ERCC4

Summary

ERCC4 (ERCC excision repair 4, endonuclease catalytic subunit, HGNC:3436) is a protein-coding gene on chromosome 16p13.12, encoding DNA repair endonuclease XPF (Q92889). Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair, and which is essential for nucleotide excision repair (NER) and interstrand cross-link (ICL) repair. It is a selective cancer dependency (DepMap: 16.1% of cell lines).

The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5’ incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).

Source: NCBI Gene 2072 — RefSeq curated summary.

At a glance

• Gene–disease (curated): xeroderma pigmentosum group F (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 22
• Clinical variants (ClinVar): 1,040 total — 37 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 249
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 16.1% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005236

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3436
Approved symbol	ERCC4
Name	ERCC excision repair 4, endonuclease catalytic subunit
Location	16p13.12
Locus type	gene with protein product
Status	Approved
Aliases	RAD1, FANCQ
Ensembl gene	ENSG00000175595
Ensembl biotype	protein_coding
OMIM	133520
Entrez	2072

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 retained_intron, 4 nonsense_mediated_decay, 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000311895, ENST00000389138, ENST00000462862, ENST00000573018, ENST00000574194, ENST00000574781, ENST00000575156, ENST00000576348, ENST00000682552, ENST00000682568, ENST00000682617, ENST00000682826, ENST00000682909, ENST00000683277, ENST00000683407, ENST00000683962

RefSeq mRNA: 1 — MANE Select: NM_005236 NM_005236

CCDS: CCDS32390

Canonical transcript exons

ENST00000311895 — 11 exons

Exon	Start	End
ENSE00001202996	13932157	13932285
ENSE00001203009	13928028	13928235
ENSE00001203014	13926561	13926756
ENSE00001203025	13947614	13952348
ENSE00003493777	13935146	13935743
ENSE00003501611	13922031	13922211
ENSE00003557784	13930710	13930890
ENSE00003631412	13944723	13944835
ENSE00003646312	13937766	13937858
ENSE00003680921	13934192	13934302
ENSE00003896673	13920154	13920372

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 86.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2968 / max 108.5483, expressed in 1780 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152847	11.2968	1780

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.54	gold quality
adrenal tissue	UBERON:0018303	86.39	gold quality
sperm	CL:0000019	86.31	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.81	gold quality
male germ cell	CL:0000015	83.23	gold quality
calcaneal tendon	UBERON:0003701	82.68	gold quality
cortical plate	UBERON:0005343	81.80	gold quality
stromal cell of endometrium	CL:0002255	80.55	gold quality
ganglionic eminence	UBERON:0004023	79.14	gold quality
secondary oocyte	CL:0000655	78.95	gold quality
right testis	UBERON:0004534	78.91	gold quality
ventricular zone	UBERON:0003053	78.52	gold quality
sural nerve	UBERON:0015488	78.40	gold quality
testis	UBERON:0000473	78.33	gold quality
left testis	UBERON:0004533	78.14	gold quality
islet of Langerhans	UBERON:0000006	77.78	gold quality
monocyte	CL:0000576	77.21	gold quality
mononuclear cell	CL:0000842	76.88	gold quality
leukocyte	CL:0000738	76.67	gold quality
right adrenal gland	UBERON:0001233	76.08	gold quality
adrenal gland	UBERON:0002369	75.99	gold quality
right adrenal gland cortex	UBERON:0035827	75.94	gold quality
left adrenal gland	UBERON:0001234	75.51	gold quality
gastrocnemius	UBERON:0001388	75.13	gold quality
muscle of leg	UBERON:0001383	75.02	gold quality
prefrontal cortex	UBERON:0000451	74.86	gold quality
left adrenal gland cortex	UBERON:0035825	74.86	gold quality
smooth muscle tissue	UBERON:0001135	74.69	gold quality
bronchial epithelial cell	CL:0002328	74.31	gold quality
corpus callosum	UBERON:0002336	74.25	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, FOS

miRNA regulators (miRDB)

197 targeting ERCC4, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4692	100.00	67.32	2066
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 16.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Data reveal an unanticipated involvement of the ERCC1/XPF NER endonuclease in the regulation of telomere integrity. (PMID:14690602)
• XPF protein has important roles in psoralen ICL-mediated DNA repair and mutagenesis. (PMID:14728600)
• the ternary complex of hRad52 and XPF/ERCC1 is the active species that processes recombination intermediates generated during the repair of DNA double strand breaks and in homology-dependent gene targeting events (PMID:14734547)
• XPA, ERCC1 and XPF DNA repair protein expression is reduced in testis neoplasms (PMID:15095299)
• We show that RAD1 is an essential gene for sustained cell proliferation and that loss of Rad1 causes destabilization of Rad9 and Hus1 and consequently disintegration of the sliding-clamp complex. (PMID:15184880)
• The combined effect of ERCC2 Asp(312)Asn and ERCC4 Ser(835)Ser genotypes might be associated with breast cancer risk in Korean women (PMID:15886521)
• The XPF binding sites of ERCC1 were located in helices H1 and H3 and in the C-terminal region, similar to the involved surface of XPF. (PMID:15932882)
• A nuclear magnetic resonance examination of the DNA binding site. (PMID:16034668)
• XPF-ERCC1 recognizes a branched DNA substrate by binding the two ssDNA arms with the two HhH2 domains of XPF and ERCC1 and by binding the 5’-ssDNA arm with the central domain of ERCC1. (PMID:16076955)
• The ERCC1 domain folds properly only in the presence of the XPF domain, which implies a role for XPF as a scaffold for the folding of ERCC1. (PMID:16338413)
• XPF is required to form gamma-H2AX and likely double strand breaks in response to interstrand crosslinks in human cells (PMID:16678501)
• results suggest that the polymorphic variants of these NER genes do not contribute to the risk of developing AD. (PMID:16806697)
• A SNP (rs744154) in intron 1 was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2. It is in the first intron, in a region that is highly conserved across species, and could be causal. (PMID:17018596)
• unanticipated nuclease-independent function of XPF in TRF2-mediated telomere shortening (PMID:17055345)
• The results suggest that the Arg415Gln polymorphism in ERCC4/XPF may not be linked with appearance and development of breast cancer. (PMID:17682675)
• The XPF HhH homodimer has a larger interaction interface, aromatic stacking interactions, and additional hydrogen bond contacts as compared to the XPF/ERCC1 HhH complex, which accounts for its higher stability (PMID:17912758)
• The gene polymorphism at ERCC4 gene had no effects on the DNA damage of lymphocytes in coke oven workers. (PMID:17945097)
• These results implicate the XPF-ERCC1 complex in initiating interstrand cross-links (ICL) repair by unhooking the ICL, which simultaneously induces a double strand break at a stalled fork. (PMID:18006494)
• Data show that incision deficiency correlates with reduced levels of DNA repair synthesis in Fanconi anemia cells and is not due to reduced levels of XPF. (PMID:18020456)
• the polymorphism rs3136038 on the promotor region of ERCC4 may contribute to the etiology of lung cancer. (PMID:18068852)
• To determine whether a human flap endonuclease could recognize and process this potential intermediate, the genetic requirement for the ERCC1/XPF heterodimer during LINE-1 retrotransposition was characterized (PMID:18396111)
• Single nucleotide polymorphism in XPF is associated with breast cancer. (PMID:18551366)
• XPF-ERCC1 controls TRF2 and telomere length maintenance through two distinctive mechanisms, with the former requiring its nuclease activity (PMID:18812185)
• Variant ERCC4 genotypes are statistically significantly associated with benign breast disease, wspecially in women with a family history of breast cancer. (PMID:19124519)
• a model for the mechanism of ICL repair in mammalian cells that implicates the DNA glycosylase activity of NEIL1 downstream of XPF/ERCC1 and translesion DNA synthesis repair steps. (PMID:19258314)
• The smoking status was also predictive of both RPA.. and XPF levels.. after adjusting for age, sex … (PMID:19297315)
• Our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (PMID:19423537)
• the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. (PMID:19920816)
• ERCC1 and XPF are upregulated during testicular germ cell tumor progression (PMID:19956886)
• XPF promoter -357A>C polymorphism may regulate the expression of XPF and thereby contribute to susceptibility to and prognosis of bladder cancer. (PMID:20062074)
• This demonstrates that at least part of the DNA repair defect and symptoms associated with mutations in XPF are due to mislocalization of XPF-ERCC1 into the cytoplasm of cells. (PMID:20221251)
• squamous cell carcinoma metastases of the head and neck show increased levels of nucleotide excision repair protein XPF in vivo that correlate with increased chemoresistance ex vivo (PMID:20372803)
• Studies indicate that a marginally statistically significant association was found for XRCC1 codon 399, XPD Asp312Asn and XRCC1 codon 194 variants and head and neck cancer. (PMID:20429839)
• sites of interaction of FANCG with ERCC1, which is different from the region of ERCC1 that binds to XPF (PMID:20518486)
• Data indicate for the first time that the exceptional sensitivity of TTC and, therefore, very likely the curability of TGCT rests on their limited ICL repair due to low level of expression of ERCC1-XPF. (PMID:20846399)
• The association of MPM with DNA repair genes support the hypothesis that an increased susceptibility to DNA damage may favour asbestos carcinogenicity. (PMID:21277872)
• results indicated that Arg399Gln polymorphism of XRCC1 gene and Arg415Gln polymorphism of ERCC4 gene may not be associated with smoking- and drinking-related larynx cancer in Polish population (PMID:21423097)
• XPF Arg415Gln may be a low-penetrant risk factor in the Caucasian ethnicity for developing breast cancer. (PMID:21424776)
• These results indicated that persistent HBV infection might trigger NER impairment in part through upregulation of miR-192, which suppressed the levels of ERCC3 and ERCC4. (PMID:21672525)
• Data show that high XPF expression correlated with early time to progression both by univariate and multivariate analysis. (PMID:21737503)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ercc4	ENSDARG00000014161
mus_musculus	Ercc4	ENSMUSG00000022545
rattus_norvegicus	Ercc4	ENSRNOG00000065745
rattus_norvegicus	Ercc4	ENSRNOG00000070542
drosophila_melanogaster	mei-9	FBGN0002707
caenorhabditis_elegans		WBGENE00008140

Protein

Protein identifiers

DNA repair endonuclease XPF — Q92889 (reviewed: Q92889)

Alternative names: DNA excision repair protein ERCC-4, DNA repair protein complementing XP-F cells, Xeroderma pigmentosum group F-complementing protein

All UniProt accessions (8): Q92889, A0A1W1GSK9, A0A1W1GSP5, A0A804HI16, A0A804HIY2, A0A804HKF9, I3L4K0, I3NI48

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair, and which is essential for nucleotide excision repair (NER) and interstrand cross-link (ICL) repair.

Subunit / interactions. Heterodimer composed of ERCC1 and ERCC4/XPF. Interacts with SLX4/BTBD12; this interaction is direct and links the ERCC1-ERCC4/XPF complex to SLX4, which may coordinate the action of the structure-specific endonuclease during DNA repair.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Acetylation at Lys-911 by KAT5 promotes interaction with ERCC1 by disrupting a salt bridge between Glu-907 and Lys-911, thereby exposing a second binding site for ERCC1. Deacetylated by SIRT1.

Disease relevance. Xeroderma pigmentosum complementation group F (XP-F) [MIM:278760] An autosomal recessive pigmentary skin disorder characterized by solar hypersensitivity of the skin, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities. The skin develops marked freckling and other pigmentation abnormalities. XP-F patients show a mild phenotype. The disease is caused by variants affecting the gene represented in this entry. XFE progeroid syndrome (XFEPS) [MIM:610965] A syndrome characterized by aged bird-like facies, lack of subcutaneous fat, dwarfism, cachexia and microcephaly. Additional features include sun-sensitivity from birth, learning disabilities, hearing loss, and visual impairment. The disease is caused by variants affecting the gene represented in this entry. Xeroderma pigmentosum type F/Cockayne syndrome (XPF/CS) [MIM:278760] A variant form of Cockayne syndrome, a disorder characterized by growth retardation, microcephaly, impairment of nervous system development, pigmentary retinopathy, peculiar facies, and progeria together with abnormal skin photosensitivity. Cockayne syndrome dermatological features are milder than those in xeroderma pigmentosum and skin cancers are not found in affected individuals. XPF/CS patients, however, present with severe skin phenotypes, including severe photosensitivity, abnormal skin pigmentation, and skin cancer predisposition. The disease is caused by variants affecting the gene represented in this entry. Fanconi anemia complementation group Q (FANCQ) [MIM:615272] A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the XPF family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92889-1	1	yes
Q92889-2	2

RefSeq proteins (1): NP_005227* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006166	ERCC4_domain	Domain
IPR006167	XPF	Family
IPR010994	RuvA_2-like	Homologous_superfamily
IPR011335	Restrct_endonuc-II-like	Homologous_superfamily
IPR047520	XPF_nuclease	Domain

Pfam: PF02732

UniProt features (64 total): sequence variant 33, region of interest 8, helix 7, modified residue 4, splice variant 2, mutagenesis site 2, strand 2, chain 1, domain 1, short sequence motif 1, compositionally biased region 1, cross-link 1, turn 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
2A1J	X-RAY DIFFRACTION	2.7
9QEC	ELECTRON MICROSCOPY	2.9
9QED	ELECTRON MICROSCOPY	3.2
9PD3	ELECTRON MICROSCOPY	3.3
9PD4	ELECTRON MICROSCOPY	3.4
9QEE	ELECTRON MICROSCOPY	3.4
6SXA	ELECTRON MICROSCOPY	3.6
9PCP	ELECTRON MICROSCOPY	4.3
6SXB	ELECTRON MICROSCOPY	7.9
1Z00	SOLUTION NMR
2AQ0	SOLUTION NMR
2KN7	SOLUTION NMR
2MUT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92889-F1	74.60	0.17

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 (5): 289, 521, 764, 911, 500

Mutagenesis-validated functional residues (2):

Position	Phenotype
911	mimics acetylation; promoting interaction with ercc1.
911	abolished acetylation by kat5, leading to decreased interaction with ercc1.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5685938	HDR through Single Strand Annealing (SSA)
R-HSA-5696395	Formation of Incision Complex in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6783310	Fanconi Anemia Pathway

MSigDB gene sets: 943 (showing top): PID_FANCONI_PATHWAY, GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, REACTOME_FORMATION_OF_INCISION_COMPLEX_IN_GG_NER, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOMF_ENDONUCLEASE_ACTIVITY, PID_TELOMERASE_PATHWAY, MORF_MSH3, GOBP_TELOMERE_CAPPING

GO Biological Process (16): resolution of meiotic recombination intermediates (GO:0000712), telomere maintenance (GO:0000723), double-strand break repair via homologous recombination (GO:0000724), DNA repair (GO:0006281), nucleotide-excision repair (GO:0006289), double-strand break repair via nonhomologous end joining (GO:0006303), response to UV (GO:0009411), UV protection (GO:0009650), regulation of autophagy (GO:0010506), negative regulation of telomere maintenance (GO:0032205), cellular response to UV (GO:0034644), telomeric DNA-containing double minutes formation (GO:0061819), nucleotide-excision repair involved in interstrand cross-link repair (GO:1901255), negative regulation of telomere maintenance via telomere lengthening (GO:1904357), negative regulation of protection from non-homologous end joining at telomere (GO:1905765), DNA damage response (GO:0006974)

GO Molecular Function (14): single-stranded DNA endonuclease activity (GO:0000014), TFIID-class transcription factor complex binding (GO:0001094), damaged DNA binding (GO:0003684), single-stranded DNA binding (GO:0003697), DNA endonuclease activity (GO:0004520), protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), hydrolase activity (GO:0016787), 3’ overhang single-stranded DNA endonuclease activity (GO:1990599)

GO Cellular Component (7): nucleotide-excision repair complex (GO:0000109), nucleotide-excision repair factor 1 complex (GO:0000110), chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), ERCC4-ERCC1 complex (GO:0070522), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Global Genome Nucleotide Excision Repair (GG-NER)	2
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1
DNA Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
double-strand break repair	2
response to UV	2
DNA binding	2
protein binding	2
nucleotide-excision repair complex	2
reciprocal meiotic recombination	1
meiosis I cell cycle process	1
telomere organization	1
recombinational repair	1
DNA damage response	1
DNA repair	1
response to light stimulus	1
autophagy	1
regulation of catabolic process	1
telomere maintenance	1
regulation of telomere maintenance	1
negative regulation of DNA metabolic process	1
negative regulation of chromosome organization	1
cellular response to light stimulus	1
telomere maintenance via recombination	1
nucleotide-excision repair	1
interstrand cross-link repair	1
telomere maintenance via telomere lengthening	1
negative regulation of telomere maintenance	1
regulation of telomere maintenance via telomere lengthening	1
protection from non-homologous end joining at telomere	1
negative regulation of telomere capping	1
negative regulation of telomere maintenance in response to DNA damage	1
regulation of protection from non-homologous end joining at telomere	1
cellular response to stress	1
DNA endonuclease activity	1
hydrolase activity, acting on ester bonds	1
RNA polymerase II general transcription initiation factor binding	1
endonuclease activity	1
DNA nuclease activity	1
molecular adaptor activity	1
chromatin binding	1
nucleic acid binding	1
catalytic activity, acting on a nucleic acid	1

Protein interactions and networks

STRING

1801 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERCC4	ERCC1	P07992	999
ERCC4	SLX4	Q8IY92	996
ERCC4	SLX1A	Q9BQ83	992
ERCC4	XPA	P23025	991
ERCC4	ERCC2	P18074	976
ERCC4	ERCC5	P28715	973
ERCC4	ERCC3	P19447	968
ERCC4	A0A090J7P6	A0A090J7P6	964
ERCC4	MUS81	Q96NY9	953
ERCC4	FAAP24	Q9BTP7	907
ERCC4	RAD23B	P54727	903
ERCC4	ERCC6	Q03468	894
ERCC4	EME1	Q96AY2	890
ERCC4	FANCD2	Q9BXW9	869
ERCC4	XRCC1	P18887	818

IntAct

93 interactions, top by confidence:

A	B	Type	Score
STAG2	RAD21	psi-mi:“MI:0914”(association)	0.970
XPA	ERCC1	psi-mi:“MI:0914”(association)	0.930
ERCC4	ERCC1	psi-mi:“MI:0915”(physical association)	0.880
ERCC1	ERCC4	psi-mi:“MI:0915”(physical association)	0.880
ERCC1	ERCC4	psi-mi:“MI:0407”(direct interaction)	0.880
ERCC4	SLX4	psi-mi:“MI:0915”(physical association)	0.790
SLX4	ERCC4	psi-mi:“MI:0915”(physical association)	0.790
PLK1	SPAG9	psi-mi:“MI:0914”(association)	0.790
PLK1	SLX4	psi-mi:“MI:0914”(association)	0.780
ERCC4	PLK1	psi-mi:“MI:0914”(association)	0.770
PLK1	ERCC4	psi-mi:“MI:0915”(physical association)	0.770
SLX1A	SLX4	psi-mi:“MI:0915”(physical association)	0.710
SLX4	TERF2	psi-mi:“MI:0914”(association)	0.660
SLX4	ERCC1	psi-mi:“MI:0914”(association)	0.640
MUS81	ERCC4	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
C10orf55	ERCC4	psi-mi:“MI:0915”(physical association)	0.590
ERCC1	EGFR	psi-mi:“MI:0914”(association)	0.570

BioGRID (208): ERCC4 (Reconstituted Complex), ERCC4 (Affinity Capture-MS), ERCC4 (Affinity Capture-MS), ERCC4 (Affinity Capture-MS), ERCC4 (Affinity Capture-Western), ERCC1 (Co-fractionation), ERCC4 (Co-fractionation), ERCC4 (Affinity Capture-MS), ERCC4 (Affinity Capture-MS), ERCC4 (Affinity Capture-MS), ERCC4 (Affinity Capture-MS), ERCC4 (Reconstituted Complex), ERCC4 (Affinity Capture-Western), ERCC4 (Affinity Capture-Western), ERCC4 (Affinity Capture-Western)

ESM2 similar proteins: A0A3L7I2I8, A0FKG7, A1Z3X3, A4GWN3, A5PK39, E9Q4Z2, O00763, O55236, O60733, O60942, P10687, P10894, P29144, P49754, P82922, P97570, P97789, P97819, Q15147, Q2KJA6, Q32PW3, Q5IH13, Q5KU39, Q5R8R4, Q5ZKK2, Q640G7, Q641K1, Q64514, Q64560, Q69YN2, Q6NY98, Q6NYU2, Q7ZVK4, Q80YV4, Q8BPM2, Q8CI33, Q8IVH8, Q8IZH2, Q8K114, Q8QFR2

Diamond homologs: P06777, P36617, Q24087, Q7LXL5, Q92889, Q9LKI5, Q9QYM7, Q9QZD4, Q58900, Q54PN5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ERCC4	“form complex”	ERCC4/ERCC1	binding
SLX4	up-regulates	ERCC4	binding
SPTAN1	“up-regulates activity”	ERCC4

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 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
Homology Directed Repair	6	30.9×	9e-06
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	6	30.9×	9e-06
Resolution of D-loop Structures through Holliday Junction Intermediates	5	25.0×	1e-04
DNA Double-Strand Break Repair	6	24.8×	2e-05
Fanconi Anemia Pathway	5	23.2×	1e-04
Formation of Incision Complex in GG-NER	5	21.1×	2e-04
SUMOylation of DNA damage response and repair proteins	7	17.1×	2e-05
Nonhomologous End-Joining (NHEJ)	6	16.8×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair via nonhomologous end joining	5	30.5×	5e-05
nucleotide-excision repair	5	27.8×	7e-05
double-strand break repair	8	23.5×	5e-07
positive regulation of transcription initiation by RNA polymerase II	5	19.7×	3e-04
DNA repair	12	11.1×	4e-07
ubiquitin-dependent protein catabolic process	6	6.5×	8e-03
DNA damage response	7	5.4×	7e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1040 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	22
Uncertain significance	563
Likely benign	278
Benign	55

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075759	NM_005236.3(ERCC4):c.22C>T (p.Arg8Ter)	Pathogenic
1338473	NM_005236.3(ERCC4):c.579G>A (p.Trp193Ter)	Pathogenic
1422307	NM_005236.3(ERCC4):c.1251T>A (p.Cys417Ter)	Pathogenic
1452810	NM_005236.3(ERCC4):c.58C>T (p.Arg20Ter)	Pathogenic
16579	NM_005236.3(ERCC4):c.2304_2307del (p.Thr770fs)	Pathogenic
16581	NM_005236.3(ERCC4):c.458G>C (p.Arg153Pro)	Pathogenic
1803967	NM_005236.3(ERCC4):c.2026G>T (p.Glu676Ter)	Pathogenic
2048716	NM_005236.3(ERCC4):c.1447_1450del (p.Arg483fs)	Pathogenic
2151562	NM_005236.3(ERCC4):c.68del (p.Val23fs)	Pathogenic
2181510	NM_005236.3(ERCC4):c.872T>A (p.Leu291Ter)	Pathogenic
2425327	NC_000016.9:g.(?14038570)(14038702_?)del	Pathogenic
2425329	NC_000016.9:g.(?14020398)(14022112_?)del	Pathogenic
2923026	NM_005236.3(ERCC4):c.663dup (p.Met222fs)	Pathogenic
2927079	NM_005236.3(ERCC4):c.856C>T (p.Gln286Ter)	Pathogenic
2931654	NM_005236.3(ERCC4):c.886C>T (p.Gln296Ter)	Pathogenic
2931871	NM_005236.3(ERCC4):c.849_856del (p.Leu284fs)	Pathogenic
2932701	NM_005236.3(ERCC4):c.148C>T (p.Gln50Ter)	Pathogenic
3027158	NM_005236.3(ERCC4):c.1315del (p.Thr439fs)	Pathogenic
3243523	NC_000016.9:g.(?14028029)(14031735_?)del	Pathogenic
3338943	NM_005236.3(ERCC4):c.307C>T (p.Gln103Ter)	Pathogenic
3748773	NM_005236.3(ERCC4):c.891T>G (p.Tyr297Ter)	Pathogenic
4072059	NM_005236.3(ERCC4):c.202G>T (p.Glu68Ter)	Pathogenic
4085538	NM_005236.3(ERCC4):c.430C>T (p.Gln144Ter)	Pathogenic
4085550	NM_005236.3(ERCC4):c.61C>T (p.Gln21Ter)	Pathogenic
4279331	GRCh37/hg19 16p13.12(chr16:13812690-14070728)x1	Pathogenic
4535666	NM_005236.3(ERCC4):c.207+196T>A	Pathogenic
4783221	NM_005236.3(ERCC4):c.2074C>T (p.Arg692Ter)	Pathogenic
4788501	NM_005236.3(ERCC4):c.2241dup (p.Met748fs)	Pathogenic
541251	NM_005236.3(ERCC4):c.1731del (p.Arg576_Tyr577insTer)	Pathogenic
541254	NC_000016.10:g.(?13928022)(13928241_?)del	Pathogenic

SpliceAI

2321 predictions. Top by Δscore:

Variant	Effect	Δscore
16:13920370:G:GT	donor_gain	1.0000
16:13920392:G:GT	donor_gain	1.0000
16:13922027:TTAG:T	acceptor_loss	1.0000
16:13922028:TA:T	acceptor_loss	1.0000
16:13922030:GGA:G	acceptor_gain	1.0000
16:13922030:GGAGT:G	acceptor_gain	1.0000
16:13926556:CTCA:C	acceptor_loss	1.0000
16:13926558:CAGGC:C	acceptor_loss	1.0000
16:13926559:A:AC	acceptor_loss	1.0000
16:13926559:A:AG	acceptor_gain	1.0000
16:13926560:G:GA	acceptor_gain	1.0000
16:13926560:G:GT	acceptor_loss	1.0000
16:13926560:GGC:G	acceptor_gain	1.0000
16:13926752:CCAAG:C	donor_loss	1.0000
16:13926753:CAAGG:C	donor_loss	1.0000
16:13926754:AAGGT:A	donor_loss	1.0000
16:13926755:AGG:A	donor_loss	1.0000
16:13926756:GGTAA:G	donor_loss	1.0000
16:13926757:G:GA	donor_loss	1.0000
16:13926758:T:G	donor_loss	1.0000
16:13930705:TTTA:T	acceptor_loss	1.0000
16:13930708:A:AG	acceptor_gain	1.0000
16:13930708:AGA:A	acceptor_loss	1.0000
16:13930709:G:GC	acceptor_gain	1.0000
16:13930709:GA:G	acceptor_gain	1.0000
16:13930709:GAC:G	acceptor_gain	1.0000
16:13930709:GACA:G	acceptor_gain	1.0000
16:13930709:GACAA:G	acceptor_gain	1.0000
16:13930816:A:AG	donor_gain	1.0000
16:13930817:G:GG	donor_gain	1.0000

AlphaMissense

6006 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:13932159:T:A	W326R	1.000
16:13932159:T:C	W326R	1.000
16:13926756:G:T	R195M	0.999
16:13928029:T:C	F196L	0.999
16:13928031:C:A	F196L	0.999
16:13928031:C:G	F196L	0.999
16:13935668:T:A	V579D	0.999
16:13935704:T:C	L591P	0.999
16:13937813:T:C	L620P	0.999
16:13947740:A:T	D715V	0.999
16:13947773:G:C	R726P	0.999
16:13947775:A:G	K727E	0.999
16:13947777:G:C	K727N	0.999
16:13947777:G:T	K727N	0.999
16:13948000:T:A	W802R	0.999
16:13948000:T:C	W802R	0.999
16:13922172:G:C	D117H	0.998
16:13922173:A:T	D117V	0.998
16:13926630:G:C	R153P	0.998
16:13926660:C:A	A163D	0.998
16:13926756:G:C	R195T	0.998
16:13928162:T:C	L240P	0.998
16:13932161:G:C	W326C	0.998
16:13932161:G:T	W326C	0.998
16:13934229:G:C	K380N	0.998
16:13934229:G:T	K380N	0.998
16:13934230:T:A	W381R	0.998
16:13934230:T:C	W381R	0.998
16:13935155:T:C	L408P	0.998
16:13935695:T:A	V588D	0.998

dbSNP variants (sampled 300 via entrez): RS1000080595 (16:13934017 T>G), RS1000267874 (16:13933792 T>G), RS1000427392 (16:13931229 C>G), RS1000678338 (16:13944111 T>A), RS1000695607 (16:13938529 A>G), RS1000712667 (16:13928891 A>C), RS1000854674 (16:13929751 G>C,T), RS1000902937 (16:13938918 G>A,T), RS1001014692 (16:13940597 C>G,T), RS1001085947 (16:13932999 T>C,G), RS1001335032 (16:13938741 A>G), RS1001375117 (16:13923396 G>A), RS1001426467 (16:13929915 G>C), RS1001431855 (16:13927060 C>A,G,T), RS1001447316 (16:13946516 C>T)

Disease associations

OMIM: gene MIM:133520 | disease phenotypes: MIM:278760, MIM:615272, MIM:278700, MIM:167000, MIM:610965, MIM:176670, MIM:108600, MIM:213200

GenCC curated gene-disease

Disease	Classification	Inheritance
xeroderma pigmentosum group F	Definitive	Autosomal recessive
XFE progeroid syndrome	Strong	Autosomal recessive
Fanconi anemia complementation group Q	Strong	Autosomal recessive
xeroderma pigmentosum-Cockayne syndrome complex	Supportive	Autosomal recessive
Fanconi anemia	Supportive	Autosomal recessive
xeroderma pigmentosum	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
xeroderma pigmentosum group F	Definitive	AR

Mondo (19): xeroderma pigmentosum group F (MONDO:0010215), Fanconi anemia complementation group Q (MONDO:0014108), Cockayne syndrome (MONDO:0016006), xeroderma pigmentosum (MONDO:0019600), ovarian cancer (MONDO:0008170), XFE progeroid syndrome (MONDO:0012590), hereditary neoplastic syndrome (MONDO:0015356), behavioral variant of frontotemporal dementia (MONDO:0017160), Hutchinson-Gilford progeria syndrome (MONDO:0008310), breast carcinoma (MONDO:0004989), exocrine pancreatic carcinoma (MONDO:0005192), primary ovarian failure (MONDO:0005387), precursor B-cell acute lymphoblastic leukemia (MONDO:0020511), xeroderma pigmentosum, type F/Cockayne syndrome (MONDO:0800313), spastic ataxia (MONDO:0017845)

Orphanet (14): Cockayne syndrome (Orphanet:191), Fanconi anemia (Orphanet:84), Xeroderma pigmentosum (Orphanet:910), Rare ovarian cancer (Orphanet:213500), Inherited cancer-predisposing syndrome (Orphanet:140162), Behavioral variant of frontotemporal dementia (Orphanet:275864), Hutchinson-Gilford progeria syndrome (Orphanet:740), Familial pancreatic carcinoma (Orphanet:1333), Rare carcinoma of pancreas (Orphanet:217074), Precursor B-cell acute lymphoblastic leukemia (Orphanet:99860), Spastic ataxia (Orphanet:316226), Autosomal recessive cerebellar ataxia (Orphanet:1172), OBSOLETE: Xeroderma pigmentosum complementation group F (Orphanet:276264), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

249 total (30 of 249 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000035	Abnormal testis morphology
HP:0000047	Hypospadias
HP:0000072	Hydroureter
HP:0000079	Abnormality of the urinary system
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000130	Abnormality of the uterus
HP:0000135	Hypogonadism
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000331	Short chin
HP:0000336	Prominent supraorbital ridges
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000364	Hearing abnormality

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000713_11	Conduct disorder (symptom count)	6.000000e-06
GCST000753_5	Metabolic syndrome	3.000000e-06
GCST001324_4	Bilirubin levels	2.000000e-06
GCST002539_81	Schizophrenia	1.000000e-09
GCST002789_5	Egg allergy	5.000000e-06
GCST002945_2	Emphysema imaging phenotypes	4.000000e-07
GCST003542_21	Night sleep phenotypes	6.000000e-06
GCST003542_97	Night sleep phenotypes	8.000000e-06
GCST003831_26	Asthma	1.000000e-06
GCST003832_24	Asthma (childhood onset)	5.000000e-06
GCST004946_12	Schizophrenia	8.000000e-10
GCST005082_8	Bipolar disorder lithium response (categorical) or schizophrenia	5.000000e-11
GCST006143_5	Bone mineral density (total hip)	1.000000e-06
GCST006803_63	Schizophrenia	4.000000e-10
GCST007201_201	Schizophrenia	7.000000e-09
GCST007201_248	Schizophrenia	1.000000e-09
GCST007323_62	Risk-taking tendency (4-domain principal component model)	1.000000e-12
GCST007326_66	Number of sexual partners	6.000000e-09
GCST007327_119	Smoking status (ever vs never smokers)	3.000000e-09
GCST007328_46	Alcohol consumption (drinks per week)	2.000000e-08
GCST008150_8	Triglyceride levels	9.000000e-06
GCST008522_86	Bitter alcoholic beverage consumption	5.000000e-06

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0000195	metabolic syndrome
EFO:0004343	waist-hip ratio
EFO:0004570	bilirubin measurement
EFO:0007018	egg allergy measurement
EFO:0007626	emphysema imaging measurement
EFO:0007702	hip bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0004530	triglyceride measurement
EFO:0010092	bitter alcoholic beverage consumption measurement

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
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
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
D014983	Xeroderma Pigmentosum	C04.834.867; C16.131.831.936; C16.320.850.970; C17.800.600.925; C17.800.621.936; C17.800.804.936; C17.800.827.970; C18.452.284.975
C564815	Spastic Ataxia (supp.)
C567043	XFE Progeroid Syndrome (supp.)
C562592	Xeroderma Pigmentosum, Complementation Group F (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3883316 (PROTEIN COMPLEX)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1799801	Efficacy	3	Platinum compounds	Non-Small Cell Lung Carcinoma

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1799801	ERCC4	3	2.25	1	Platinum compounds
rs2276464	ERCC4		0.00	0
rs2276466	ERCC4		0.00	0
rs6498486	ERCC4		0.00	0

ChEMBL bioactivities

62 potent at pChembl≥5 of 88 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.07	Kd	85	nM	CHEMBL4759590
7.00	Kd	100	nM	CHEMBL4470176
6.85	Kd	140	nM	CHEMBL463783
6.48	IC50	330	nM	CHEMBL4470176
6.31	IC50	490	nM	CHEMBL4759590
6.30	IC50	500	nM	CHEMBL3617281
6.22	IC50	600	nM	CHEMBL3617209
6.22	IC50	600	nM	CHEMBL3617205
6.20	IC50	630	nM	CHEMBL3617002
6.16	IC50	700	nM	CHEMBL3617284
6.16	IC50	700	nM	CHEMBL3617207
6.13	IC50	740	nM	CHEMBL3617018
6.10	IC50	800	nM	CHEMBL3617014
6.10	IC50	800	nM	CHEMBL3617001
6.10	IC50	800	nM	CHEMBL3617286
6.10	IC50	800	nM	CHEMBL3617283
6.10	IC50	800	nM	CHEMBL3617282
6.05	IC50	900	nM	CHEMBL3616993
6.00	IC50	1000	nM	CHEMBL3617013
6.00	IC50	1000	nM	CHEMBL3617000
6.00	IC50	1000	nM	CHEMBL3617285
6.00	IC50	1000	nM	CHEMBL223338
5.96	IC50	1100	nM	CHEMBL3617016
5.85	IC50	1400	nM	CHEMBL3617007
5.82	IC50	1500	nM	CHEMBL3617203
5.82	IC50	1500	nM	CHEMBL182381
5.80	IC50	1600	nM	CHEMBL3617015
5.80	IC50	1600	nM	CHEMBL3617004
5.80	IC50	1600	nM	CHEMBL3616994
5.77	IC50	1700	nM	CHEMBL3617287
5.75	IC50	1800	nM	CHEMBL3616999
5.75	IC50	1800	nM	CHEMBL361011
5.73	IC50	1860	nM	CHEMBL463783
5.70	IC50	2000	nM	CHEMBL3616991
5.58	IC50	2600	nM	CHEMBL3617003
5.57	IC50	2700	nM	CHEMBL3617206
5.54	IC50	2900	nM	CHEMBL3617017
5.54	IC50	2900	nM	CHEMBL181653
5.46	Kd	3500	nM	CHEMBL2443225
5.41	IC50	3900	nM	CHEMBL440562
5.41	IC50	3900	nM	CHEMBL3617197
5.41	IC50	3900	nM	CHEMBL361350
5.40	IC50	4000	nM	CHEMBL3617008
5.40	Kd	4000	nM	CHEMBL3617205
5.39	IC50	4100	nM	CHEMBL3617020
5.38	IC50	4200	nM	CHEMBL216874
5.34	IC50	4600	nM	CHEMBL3617208
5.32	IC50	4800	nM	CHEMBL3617019
5.28	IC50	5200	nM	CHEMBL3617023
5.24	IC50	5800	nM	CHEMBL3617012

PubChem BioAssay actives

62 with measured affinity, of 129 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
6-chloro-9-[3-[[4-[2-(dimethylamino)ethyl]piperazin-1-yl]methyl]-4-hydroxyanilino]acridin-2-ol	1704038: Binding affinity to His-tagged human ERCC1-XPF expressed in Escherichia coli BL21 (DE3) cells by steady-state fluorescence assay	kd	0.0850	uM
4-[(6-chloro-2-methoxyacridin-9-yl)amino]-2-[[4-[2-(dimethylamino)ethyl]piperazin-1-yl]methyl]phenol	1516751: Binding affinity to human His6-tagged ERCC1-XPF expressed in Escherichia coli BL21 (DE3) by spectrofluorimetric method	kd	0.1000	uM
4-[(6-chloro-2-methoxyacridin-9-yl)amino]-2-[(4-methylpiperazin-1-yl)methyl]phenol	1704038: Binding affinity to His-tagged human ERCC1-XPF expressed in Escherichia coli BL21 (DE3) cells by steady-state fluorescence assay	kd	0.1400	uM
5-hydroxy-N-(3-methylbutyl)-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.5000	uM
5-hydroxy-N-methyl-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.6000	uM
N-butan-2-yl-5-hydroxy-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.6000	uM
2-(2,4-dichlorophenyl)-N-[(3,4-dihydroxyphenyl)methyl]acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.6300	uM
5-hydroxy-N-(2-hydroxyethyl)-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.7000	uM
5-hydroxy-6-oxo-N-pyridin-3-yl-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.7000	uM
N-[(2,4-dichlorophenyl)methyl]-2-(3,4-dihydroxyphenyl)acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.7400	uM
2-(2-chlorophenyl)-N-[(3,4-dihydroxyphenyl)methyl]acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.8000	uM
2-(2,4-dichlorophenyl)-N-[(3,4-dihydroxyphenyl)methyl]-N-methylacetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.8000	uM
N-(2-acetamidoethyl)-5-hydroxy-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.8000	uM
N-(4-fluorophenyl)-5-hydroxy-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.8000	uM
5-hydroxy-N-(3-methylbutyl)-2-[4-(morpholin-4-ylmethyl)phenyl]-6-oxo-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.8000	uM
2-anilino-N-[(3,4-dihydroxyphenyl)methyl]acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	0.9000	uM
2-(4-chlorophenyl)-N-[(3,4-dihydroxyphenyl)methyl]acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.0000	uM
2-(2,4-dichlorophenyl)-1-(6,7-dihydroxy-3,4-dihydro-1H-isoquinolin-2-yl)ethanone	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.0000	uM
5-hydroxy-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.0000	uM
5-hydroxy-N-(2-morpholin-4-ylethyl)-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.0000	uM
2-(2,4-dichlorophenyl)-N-[(2-fluoro-4,5-dihydroxyphenyl)methyl]acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.1000	uM
2-cyclohexyl-N-[(3,4-dihydroxyphenyl)methyl]acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.4000	uM
3-hydroxy-6-phenyl-1H-pyrimidine-2,4-dione	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.5000	uM
3-hydroxy-7-(4-methylphenyl)-1H-furo[3,2-d]pyrimidine-2,4-dione	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.5000	uM
2-anilino-N-(3,4-dihydroxyphenyl)acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.6000	uM
N-[(3,4-dihydroxyphenyl)methyl]-1-phenylcyclohexane-1-carboxamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.6000	uM
N-[(2-chloro-3,4-dihydroxyphenyl)methyl]-2-(2,4-dichlorophenyl)acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.6000	uM
2-[4-[(dimethylamino)methyl]phenyl]-5-hydroxy-N-(3-methylbutyl)-6-oxo-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.7000	uM
3-hydroxy-7-phenyl-1H-thieno[3,2-d]pyrimidine-2,4-dione	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.8000	uM
N-[(3,4-dihydroxyphenyl)methyl]-2-phenylpropanamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	1.8000	uM
2-anilino-N-[(E)-(3,4-dihydroxyphenyl)methylideneamino]acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	2.0000	uM
N-[(3,4-dihydroxyphenyl)methyl]-2-(4-methoxyphenyl)acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	2.6000	uM
5-hydroxy-6-oxo-N-propyl-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	2.7000	uM
1-(2,4-dichlorophenyl)-N-[(3,4-dihydroxyphenyl)methyl]methanesulfonamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	2.9000	uM
5-hydroxy-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxylic acid	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	2.9000	uM
5-(4-fluorophenyl)-3-hydroxy-1H-pyridin-2-one	1247666: Binding affinity to ERCC1-XPF (unknown origin) by SPR assay	kd	3.5000	uM
7-anilino-3-hydroxy-1H-quinazoline-2,4-dione	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	3.9000	uM
5-hydroxy-6-oxo-2-phenyl-1H-pyrimidine-4-carboxylic acid	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	3.9000	uM
3-hydroxy-1H-thieno[2,3-d]pyrimidine-2,4-dione	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	3.9000	uM
2-(3-cyanophenyl)-N-[(3,4-dihydroxyphenyl)methyl]acetamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	4.0000	uM
1-[(4-chlorophenyl)methyl]-3-[(3,4-dihydroxyphenyl)methyl]imidazolidin-2-one	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	4.1000	uM
N-[(4-fluorophenyl)methyl]-5-hydroxy-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	4.2000	uM
5-hydroxy-4-(pyrrolidine-1-carbonyl)-2-thiophen-2-yl-1H-pyrimidin-6-one	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	4.6000	uM
1-(4-chlorophenyl)-3-[(3,4-dihydroxyphenyl)methyl]urea	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	4.8000	uM
3-hydroxy-5-(3-pyrazol-1-ylphenyl)-1H-pyridin-2-one	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	5.2000	uM
N-[(3,4-dihydroxyphenyl)methyl]-1-[(4-fluorophenyl)methyl]piperidine-4-carboxamide	1247658: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	5.8000	uM
N-(3-hydroxy-2,4-dioxo-1H-quinazolin-8-yl)acetamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	6.1000	uM
5-hydroxy-N-(3-methylbutyl)-6-oxo-2-piperidin-2-yl-1H-pyrimidine-4-carboxamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	6.3000	uM
N-(3-hydroxy-2,4-dioxo-1H-quinazolin-7-yl)acetamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	6.4000	uM
N-(3-hydroxy-2,4-dioxo-1H-quinazolin-6-yl)acetamide	1247798: Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	ic50	6.6000	uM

CTD chemical–gene interactions

65 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, decreases expression, affects cotreatment, increases abundance, increases expression	4
trichostatin A	decreases reaction, increases expression, decreases expression, increases abundance	3
Arsenic	decreases reaction, decreases expression, affects cotreatment, increases abundance, increases expression	3
Cisplatin	decreases response to substance, increases expression, decreases reaction, affects binding	3
Particulate Matter	increases abundance, increases methylation, increases expression, decreases expression	3
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
potassium chromate(VI)	decreases reaction, affects cotreatment, increases expression, decreases expression	2
Air Pollutants	increases methylation, decreases expression, increases abundance	2
Valproic Acid	decreases expression, increases expression	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
sulforaphane	increases expression	1
potassium bromate	decreases expression	1
3-aminobenzamide	decreases reaction, increases expression, decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
coumarin	decreases phosphorylation	1
epigallocatechin gallate	decreases reaction, affects cotreatment, decreases expression	1
cisplatin-DNA adduct	decreases abundance	1
phenethyl isothiocyanate	increases expression	1
cobalt oxide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
benzo(a)pyrene diolepoxide I	increases expression	1
chromium hexavalent ion	affects expression	1
cylindrospermopsin	increases expression	1
mirdametinib	increases expression	1
veliparib	increases expression, increases reaction	1
riccardin D	increases expression	1

ChEMBL screening assays

28 unique, capped per target: 28 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3619484	Binding	Inhibition of ERCC1-XPF (unknown origin) by high-throughput fluorescence based in-vitro endonuclease assay	N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF. — Bioorg Med Chem Lett

Cellosaurus cell lines

28 cell lines: 19 finite cell line, 5 cancer cell line, 2 transformed cell line, 2 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_3244	XP2YO(SV)	Transformed cell line	Female
CVCL_B8FI	Abcam HCT 116 ERCC4 KO	Cancer cell line	Male
CVCL_B8VE	Abcam MCF-7 ERCC4 KO	Cancer cell line	Female
CVCL_B9HR	Abcam A-549 ERCC4 KO	Cancer cell line	Male
CVCL_B9VH	Abcam HeLa ERCC4 KO	Cancer cell line	Female
CVCL_F598	XP2YO	Finite cell line	Female
CVCL_KU27	HeLa SilenciX XPF	Cancer cell line	Female
CVCL_M284	XP3YO	Finite cell line	Male
CVCL_UH37	XP101OS	Finite cell line	Female
CVCL_UH38	XP7KA	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	PHASE4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	PHASE4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	PHASE4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	PHASE4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	PHASE4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	PHASE4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	PHASE4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	PHASE4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	PHASE4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	PHASE4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	PHASE4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	PHASE4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	PHASE4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	PHASE4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	PHASE4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	PHASE4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	PHASE4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	PHASE4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	PHASE4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	PHASE4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	PHASE4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT06519786	PHASE3	UNKNOWN	Safety and Efficacy of Metformin for Treatment of Cytopenia in Children and Adolescents With Fanconi Anemia
NCT00001806	PHASE3	COMPLETED	Methods in Education for Breast Cancer Genetics
NCT00002477	PHASE3	UNKNOWN	Adjuvant Chemotherapy Compared With Observation in Treating Patients With Resected Early Stage Ovarian Epithelial Cancer
NCT00002568	PHASE3	COMPLETED	Combination Chemotherapy With or Without Surgery in Treating Patients With Stage III Ovarian Epithelial Cancer
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002717	PHASE3	COMPLETED	Paclitaxel and Cisplatin in Treating Patients With Stage III or Stage IV Ovarian Cancer or Primary Peritoneal Cancer
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002819	PHASE3	TERMINATED	Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Persistent Ovarian Epithelial Cancer
NCT00002894	PHASE3	COMPLETED	Platinum-based Chemotherapy With or Without Paclitaxel in Treating Patients With Relapsed Ovarian Cancer
NCT00002895	PHASE3	COMPLETED	Early Chemotherapy Based on CA 125 Level Alone Compared With Delayed Chemotherapy in Treating Patients With Recurrent Ovarian Epithelial , Fallopian Tube, or Primary Peritoneal Cancer
NCT00003120	PHASE3	COMPLETED	S9701 Paclitaxel in Treating Patients With Advanced Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Remission
NCT00003214	PHASE3	COMPLETED	Chemosensitivity Testing to Assign Treatment for Patients With Stage III or Stage IV Ovarian Cancer
NCT00003322	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Primary Peritoneal or Stage III Epithelial Ovarian Cancer
NCT00003636	PHASE3	COMPLETED	Chemotherapy Plus Surgery in Treating Patients With Stage III or Stage IV Ovarian, Peritoneal, or Fallopian Tube Cancer