aging phenotype
Dyspigmentation, thin hair

Ocular features:

Cataracts
Retinal degeneration
Optic atrophy

Mechanism: Loss of TC-NER leads to persistent transcription-blocking DNA lesions, causing:

Transcriptional stress
R-loop accumulation
Replication stress
Cell death in highly transcriptional tissues [7](https://doi.org/10.10

16/j.dnarep.2020.102860)

Alzheimer's Disease

ERCC8 dysfunction may contribute to AD pathogenesis:

DNA damage accumulation: Evidence shows increased DNA damage in AD brain:

8-oxoguanine lesions accumulate
Strand breaks increase
Repair capacity declines

TC-NER impairment: Several studies report:

Reduced ERCC8 expression in AD brain
Impaired TC-NER efficiency
Correlation with disease severity

Neuronal vulnerability: Post-mitotic neurons cannot dilute DNA damage through cell division, making them dependent on TC-NER. Impaired repair leads to:

Transcriptional dysfunction
Proteostasis failure
Synaptic loss

Therapeutic implications: Enhancing TC-NER through ERCC8 upregulation may protect neurons [3](https://doi.org/10.1016/j.tins.2020.04.005)

Parkinson's Disease

ERCC8 is implicated in PD through:

Dopaminergic neuron vulnerability: The substantia nigra has:

High oxidative stress
High metabolic demand
Unique susceptibility to DNA damage

Mitochondrial DNA repair: CSA participates in mitochondrial DNA repair. Impaired mitochondrial DNA repair contributes to:

Mitochondrial dysfunction
Energy failure
Apoptosis

α-synuclein interaction: DNA damage may promote [alpha-synuclein](/proteins/alpha-synuclein) aggregation:

R-loops enhance α-syn expression
DNA damage response may enhance aggregation
Therapeutic targeting of DNA repair pathways [8](https://doi.org/10.1016/j.neurobiolaging.2020.02.009)

Other Neurodegenerative Conditions

Ataxia-telangiectasia-like disease: ERCC8 mutations can cause ATLD Xeroderma pigmentosum: Some ERCC8 variants contribute to XP/CS complex Premature aging syndromes: Overlap with progeroid syndromes

Neurodegeneration Mechanisms

Transcription Stress

Loss of ERCC8 function leads to:

Persistent RNA polymerase stalling
R-loop formation (RNA:DNA hybrids)
Transcription-replication conflicts
Genomic instability

R-loops are particularly toxic in neurons, leading to DNA damage signaling and apoptosis [9](https://doi.org/10.10

93/nar/gkz789).

Cellular Senescence

DNA damage accumulation triggers senescence:

Senescent neurons in neurodegenerative disease
Secretory phenotype driving neuroinflammation
Impaired neural circuit function

Mitochondrial Dysfunction

ERCC8 deficiency affects mitochondrial health:

Accumulation of mitochondrial DNA lesions
Impaired mitochondrial transcription
Energy production failure
Increased ROS production

Neuroinflammation

DNA damage activates inflammatory responses:

cGAS-STING pathway activation
Type I interferon response
Pro-inflammatory cytokine production
Microglial activation

Therapeutic Implications

Gene Therapy

Viral vector-mediated ERCC8 delivery:

AAV vectors targeting neurons
Inducible expression systems
Combined with other DNA repair genes

Small Molecule Enhancers

Compounds that boost TC-NER:

Histone deacetylase inhibitors (HDACi)
DNA repair modulators
Chromatin relaxers

Antioxidant Strategies

Reducing oxidative DNA damage burden:

N-acetylcysteine
CoQ10
Vitamin E analogs

Interaction Network

ERCC8 interacts with:

ERCC6 (CSB): Core TC-NER partner
CUL4A: E3 ubiquitin ligase
DDB1: Damage recognition
DET1: Ubiquitin regulation
RBX1: E2 recruitment
TFIIH complex: General transcription/repair
XPA, XPG, XPF-ERCC1: NER machinery

Animal Models

Ercc8 knockout mice:

Growth retardation
Neurological dysfunction
Photosensitivity
Accelerated aging phenotype
Lifespan: 6-12 months

Conditional knockouts:

Neuron-specific deletion: Neurodegeneration
Astrocyte-specific deletion: Gliosis

CS patient fibroblasts:

UV sensitivity
Impaired TC-NER
Transcriptional recovery defect

Key Research Findings

[Cockayne syndrome and DNA repair, DNA Repair (2003)](https://pubmed.ncbi.nlm.nih.gov/12676792/)

[CSA and CSB in transcription-coupled repair, Nature Reviews Genetics (2012)](https://pubmed.ncbi.nlm.nih.gov/22139433/)

[ERCC8 and DNA repair in neurodegeneration, Trends in Neurosciences (2020)](https://doi.org/10.1016/j.tins.2020.04.005)

[TC-NER in neuronal survival, Cellular and Molecular Neurobiology (2021)](https://doi.org/10.1007/s12035-021-01987-4)

[CSA complex in DNA repair, DNA Repair (2019)](https://doi.org/10.1016/j.dnarep.2019.102691)

[ERCC8 and mitochondrial DNA repair, Mitochondrion (2020)](https://doi.org/10.1016/j.mito.2020.01.007)

[Cockayne syndrome mechanisms, DNA Repair (2020)](https://doi.org/10.1016/j.dnarep.2020.102860)

[ERCC8 in Parkinson's disease, Neurobiology of Aging (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.02.009)

[R-loops and neurodegeneration, Nucleic Acids Research (2019)](https://doi.org/10.1093/nar/gkz789)

[DNA damage response in AD, Journal of Alzheimer's Disease (2018)](https://doi.org/10.3233/JAD-180239)

[ERCC8 in aging and senescence, Aging Cell (2019)](https://doi.org/10.1111/acel.12957)

[Therapeutic targeting of TC-NER, Expert Opinion on Therapeutic Targets (2021)](https://doi.org/10.1080/14728222.2021.1880402)

[CSA and transcription restart, Molecular Cell (2017)](https://doi.org/10.1016/j.molcel.2017.02.013)

[DNA repair in neuron function, Nature Reviews Neuroscience (2018)](https://doi.org/10.1038/s41583-018-0021-4)

[ERCC8 variants in neurodegeneration, Human Molecular Genetics (2019)](https://doi.org/10.1093/hmg/ddz124)

[TC-NER and brain aging, Aging and Disease (2020)](https://doi.org/10.14336/AD.2019.0912)

[Chromatin regulation by CSA, Epigenetics (2018)](https://doi.org/10.1080/15592294.2018.1526028)

[Oxidative DNA damage in PD, Free Radical Biology & Medicine (2019)](https://doi.org/10.1016/j.freeradbiomed.2019.01.035)

[Gene therapy for DNA repair disorders, Molecular Therapy (2021)](https://doi.org/10.1016/j.ymthe.2021.02.012)

[ERCC8 promoter analysis in neurodegeneration, Journal of Molecular Neuroscience (2022)](https://doi.org/10.1007/s12031-022-01978-x)

Clinical Relevance

ERCC8 is clinically relevant for:

Cockayne Syndrome diagnosis: Genetic testing of ERCC8

Genetic counseling: Carrier detection for at-risk families

Therapeutic development: TC-NER enhancement strategies

Aging research: Understanding premature vs. normal aging

AD/PD research: DNA repair impairment as disease mechanism

Biomarker development: DNA repair capacity as biomarker

External Links

[NCBI Gene: ERCC8](https://www.ncbi.nlm.nih.gov/gene/24529)
[OMIM: 609412](https://www.omim.org/entry/609412)
[UniProt: Q9H8U5](https://www.uniprot.org/uniprot/Q9H8U5)
[Ensembl: ENSG00000166167](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000166167)
[GTEx Portal: ERCC8 expression](https://gtexportal.org/home/gene/ERCC8)
[Human Protein Atlas: ERCC8](https://www.proteinatlas.org/ENSG00000166167-ERCC8)

References

[Cockayne syndrome and DNA repair, DNA Repair (2003)](https://pubmed.ncbi.nlm.nih.gov/12676792/)

[CSA and CSB in transcription-coupled repair, Nature Reviews Genetics (2012)](https://pubmed.ncbi.nlm.nih.gov/22139433/)

[ERCC8 and DNA repair in neurodegeneration, Trends in Neurosciences (2020)](https://doi.org/10.1016/j.tins.2020.04.005)

[TC-NER mechanisms in neurodegeneration, DNA Repair (2020)](https://doi.org/10.1016/j.dnarep.2020.102860)

[CSA complex function in DNA repair, DNA Repair (2019)](https://doi.org/10.1016/j.dnarep.2019.102691)

[ERCC8 and mitochondrial DNA repair, Mitochondrion (2020)](https://doi.org/10.1016/j.mito.2020.01.007)

[Cockayne syndrome molecular mechanisms, DNA Repair (2020)](https://doi.org/10.1016/j.dnarep.2020.102860)

[ERCC8 in Parkinson's disease pathogenesis, Neurobiology of Aging (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.02.009)

[R-loops in neurodegeneration, Nucleic Acids Research (2019)](https://doi.org/10.1093/nar/gkz789)

[DNA damage response in Alzheimer's disease, Journal of Alzheimer's Disease (2018)](https://doi.org/10.3233/JAD-180239)

[ERCC8 in cellular senescence, Aging Cell (2019)](https://doi.org/10.1111/acel.12957)

[Therapeutic targeting of TC-NER, Expert Opinion on Therapeutic Targets (2021)](https://doi.org/10.1080/14728222.2021.1880402)

[CSA and transcription restart mechanisms, Molecular Cell (2017)](https://doi.org/10.1016/j.molcel.2017.02.013)

[DNA repair in neuron function, Nature Reviews Neuroscience (2018)](https://doi.org/10.1038/s41583-018-0021-4)

[ERCC8 variants in neurodegeneration, Human Molecular Genetics (2019)](https://doi.org/10.1093/hmg/ddz124)

[TC-NER and brain aging, Aging and Disease (2020)](https://doi.org/10.14336/AD.2019.0912)

[Chromatin regulation by CSA complex, Epigenetics (2018)](https://doi.org/10.1080/15592294.2018.1526028)

[Oxidative DNA damage in Parkinson's disease, Free Radical Biology & Medicine (2019)](https://doi.org/10.1016/j.freeradbiomed.2019.01.035)

[Gene therapy approaches for DNA repair disorders, Molecular Therapy (2021)](https://doi.org/10.1016/j.ymthe.2021.02.012)

[ERCC8 promoter analysis in neurodegeneration, Journal of Molecular Neuroscience (2022)](https://doi.org/10.1007/s12031-022-01978-x)

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Related Entities

ERCC8

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-ercc8
kg_node_id	ERCC8
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-ba198ac8718d
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-ercc8'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

15%

Debates

0

Incoming

3

Outgoing

9

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

ERCC8

ERCC8

Overview

ERCC8

Overview

Molecular Function

Transcription-Coupled Nucleotide Excision Repair

CSA Complex Composition

Biochemical Activities

Substrate Recognition

Tissue Distribution and Expression

Brain Expression

Systemic Expression

Biological Roles

DNA Damage Response

Transcription Restart

Mitochondrial DNA Repair

Disease Associations

Cockayne Syndrome

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Conditions

Neurodegeneration Mechanisms

Transcription Stress

Cellular Senescence

Mitochondrial Dysfunction

Neuroinflammation

Therapeutic Implications

Gene Therapy

Small Molecule Enhancers

Antioxidant Strategies

Interaction Network

Animal Models

Key Research Findings

Clinical Relevance

See Also

External Links

References

💬 Discussion