ERCC8

Summary

ERCC8 (ERCC excision repair 8, CSA ubiquitin ligase complex subunit, HGNC:3439) is a protein-coding gene on chromosome 5q12.1, encoding DNA excision repair protein ERCC-8 (Q13216). Substrate-recognition component of the CSA complex, a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, involved in transcription-coupled nucleotide excision repair (TC-NER), a process during which RNA polymerase II-blocking lesions are rapidly removed from the transcri….

This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1161 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Cockayne syndrome type 1 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 661 total — 93 pathogenic, 48 likely-pathogenic
• Phenotypes (HPO): 172
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000082

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3439
Approved symbol	ERCC8
Name	ERCC excision repair 8, CSA ubiquitin ligase complex subunit
Location	5q12.1
Locus type	gene with protein product
Status	Approved
Aliases	CSA
Ensembl gene	ENSG00000049167
Ensembl biotype	protein_coding
OMIM	609412
Entrez	1161

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 13 retained_intron, 10 protein_coding, 10 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000265038, ENST00000381118, ENST00000439176, ENST00000462279, ENST00000477893, ENST00000484330, ENST00000495985, ENST00000497892, ENST00000643034, ENST00000643708, ENST00000647431, ENST00000647486, ENST00000675042, ENST00000675229, ENST00000675378, ENST00000675452, ENST00000675920, ENST00000676185, ENST00000682041, ENST00000682217, ENST00000682246, ENST00000682375, ENST00000682380, ENST00000682418, ENST00000682750, ENST00000682874, ENST00000683052, ENST00000683199, ENST00000683216, ENST00000683460, ENST00000683688, ENST00000684394, ENST00000684453, ENST00000684621, ENST00000891472, ENST00000891473, ENST00000940243

RefSeq mRNA: 4 — MANE Select: NM_000082 NM_000082, NM_001007233, NM_001007234, NM_001290285

CCDS: CCDS3978, CCDS93715

Canonical transcript exons

ENST00000676185 — 12 exons

Exon	Start	End
ENSE00003500743	60904792	60904873
ENSE00003501361	60898276	60898400
ENSE00003551792	60899627	60899727
ENSE00003589574	60903648	60903716
ENSE00003593239	60922054	60922155
ENSE00003608582	60902442	60902508
ENSE00003644443	60887440	60887520
ENSE00003677455	60928864	60928959
ENSE00003678608	60890889	60891086
ENSE00003679669	60918265	60918388
ENSE00003901251	60944932	60945070
ENSE00003903172	60866454	60874683

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 84.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.5344 / max 110.7990, expressed in 1768 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61904	12.3893	1768
61905	0.1451	57

Top tissues by expression

277 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	84.25	gold quality
ventricular zone	UBERON:0003053	84.05	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.75	gold quality
ganglionic eminence	UBERON:0004023	83.49	gold quality
cortical plate	UBERON:0005343	83.15	gold quality
monocyte	CL:0000576	81.69	gold quality
mononuclear cell	CL:0000842	81.29	gold quality
calcaneal tendon	UBERON:0003701	81.06	gold quality
leukocyte	CL:0000738	80.94	gold quality
stromal cell of endometrium	CL:0002255	80.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.53	gold quality
islet of Langerhans	UBERON:0000006	79.05	gold quality
embryo	UBERON:0000922	78.91	gold quality
rectum	UBERON:0001052	78.57	gold quality
pancreatic ductal cell	CL:0002079	76.53	silver quality
left lobe of thyroid gland	UBERON:0001120	76.41	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.20	gold quality
thyroid gland	UBERON:0002046	76.03	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	75.94	gold quality
tibialis anterior	UBERON:0001385	75.84	silver quality
pancreas	UBERON:0001264	75.76	gold quality
endothelial cell	CL:0000115	75.75	silver quality
right lobe of thyroid gland	UBERON:0001119	75.74	gold quality
muscle of leg	UBERON:0001383	75.58	gold quality
left coronary artery	UBERON:0001626	75.57	gold quality
hindlimb stylopod muscle	UBERON:0004252	75.56	gold quality
metanephros cortex	UBERON:0010533	75.54	gold quality
tibial artery	UBERON:0007610	75.53	gold quality
popliteal artery	UBERON:0002250	75.52	gold quality
ascending aorta	UBERON:0001496	75.47	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.53
E-HCAD-5	no	2.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

41 targeting ERCC8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-8066	99.05	68.66	1532

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• We found that CSA protein is rapidly translocated to the nuclear matrix after UV irradiation (PMID:11782547)
• DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1. Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity. (PMID:12732143)
• The Mutation of Cockayne syndrome type A can also cause defective transcription-coupled repair and Cockayne syndrome. (PMID:16246722)
• examines functional relationship between CSA and CSB in Cockayne syndrome (PMID:16751180)
• Alterations of chromatin at the RNA polymerase II stall site, which depend on CSB and TFIIH at least, are necessary for the UV-induced translocation of CSA to the nuclear matrix. (PMID:17242193)
• CSA protein contributes to prevent accumulation of various oxidized DNA bases and underline specific functions of CSB not shared with CSA. (PMID:17297471)
• CSA is not required for the ubiquitylation of human RNA polymerase II. (PMID:17996703)
• The 45 published mutations in CSA and CSB to date and 43 new mutations in these genes together with the corresponding clinical data, are reported. (PMID:19894250)
• role in protect from aging- and stress-induced mtDNA mutations and apoptosis-mediated loss of subcutaneous fat, a hallmark of aging (PMID:20100872)
• High carriers frequency of an apparently ancient founder mutation p.Tyr322X in the ERCC8 gene responsible for Cockayne syndrome among Christian Arabs in northern Israel is reported. (PMID:21108394)
• Studies indicate the modular architecture of DDB1-CUL4 in complex with DDB2, CSA and CDT2 in DNA repair of UV-induced DNA lesions. (PMID:21550341)
• CSA and CSB are identified as the key elements of a regulatory mechanism that equilibrate beneficial and detrimental effects of p53 activity upon cellular stress. (PMID:22032989)
• crystals of CSA-DDB1 had unit-cell parameters a = b = 142.03, c = 250.19 A and diffracted to 2.9 A resolution on beamline ID14-1 (PMID:22232169)
• KIAA1530 protein is recruited by Cockayne syndrome complementation group protein A (CSA) to participate in transcription-coupled repair (TCR). (PMID:22902626)
• Mitochondrial CSA and CSB: protein interactions and protection from ageing associated DNA mutations. (PMID:23562423)
• The role of CSA and CSB protein in the oxidative stress response. (PMID:23562424)
• The role of CSA protein in TC-NER is described in this review (PMID:23571135)
• The review focuses on the participation of the CSB and CSA proteins in many different protein interactions and complexes, and how these interactions inform us about pathways that are defective in the disease. (PMID:23583689)
• A novel function of Cockayne syndrome A protein as transcription factor of RNA polymerase I in the nucleolus is shown. (PMID:24781187)
• Our findings suggested that ERCC8 rs158572 and rs158916, alone or together with environmental factors, might be associated with gastric cancer and atrophic gastritis susceptibility. (PMID:26130415)
• Although the absence of CSA had no effect on CSB recruitment, CSA itself localized at sites of interstrand crosslinks, double-strand breaks and monoadducts but not at oxidative DNA lesions. (PMID:26616585)
• Loss of Cockayne syndrome group A protein (CSA) or Cockayne syndrome group B protein (CSB) leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures. (PMID:27791127)
• The role of CSA in oxidative stress (PMID:28302478)
• A complex intragenic rearrangement of ERCC8 in Chinese siblings with Cockayne syndrome has been reported. (PMID:28333167)
• ERCC6 rs1917799, ERCC8 rs158572 and rs158916 demonstrated pairwise epistatic interactions to associate with chronic atrophic gastritis and gastric cancer risk. The ERCC6 rs1917799-ERCC8 rs158572 pair significantly influence ERCC6 and ERCC6-ERCC8 expression. (PMID:28562347)
• 21 Han Chinese patients with Cockayne syndrome type A were investigated to identify mutations in ERCC8/ERCC6, of which thirteen cases with CS-A were identified with the mutations of ERCC8. 5 types mutations of ERCC8 were identified. Exon 4 rearrangement mutation and c.394_398delTTACA were the major mutations present in Han Chinese patients with CS-A, and also discovered three novel mutations. (PMID:29057985)
• Pathogenic nucleotide variant NG_009289.1(NM_000082.3):c.173+1119G>C was identified in two siblings with severe but long-term survival Cockayne syndrome. (PMID:29422660)
• By identifying >70 novel homozygous or compound heterozygous genetic variants in 124 patients with Cockayne syndrome (CS) with different disease severity and ethnic backgrounds, we considerably broaden the CSA and CSB mutation spectrum responsible for CS. (PMID:29572252)
• the CSA protein plays an important role in protecting cells from senescence by facilitating DNA damage processing, maintaining physiological redox status and keratinocyte clonogenic ability, and reducing the senescence-associated secretory phenotype-mediated inflammatory phenotype. (PMID:30009828)
• c.1053delT in ERCC8 gene in an Iranian family with Cockayne syndrome (PMID:30039856)
• Case Report: ERCC8 gene mutations in a patient with ultraviolet-sensitive syndrome. (PMID:30182135)
• Three different mutations were identified in unrelated Lebanese Cockayne syndrome patients: one in ERCC6 and two in ERCC8 genes. (PMID:30200888)
• Results showed that the odds ratio for gastric cancer of the different ERCC8 rs158572 and rs158916 genotypes was not significantly increased in the observation group compared with that in the control group. By contrast, in patients with H. pylori infection, the ERCC8 rs158572 GA/GG and rs158916 TT genotypes showed a 7.921-fold and 8.021-fold increased risk of gastric cancer than the AA and CT/CC genotypes, respectively. (PMID:30249552)
• identification of a novel ERCC8 mutation and new unique disease phenotype; results also confirmed the genotype-phenotype relationship between mutations in ERCC8 and clinical findings (PMID:30871974)
• convergent and divergent roles for CSA and CSB in DNA repair and transcription regulation (PMID:31546172)
• The results indicate that the CSA, CSB, RNA polymerase II triad is coordinated by ubiquitin and SUMO in response to UV irradiation. (PMID:31722399)
• CSA and CSB are positive regulators of ribosomal RNA synthesis via Ncl regulation. (PMID:31970402)
• Multimodal imaging in a family with Cockayne syndrome with a novel pathogenic mutation in the ERCC8 gene, and significant phenotypic variability. (PMID:32048102)
• Atypical features and de novo heterozygous mutations in two siblings with Cockayne syndrome. (PMID:32160415)
• TCR is initiated by RNAPIIo-bound CSB, which recruits CSA through a newly identified CSA-interaction motif (CIM); once recruited, CSA facilitates the association of UVSSA with stalled RNAPIIo; in addition, UVSSA is the key factor that recruits the TFIIH complex in a manner that is stimulated by CSB and CSA (PMID:32355176)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ercc8	ENSDARG00000069283
mus_musculus	Ercc8	ENSMUSG00000021694
rattus_norvegicus	Ercc8	ENSRNOG00000009968
caenorhabditis_elegans		WBGENE00008403

Paralogs (9): GEMIN5 (ENSG00000082516), RBBP7 (ENSG00000102054), WDR59 (ENSG00000103091), GRWD1 (ENSG00000105447), PEX7 (ENSG00000112357), WDR77 (ENSG00000116455), WDR24 (ENSG00000127580), RBBP4 (ENSG00000162521), WDR73 (ENSG00000177082)

Protein

Protein identifiers

DNA excision repair protein ERCC-8 — Q13216 (reviewed: Q13216)

Alternative names: Cockayne syndrome WD repeat protein CSA

All UniProt accessions (14): A0A0S2Z3L1, A0A2R8Y5I1, A0A2R8YD24, A0A2R8YEZ3, A0A6Q8PFI5, A0A6Q8PH55, A0A7I2PE23, A0A804HIH7, Q13216, A0A804HJL3, A0A804HJN0, B3KPW7, C9JNT2, G3XAG7

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the CSA complex, a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, involved in transcription-coupled nucleotide excision repair (TC-NER), a process during which RNA polymerase II-blocking lesions are rapidly removed from the transcribed strand of active genes. Following recruitment to lesion-stalled RNA polymerase II (Pol II), the CSA complex mediates ubiquitination of Pol II subunit POLR2A/RPB1 at ‘Lys-1268’, a critical TC-NER checkpoint, governing RNA Pol II stability and initiating DNA damage excision by TFIIH recruitment. The CSA complex also promotes the ubiquitination and subsequent proteasomal degradation of ERCC6/CSB in a UV-dependent manner; ERCC6 degradation is essential for the recovery of RNA synthesis after transcription-coupled repair. Also plays a role in DNA double-strand breaks (DSSBs) repair by non-homologous end joining (NHEJ).

Subunit / interactions. Part of the CSA complex (also named DCX(ERCC8) complex), a DCX E3 ubiquitin-protein ligase complex containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II. Interacts with ERCC6/CSB (via CIM motif); promoting recruitment to lesion-stalled RNA polymerase II (Pol II). Interacts with KIAA1530/UVSSA. Interacts with a subunit of RNA polymerase II TFIIH.

Subcellular location. Nucleus. Chromosome. Nucleus matrix.

Disease relevance. Cockayne syndrome A (CSA) [MIM:216400] A rare disorder characterized by cutaneous sensitivity to sunlight, abnormal and slow growth, cachectic dwarfism, progeroid appearance, progressive pigmentary retinopathy and sensorineural deafness. There is delayed neural development and severe progressive neurologic degeneration resulting in intellectual disability. Two clinical forms are recognized: in the classical form or Cockayne syndrome type 1, the symptoms are progressive and typically become apparent within the first few years or life; the less common Cockayne syndrome type 2 is characterized by more severe symptoms that manifest prenatally. Cockayne syndrome shows some overlap with certain forms of xeroderma pigmentosum. Unlike xeroderma pigmentosum, patients with Cockayne syndrome do not manifest increased freckling and other pigmentation abnormalities in the skin and have no significant increase in skin cancer. The disease is caused by variants affecting the gene represented in this entry. UV-sensitive syndrome 2 (UVSS2) [MIM:614621] An autosomal recessive disorder characterized by cutaneous photosensitivity and mild freckling in the absence of neurological abnormalities or skin tumors. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13216-1	1	yes
Q13216-2	2

RefSeq proteins (4): NP_000073, NP_001007234, NP_001007235, NP_001277214 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR042238	Rad28/ERCC8/Ckn1/ATCSA-1	Family

Pfam: PF00400

UniProt features (70 total): strand 35, sequence variant 10, repeat 7, turn 7, modified residue 3, helix 3, splice variant 2, chain 1, mutagenesis site 1, region of interest 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
9BZ0	ELECTRON MICROSCOPY	1.9
8B3D	ELECTRON MICROSCOPY	2.6
7OOB	ELECTRON MICROSCOPY	2.7
7OO3	ELECTRON MICROSCOPY	2.8
7OOP	ELECTRON MICROSCOPY	2.9
6FCV	X-RAY DIFFRACTION	2.92
7OPC	ELECTRON MICROSCOPY	3
7OPD	ELECTRON MICROSCOPY	3
8B3F	ELECTRON MICROSCOPY	3.1
9ER2	ELECTRON MICROSCOPY	3.3
4A11	X-RAY DIFFRACTION	3.31
8QH5	ELECTRON MICROSCOPY	3.4
9FD2	ELECTRON MICROSCOPY	3.4
8B3I	ELECTRON MICROSCOPY	3.5
9HWG	ELECTRON MICROSCOPY	3.5
8B3G	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13216-F1	91.72	0.87

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 391, 392, 390

Mutagenesis-validated functional residues (1):

Position	Phenotype
334	defects in transcription-coupled nucleotide excision repair (tc-ner).

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6781823	Formation of TC-NER Pre-Incision Complex
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-8951664	Neddylation

MSigDB gene sets: 477 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_TRANSCRIPTION_COUPLED_NUCLEOTIDE_EXCISION_REPAIR, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, KAUFFMANN_DNA_REPAIR_GENES, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_NUCLEOTIDE_EXCISION_REPAIR, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_PROTEIN_AUTOUBIQUITINATION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_RESPONSE_TO_UV, GOBP_DNA_DAMAGE_RESPONSE, GOBP_RESPONSE_TO_RADIATION, GOBP_POSITIVE_REGULATION_OF_DNA_REPAIR

GO Biological Process (15): single strand break repair (GO:0000012), protein polyubiquitination (GO:0000209), transcription-coupled nucleotide-excision repair (GO:0006283), DNA damage response (GO:0006974), response to oxidative stress (GO:0006979), response to UV (GO:0009411), response to X-ray (GO:0010165), response to auditory stimulus (GO:0010996), protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of DNA repair (GO:0045739), protein autoubiquitination (GO:0051865), regulation of transcription-coupled nucleotide-excision repair (GO:0090262), double-strand break repair via classical nonhomologous end joining (GO:0097680), DNA repair (GO:0006281)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (10): nucleotide-excision repair complex (GO:0000109), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear matrix (GO:0016363), Cul4A-RING E3 ubiquitin ligase complex (GO:0031464), protein-containing complex (GO:0032991), perikaryon (GO:0043204), Cul4-RING E3 ubiquitin ligase complex (GO:0080008), site of DNA damage (GO:0090734), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	3
Nucleotide Excision Repair	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA repair	2
protein ubiquitination	2
nuclear lumen	2
nucleotide-excision repair	1
cellular response to stress	1
response to stress	1
response to light stimulus	1
response to ionizing radiation	1
response to mechanical stimulus	1
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
regulation of DNA repair	1
positive regulation of response to stimulus	1
positive regulation of DNA metabolic process	1
transcription-coupled nucleotide-excision repair	1
regulation of nucleotide-excision repair	1
double-strand break repair via nonhomologous end joining	1
DNA metabolic process	1
DNA damage response	1
enzyme-substrate adaptor activity	1
binding	1
nuclear protein-containing complex	1
intracellular membrane-bounded organelle	1
Cul4-RING E3 ubiquitin ligase complex	1
cellular_component	1
neuronal cell body	1
cullin-RING ubiquitin ligase complex	1
chromosome	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1113 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERCC8	ERCC6	Q03468	991
ERCC8	UVSSA	Q2YD98	917
ERCC8	A0A090J7P6	A0A090J7P6	914
ERCC8	ERCC5	P28715	908
ERCC8	XAB2	Q9HCS7	897
ERCC8	GTF2H2	Q13888	864
ERCC8	ERCC3	P19447	852
ERCC8	ERCC2	P18074	830
ERCC8	XPA	P23025	823
ERCC8	ERCC1	P07992	786
ERCC8	DDB1	Q16531	770
ERCC8	HMGN1	P05114	764
ERCC8	CUL4A	Q13619	764
ERCC8	ERCC4	Q92889	764
ERCC8	USP7	Q93009	712

IntAct

47 interactions, top by confidence:

A	B	Type	Score
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
PFDN4	PFDN6	psi-mi:“MI:0914”(association)	0.730
CCT2	TXNDC9	psi-mi:“MI:0914”(association)	0.730
CUL4A	COPS2	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
COPS5	KLHL18	psi-mi:“MI:0914”(association)	0.530
GPS1	PXDNL	psi-mi:“MI:0914”(association)	0.530
ERCC8	XAB2	psi-mi:“MI:0915”(physical association)	0.520
Ddb1	PHGDH	psi-mi:“MI:0915”(physical association)	0.400
CSNK2B	ERCC8	psi-mi:“MI:0915”(physical association)	0.370
CUL4B	GPS1	psi-mi:“MI:0914”(association)	0.350
CUL4A	HAX1	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
CUL4B	APBB1	psi-mi:“MI:0914”(association)	0.350
COPS6	DDX3X	psi-mi:“MI:0914”(association)	0.350

BioGRID (390): DDB1 (Affinity Capture-Western), CUL4A (Affinity Capture-Western), ERCC8 (Affinity Capture-MS), ERCC6 (Affinity Capture-Western), VCP (Affinity Capture-Western), CUL4A (Affinity Capture-Western), DDB1 (Affinity Capture-Western), UBXN7 (Affinity Capture-Western), ERCC8 (Affinity Capture-MS), ERCC8 (Affinity Capture-MS), ERCC8 (Affinity Capture-MS), ERCC8 (Affinity Capture-MS), ERCC8 (Affinity Capture-MS), ERCC6 (Affinity Capture-Western), ERCC6 (Co-fractionation)

ESM2 similar proteins: A1L112, A4IHS2, A8NZM5, B2ZZS9, O00423, O80775, O95834, P93107, P97452, Q05BC3, Q0DYP5, Q13216, Q13610, Q13685, Q15269, Q1JQD2, Q2HJ56, Q32KQ2, Q32P44, Q3SZK1, Q4V8C3, Q562C2, Q58DT8, Q5BIM8, Q5F3K4, Q5R9T6, Q5RCG7, Q5RFQ3, Q5VU92, Q5XI13, Q5ZK69, Q6DRF9, Q6P6T4, Q6PFM9, Q7TNG5, Q7YR70, Q810D6, Q8BH57, Q8BHB4, Q8BU03

Diamond homologs: A1CH75, A1CXL0, A2QI22, A3LQ86, A4R2Q6, A5DL92, A5DST9, A6NE52, A6R3K5, A6S0T8, A6ZPA9, A7ECP3, A7TMF9, A8PD13, B0DWM8, B0Y5V6, B2B5V0, B2VZH2, B3RQN1, C4Y5P7, C4YN69, G0SFB5, O94289, P38262, P41318, Q0CLJ4, Q0UXP3, Q12024, Q13216, Q1DJF7, Q2GXT0, Q2UGK1, Q4WP10, Q54W52, Q54ZP5, Q5ACL4, Q5APF0, Q5B4R1, Q5BIM8, Q6BLS5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ERCC8	“down-regulates quantity by destabilization”	ERCC6	ubiquitination
DNA_damage	up-regulates	ERCC8
ERCC8	“up-regulates activity”	RAD23B

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
DNA Damage Recognition in GG-NER	8	84.6×	1e-12
Formation of TC-NER Pre-Incision Complex	9	70.5×	2e-13
Cargo recognition for clathrin-mediated endocytosis	5	19.4×	7e-05
Neddylation	9	15.8×	7e-08

GO biological processes:

GO term	Partners	Fold	FDR
regulation of protein neddylation	5	133.8×	3e-08
protein neddylation	5	100.3×	9e-08
protein ubiquitination	6	7.1×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

661 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	93
Likely pathogenic	48
Uncertain significance	161
Likely benign	252
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069323	NM_000082.4(ERCC8):c.356C>A (p.Ser119Ter)	Pathogenic
1070218	NM_000082.4(ERCC8):c.505C>T (p.Gln169Ter)	Pathogenic
1070919	NM_000082.4(ERCC8):c.445_446del (p.Met149fs)	Pathogenic
1074547	NC_000005.9:g.(?60170432)(60224796_?)del	Pathogenic
1074548	NC_000005.9:g.(?60170432)(60217992_?)del	Pathogenic
1074549	NC_000005.9:g.(?60170432)(60195564_?)del	Pathogenic
1075667	NM_000082.4(ERCC8):c.816G>A (p.Trp272Ter)	Pathogenic
1075749	NM_000082.4(ERCC8):c.581G>A (p.Trp194Ter)	Pathogenic
1076456	NC_000005.9:g.(?60240749)(60241219_?)del	Pathogenic
1357030	NM_000082.4(ERCC8):c.825del (p.Asn276fs)	Pathogenic
1385399	NM_000082.4(ERCC8):c.445dup (p.Met149fs)	Pathogenic
1401819	NM_000082.4(ERCC8):c.914C>G (p.Ser305Ter)	Pathogenic
1422572	NM_000082.4(ERCC8):c.994G>T (p.Gly332Ter)	Pathogenic
1439531	NM_000082.4(ERCC8):c.856A>T (p.Lys286Ter)	Pathogenic
1451974	NM_000082.4(ERCC8):c.966C>G (p.Tyr322Ter)	Pathogenic
1453268	NM_000082.4(ERCC8):c.381G>A (p.Trp127Ter)	Pathogenic
1455111	NM_000082.4(ERCC8):c.843+1G>C	Pathogenic
1455112	NM_000082.4(ERCC8):c.223_227del (p.Asn75fs)	Pathogenic
1459214	NC_000005.9:g.(?60186706)(60200710_?)del	Pathogenic
1459262	NM_000082.4(ERCC8):c.101_104del (p.Lys34fs)	Pathogenic
1459508	NC_000005.9:g.(?60183257)(60394869_?)del	Pathogenic
148815	GRCh38/hg38 5q12.1(chr5:60884948-61132933)x0	Pathogenic
1714	NM_000082.3:c.844_1122del	Pathogenic
1715	NM_000082.4(ERCC8):c.966C>A (p.Tyr322Ter)	Pathogenic
190175	NM_000082.4(ERCC8):c.141del (p.Asn47fs)	Pathogenic
1935017	NM_000082.4(ERCC8):c.350C>G (p.Ser117Ter)	Pathogenic
1995423	NM_000082.4(ERCC8):c.786_789del (p.Gly264fs)	Pathogenic
2102658	NM_000082.4(ERCC8):c.867dup (p.Asn290Ter)	Pathogenic
2152001	NM_000082.4(ERCC8):c.659C>G (p.Ser220Ter)	Pathogenic
2243326	NM_000082.4(ERCC8):c.577del (p.Ser193fs)	Pathogenic

SpliceAI

2192 predictions. Top by Δscore:

Variant	Effect	Δscore
5:60898264:A:C	donor_gain	1.0000
5:60898274:A:AC	donor_gain	1.0000
5:60898275:C:CC	donor_gain	1.0000
5:60898275:CAA:C	donor_gain	1.0000
5:60898275:CAAG:C	donor_gain	1.0000
5:60898275:CAAGT:C	donor_gain	1.0000
5:60898397:TTTG:T	acceptor_gain	1.0000
5:60898398:TTG:T	acceptor_gain	1.0000
5:60898399:TG:T	acceptor_gain	1.0000
5:60898401:C:CC	acceptor_gain	1.0000
5:60899621:CCTTA:C	donor_loss	1.0000
5:60899622:CTTAC:C	donor_loss	1.0000
5:60899623:TTACC:T	donor_loss	1.0000
5:60899624:TACC:T	donor_loss	1.0000
5:60899625:A:T	donor_loss	1.0000
5:60899626:C:CA	donor_loss	1.0000
5:60899723:CAGCA:C	acceptor_gain	1.0000
5:60899725:GCA:G	acceptor_gain	1.0000
5:60899726:CA:C	acceptor_gain	1.0000
5:60899726:CAC:C	acceptor_gain	1.0000
5:60899728:C:CA	acceptor_loss	1.0000
5:60899728:C:CC	acceptor_gain	1.0000
5:60899729:T:G	acceptor_loss	1.0000
5:60927668:T:A	donor_gain	1.0000
5:60928857:AACTT:A	donor_loss	1.0000
5:60928858:ACTTA:A	donor_loss	1.0000
5:60928859:CT:C	donor_loss	1.0000
5:60928860:TT:T	donor_loss	1.0000
5:60928861:TA:T	donor_loss	1.0000
5:60928862:A:AC	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000052400 (5:60945024 C>A,T), RS1000055237 (5:60941349 T>C), RS1000130532 (5:60875009 A>G), RS1000152795 (5:60940501 G>A), RS1000184015 (5:60909969 A>T), RS1000184801 (5:60938880 T>C), RS1000320160 (5:60894199 T>A), RS1000325333 (5:60874013 G>C,T), RS1000349236 (5:60872511 C>A), RS1000357053 (5:60888052 T>A), RS1000413231 (5:60909468 T>C), RS1000503279 (5:60921973 G>A,C), RS1000510324 (5:60879864 C>T), RS1000513291 (5:60908588 T>A), RS1000519084 (5:60940118 T>C)

Disease associations

OMIM: gene MIM:609412 | disease phenotypes: MIM:216400, MIM:614621, MIM:618233, MIM:252010

GenCC curated gene-disease

Disease	Classification	Inheritance
Cockayne syndrome type 1	Definitive	Autosomal recessive
UV-sensitive syndrome 2	Strong	Autosomal recessive
UV-sensitive syndrome	Supportive	Autosomal recessive
Cockayne syndrome type 2	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Cockayne syndrome type 1	Definitive	AR

Mondo (10): congenital nervous system disorder (MONDO:0002320), Cockayne syndrome type 1 (MONDO:0019569), UV-sensitive syndrome 2 (MONDO:0013829), Cockayne syndrome (MONDO:0016006), hereditary breast ovarian cancer syndrome (MONDO:0003582), breast ductal adenocarcinoma (MONDO:0005590), mitochondrial complex I deficiency, nuclear type 10 (MONDO:0032616), mitochondrial complex I deficiency, nuclear type 1 (MONDO:0100224), UV-sensitive syndrome (MONDO:0015797), Cockayne syndrome type 2 (MONDO:0019570)

Orphanet (4): Cockayne syndrome (Orphanet:191), Cockayne syndrome type 1 (Orphanet:90321), UV-sensitive syndrome (Orphanet:178338), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

172 total (30 of 172 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000016	Urinary retention
HP:0000026	Male hypogonadism
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000072	Hydroureter
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000093	Proteinuria
HP:0000122	Unilateral renal agenesis
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000164	Abnormality of the dentition
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000276	Long face
HP:0000292	Loss of facial adipose tissue
HP:0000303	Mandibular prognathia
HP:0000331	Short chin
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000400	Macrotia
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000417	Slender nose
HP:0000448	Prominent nose
HP:0000460	Narrow nose
HP:0000482	Microcornea
HP:0000486	Strabismus

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004521_137	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_26	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_260	Autism spectrum disorder or schizophrenia	6.000000e-09
GCST010701_32	Cortical surface area (MOSTest)	2.000000e-29
GCST010702_115	Subcortical volume (MOSTest)	2.000000e-09
GCST010703_98	Brain morphology (MOSTest)	5.000000e-41

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D003057	Cockayne Syndrome	C05.116.099.343.250; C10.574.500.362; C16.131.077.250; C16.320.240.562; C16.320.400.200; C18.452.284.250
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
C563466	UV-Sensitive Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	4
Glyphosate	affects methylation, decreases expression	2
Tretinoin	decreases expression	2
dicrotophos	decreases expression, decreases reaction, decreases response to substance	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
tamibarotene	decreases expression	1
CPG-oligonucleotide	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Acetylcysteine	decreases expression, decreases reaction	1
Methotrexate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Pesticides	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Silicon Dioxide	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Genistein	increases expression	1

Cellosaurus cell lines

31 cell lines: 20 finite cell line, 6 transformed cell line, 3 telomerase immortalized cell line, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0N64	AG07075	Transformed cell line	Female
CVCL_0N65	AG07076	Finite cell line	Female
CVCL_2879	CS2AW	Finite cell line	Female
CVCL_2880	CS2AWTERT	Telomerase immortalized cell line	Female
CVCL_2881	CS2OS	Finite cell line	Male
CVCL_2882	CS2OS(SVT)	Transformed cell line	Male
CVCL_B0IH	GM28257	Finite cell line	Male
CVCL_F631	CS3BE-S3-G1	Transformed cell line	Male
CVCL_F632	CS3BE	Finite cell line	Male
CVCL_F633	CS3BE LCL	Transformed cell line	Male

Clinical trials (associated diseases)

73 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT06009965	PHASE4	UNKNOWN	Efficacy of IST Combined With TPO-RA in the Treatment of AA and Establishment of a Recurrence Prediction System
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT01142154	PHASE1/PHASE2	COMPLETED	Pharmacokinetics and Safety Study of Single and Multiple Oral Doses Prodarsan™ in Patients With Cockayne Syndrome
NCT00001813	Not specified	COMPLETED	Examination of Clinical and Laboratory Abnormalities in Patients With Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy
NCT00985413	Not specified	TERMINATED	Observational Study to Assess Natural History in Cockayne Syndrome Patients
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03044210	Not specified	TERMINATED	Metabolic Study of Cockayne Syndrome
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT05484570	Not specified	RECRUITING	Natural History Study for DNA Repair Disorders
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women