XRCC4

Summary

XRCC4 (X-ray repair cross complementing 4, HGNC:12831) is a protein-coding gene on chromosome 5q14.2, encoding DNA repair protein XRCC4 (Q13426). DNA non-homologous end joining (NHEJ) core factor, required for double-strand break repair and V(D)J recombination.

The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site.

Source: NCBI Gene 7518 — RefSeq curated summary.

At a glance

• Gene–disease (curated): short stature, microcephaly, and endocrine dysfunction (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 199 total — 17 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 94
• Druggable target: yes
• MANE Select transcript: NM_003401

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12831
Approved symbol	XRCC4
Name	X-ray repair cross complementing 4
Location	5q14.2
Locus type	gene with protein product
Status	Approved
Aliases	hXRCC4
Ensembl gene	ENSG00000152422
Ensembl biotype	protein_coding
OMIM	194363
Entrez	7518

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000282268, ENST00000338635, ENST00000396027, ENST00000509268, ENST00000511817, ENST00000542685, ENST00000888905, ENST00000933725, ENST00000933726, ENST00000933727, ENST00000957027, ENST00000957028, ENST00000957029

RefSeq mRNA: 5 — MANE Select: NM_003401 NM_001318012, NM_001318013, NM_003401, NM_022406, NM_022550

CCDS: CCDS4058, CCDS4059

Canonical transcript exons

ENST00000396027 — 8 exons

Exon	Start	End
ENSE00001925161	83077547	83077615
ENSE00001931094	83353131	83353760
ENSE00003543260	83111028	83111203
ENSE00003552322	83195770	83195936
ENSE00003555181	83204815	83204921
ENSE00003562239	83203552	83203707
ENSE00003622290	83258530	83258677
ENSE00003631002	83104910	83105058

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 89.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.1479 / max 528.4378, expressed in 1655 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57378	5.3187	1576
57377	1.5387	845
57383	0.1408	4
57381	0.0874	1
57382	0.0423	2
57384	0.0100	1
57385	0.0099	1

Top tissues by expression

277 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	89.93	gold quality
monocyte	CL:0000576	88.16	gold quality
mononuclear cell	CL:0000842	87.56	gold quality
leukocyte	CL:0000738	87.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.96	gold quality
secondary oocyte	CL:0000655	85.09	gold quality
oocyte	CL:0000023	84.98	gold quality
ventricular zone	UBERON:0003053	81.13	gold quality
descending thoracic aorta	UBERON:0002345	81.06	gold quality
calcaneal tendon	UBERON:0003701	80.23	gold quality
ganglionic eminence	UBERON:0004023	80.17	gold quality
thoracic aorta	UBERON:0001515	79.26	gold quality
islet of Langerhans	UBERON:0000006	79.20	gold quality
ascending aorta	UBERON:0001496	79.09	gold quality
right atrium auricular region	UBERON:0006631	79.05	gold quality
rectum	UBERON:0001052	78.92	gold quality
heart left ventricle	UBERON:0002084	78.68	gold quality
granulocyte	CL:0000094	78.07	gold quality
cardiac ventricle	UBERON:0002082	77.94	gold quality
right adrenal gland cortex	UBERON:0035827	77.85	gold quality
adrenal tissue	UBERON:0018303	77.76	gold quality
aorta	UBERON:0000947	77.70	gold quality
right coronary artery	UBERON:0001625	77.68	gold quality
tendon	UBERON:0000043	77.51	gold quality
cardiac atrium	UBERON:0002081	77.45	gold quality
heart	UBERON:0000948	77.44	gold quality
right adrenal gland	UBERON:0001233	77.38	gold quality
left coronary artery	UBERON:0001626	77.34	gold quality
gall bladder	UBERON:0002110	77.02	gold quality
embryo	UBERON:0000922	76.96	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-98556	yes	255.02
E-ANND-3	yes	3.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

33 targeting XRCC4, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-1257	98.97	68.02	1133
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-455-5P	98.74	67.31	795
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-6818-5P	97.50	67.10	1167

Literature-anchored findings (GeneRIF, showing 40)

• crystal structure of an Xrcc4-DNA ligase IV complex (PMID:11702069)
• Coordinated assembly of Ku and p460 subunits of the DNA-dependent protein kinase on DNA ends is necessary for XRCC4-ligase IV recruitment (PMID:12547193)
• HeLa cells, supplemented with recombinant XRCC4-DNA ligase IV complex (XRCC4/ligase IV), were capable of accurately rejoining model double-strand break substrates. (PMID:14561766)
• the protein expression of XRCC4 was found to be decreased after SYT-SSX inhibition (PMID:14576825)
• DNAPK was physically required for the mobilization of the XRCC4-ligase IV complex, and for stable recruitment of XRCC4; phosphorylation of either H2AX or XRCC4 was unnecessary for DNAPK or XRCC4-ligase IV recruitment (PMID:15520013)
• We confirmed that DNA ligase IV is unstable in the absence of XRCC4, with a half-life of approximately 30-90 min. (PMID:16412978)
• association of SUMO modification of XRCC4 with the control of the repair and recombination associated with DNA breaks (PMID:16478998)
• Cernunnos physically interacts with the XRCC4 x DNA-ligase IV complex (PMID:16571728)
• Single Nucleotide Polymorphisms in XRCC4 is associated with breast cancer (PMID:16835328)
• Functions in nonhomologous DNA end joining, and may serve as a flexible tether between Ku70/80 and ligase IV. (PMID:17124166)
• DNA-PK kinase activity results in disassembly of the Ku/DNA ligase IV/Xrcc4 complex (PMID:17241822)
• NHEJ suppresses processing to optimize the preservation of DNA sequence through kinase activity and XRCC4/ligase IV (PMID:17272270)
• XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps. (PMID:17290226)
• mutant protein retained its ability to stimulate XRCC4.DNA ligase IV but failed to translocate to the nucleus, and this appears to be the basis for the non-homologous DNA end joining defect in this patient (PMID:17317666)
• Transfected into knockout mice in order to join the DNA repair pathwayto immunoglobulin class switch recombination. (PMID:17606631)
• Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma. (PMID:17901044)
• DNA Ligase IV/XRCC4 recruitment by DNA-PK to DNA double-strand breaks prevents the formation of long ssDNA ends at double-strand breaks during the S phase. (PMID:17963495)
• Our findings suggest that the G allele of the XRCC4 G-1394T may contribute to gastric carcinogenesis and may be useful for gastric cancer early detection and prevention. (PMID:17987338)
• The XRCC4 dimer adopts a similar overall structure to that of the XLF dimer, supporting the contention that these two factors are related in function and have arisen from a common evolutionary ancestor. (PMID:18046455)
• Mutational analysis of XLF and XRCC4 reveals a potential interaction interface, suggesting a mechanism for how XLF stimulates the ligation of mismatched ends. (PMID:18158905)
• results firstly suggest that the XRCC4 intron 3 del genotype may be associated with oral oncology and may be a novel useful marker for primary prevention and anticancer intervention. (PMID:18164646)
• Haplotype analysis revealed an association of glioma risk with genetic variants in LIG4 block 1 (global P=0.011), and XRCC4 blocks 2 and 4 (both global P<0.0001). (PMID:18165945)
• Polymorphisms of XRCC4 promoter are associated with higher susceptibility of leiomyoma, and XPD promoter polymorphisms are not. (PMID:18177646)
• XRCC4 codon 247*A and XRCC4 promoter -1394*T related genotypes and alleles, but not XRCC4 intron 3 I/D polymorphism, might be associated with endometriosis susceptibilities and pathogenesis. (PMID:18246529)
• combined XRCCs 1-4 polymorphisms associated with oral cancer risk (PMID:18410587)
• Results provide the first evidence that the heterozygous A allele of the XRCC4 codon 247 may be associated with the development of oral cancer. (PMID:18630527)
• Carrying at least one copy of the variant XRCC4 allele (rs1805377) was associated with a significantly increased risk of renal cell carcinoma. (PMID:18768505)
• these results indicated that SLE leucocytes repair less efficiently the radiation-induced DNA damage, and DNA repair polymorphic sites may predispose to the development of particular clinical and laboratory features (PMID:18852222)
• In cells infected with E1B 55k-deficient adenovirus, ligase IV could not be found in XRCC4-containing complexes and was observed in a novel ligase IV/E4 34k/Cul5/Elongin BC complex. (PMID:18952251)
• the heads and coiled-coil regions of Cernunnos and X4 are not interchangeable, and they suggest specific roles for each in NHEJ (PMID:19103754)
• The high-resolution crystal structure of human XRCC4 bound to the carboxy-terminal tandem BRCT repeat of DNA ligase IV, is reported. (PMID:19332554)
• findings suggest that the G allele of XRCC4 G-1394T may be involved in bladder carcinogenesis and useful in early detection of bladder cancer (PMID:19443403)
• effect for smoking habit and XRCC4 G-1394T polymorphism was that people with GT genotype & smoking habit present the highest risk of lung cancer than other groups. G allele of the XRCC4 G-1394T may be responsible for lung carcinogenesis. (PMID:19729825)
• provide a first sight of the structural organization of the DNA ligase IV (Lig4)-Xrcc4 complex, which suggests that the BRCT domains could provide the link of the ligase to Xrcc4 while permitting some movements of the catalytic domains of Lig4. (PMID:19837014)
• The results suggested that the polymorphisms of XPD codon 751 and XRCC4 codon 298 are associated with an increased risk of developing H. pylori-related gastric antrum adenocarcinoma among Guangxi population. (PMID:20232359)
• XRCC4 single nucleotide polymorphisms are associated with childhood leukemia (PMID:20332465)
• Significant differences in the genetic and allelic frequencies of the XRCC4 G-1394T between the colorectal cancer and control groups (p=0.0003 and 8.32 x 10(-5), respectively)were found. (PMID:20683005)
• Polymorphisms of XRCC4 A245G and T1394G could influence the chromosomal damage levels in 1,3-butadiene exposed workers. (PMID:20726224)
• these results suggest that some variants in XRCC4, LIG4 and Ku80 genes can contribute to thyroid cancer susceptibility (PMID:20811692)
• NHEJ in human embryonic stem cells is largely independent of ATM, DNA-PKcs, and PARP but dependent on XRCC4 with repair fidelity several-fold greater than in astrocytes. (PMID:20844317)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Xrcc4	ENSMUSG00000021615
rattus_norvegicus	Xrcc4	ENSRNOG00000029966

Protein

Protein identifiers

DNA repair protein XRCC4 — Q13426 (reviewed: Q13426)

Alternative names: X-ray repair cross-complementing protein 4

All UniProt accessions (1): Q13426

UniProt curated annotations — full annotation on UniProt →

Function. DNA non-homologous end joining (NHEJ) core factor, required for double-strand break repair and V(D)J recombination. Acts as a scaffold protein that regulates recruitment of other proteins to DNA double-strand breaks (DSBs). Associates with NHEJ1/XLF to form alternating helical filaments that bridge DNA and act like a bandage, holding together the broken DNA until it is repaired. The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, holding the broken DNA fragments in close proximity to one other. The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors. Plays a key role in the NHEJ ligation step of the broken DNA during DSB repair via direct interaction with DNA ligase IV (LIG4): the LIG4-XRCC4 subcomplex reseals the DNA breaks after the gap filling is completed. XRCC4 stabilizes LIG4, regulates its subcellular localization and enhances LIG4’s joining activity. Binding of the LIG4-XRCC4 subcomplex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends. Promotes displacement of PNKP from processed strand break termini. Acts as an activator of the phospholipid scramblase activity of XKR4. This form, which is generated upon caspase-3 (CASP3) cleavage, translocates into the cytoplasm and interacts with XKR4, thereby promoting phosphatidylserine scramblase activity of XKR4 and leading to phosphatidylserine exposure on apoptotic cell surface.

Subunit / interactions. Homodimer and homotetramer in solution. Interacts with NHEJ1/XLF; the interaction is direct and is mediated via a head-to-head interaction between N-terminal head regions. Interacts with LIG4; the LIG4-XRCC4 subcomplex has a 1:2 stoichiometry and XRCC4 is required for LIG4 stability. Component of the core long-range non-homologous end joining (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF. Additional component of the NHEJ complex includes PAXX. Following autophosphorylation, PRKDC dissociates from DNA, leading to formation of the short-range NHEJ complex, composed of LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF. Interacts with PRKDC; the interaction is direct. Interacts with XRCC6/Ku70; the interaction is direct. Interacts with APTX and APLF. Forms a heterotetramer with IFFO1; the interaction involves LIG4-free XRCC4 and leads to the relocalization of IFFO1 to the sites of DNA damage. Interacts with PNKP; mainly interacts with PNKP when phosphorylated at Thr-233, but is also able to interact at much lower level with PNKP when not unphosphorylated. Interacts with POLL (DNA polymerase lambda). Interacts with XKR4; interacts with the processed form of XKR4, which is cleaved by caspase.

Subcellular location. Nucleus. Chromosome Cytoplasm.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylated by PRKDC at the C-terminus in response to DNA damage; Ser-260 and Ser-320 constitute the main phosphorylation sites. Phosphorylations by PRKDC at the C-terminus of XRCC4 and NHEJ1/XLF are highly redundant and regulate ability of the XRCC4-NHEJ1/XLF subcomplex to bridge DNA. Phosphorylation by PRKDC does not prevent interaction with NHEJ1/XLF but disrupts ability to bridge DNA and promotes detachment from DNA. Phosphorylation at Ser-327 and Ser-328 by PRKDC promotes recognition by the SCF(FBXW7) complex and subsequent ubiquitination via ‘Lys-63’-linked ubiquitin. Phosphorylation at Thr-233 by CK2 promotes interaction with PNKP; regulating PNKP activity and localization to DNA damage sites. Phosphorylation by CK2 promotes interaction with APTX. Ubiquitinated at Lys-296 by the SCF(FBXW7) complex via ‘Lys-63’-linked ubiquitination, thereby promoting double-strand break repair: the SCF(FBXW7) complex specifically recognizes XRCC4 when phosphorylated at Ser-327 and Ser-328 by PRKDC, and ‘Lys-63’-linked ubiquitination facilitates DNA non-homologous end joining (NHEJ) by enhancing association with XRCC5/Ku80 and XRCC6/Ku70. Monoubiquitinated. Undergoes proteolytic processing by caspase-3 (CASP3). This generates the protein XRCC4, C-terminus (XRCC4/C), which translocates to the cytoplasm and activates phospholipid scramblase activity of XKR4, thereby promoting phosphatidylserine exposure on apoptotic cell surface.

Disease relevance. Short stature, microcephaly, and endocrine dysfunction (SSMED) [MIM:616541] A disease characterized by short stature and microcephaly apparent at birth, progressive postnatal growth failure, and endocrine dysfunction. In affected adults endocrine features include hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus. Variable features observed in some patients are progressive ataxia, and lymphopenia or borderline leukopenia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the XRCC4-XLF family. XRCC4 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13426-1	1	yes
Q13426-2	2
Q13426-3	3

RefSeq proteins (5): NP_001304941, NP_001304942, NP_003392, NP_071801, NP_072044 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009089	XRCC4_N_sf	Homologous_superfamily
IPR010585	DNA_repair_prot_XRCC4	Family
IPR014751	XRCC4-like_C	Homologous_superfamily
IPR038051	XRCC4-like_N_sf	Homologous_superfamily
IPR053961	XRCC4_N	Domain
IPR053962	XRCC4_CC	Domain
IPR053963	XRCC4_C	Domain

Pfam: PF06632, PF21924, PF21925

UniProt features (120 total): mutagenesis site 60, modified residue 15, sequence variant 13, strand 7, helix 6, region of interest 4, turn 3, chain 2, compositionally biased region 2, cross-link 2, splice variant 2, coiled-coil region 2, site 1, short sequence motif 1

Structure

Experimental structures (PDB)

35 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5E50	X-RAY DIFFRACTION	1.38
7M3P	X-RAY DIFFRACTION	2
3MUD	X-RAY DIFFRACTION	2.2
1IK9	X-RAY DIFFRACTION	2.3
5CHX	X-RAY DIFFRACTION	2.3
5CJ0	X-RAY DIFFRACTION	2.3
4XA4	X-RAY DIFFRACTION	2.33
3II6	X-RAY DIFFRACTION	2.4
5WJ7	X-RAY DIFFRACTION	2.5
6ABO	X-RAY DIFFRACTION	2.65
1FU1	X-RAY DIFFRACTION	2.7
9CQ3	ELECTRON MICROSCOPY	2.8
9N81	ELECTRON MICROSCOPY	2.8
9CQ6	ELECTRON MICROSCOPY	3.1
9N83	ELECTRON MICROSCOPY	3.1
5CJ4	X-RAY DIFFRACTION	3.1
9N82	ELECTRON MICROSCOPY	3.3
9CQC	ELECTRON MICROSCOPY	3.4
5WLZ	X-RAY DIFFRACTION	3.5
3RWR	X-RAY DIFFRACTION	3.94
9IAX	ELECTRON MICROSCOPY	3.97
3SR2	X-RAY DIFFRACTION	3.97
7NFC	ELECTRON MICROSCOPY	4.14
9GD7	ELECTRON MICROSCOPY	4.25
7NFE	ELECTRON MICROSCOPY	4.29
8EZA	ELECTRON MICROSCOPY	4.39
8BHV	ELECTRON MICROSCOPY	4.51
8BH3	ELECTRON MICROSCOPY	4.55
7LT3	ELECTRON MICROSCOPY	4.6
8BHY	ELECTRON MICROSCOPY	5.33

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13426-F1	75.50	0.57

Functional residue map

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

Catalytic / active sites (1): 265–266 (cleavage; by caspase-3)

Post-translational modifications (17): 53, 193, 229, 232, 233, 237, 256, 260, 303, 304, 315, 320, 323, 327, 328, 210, 296

Mutagenesis-validated functional residues (60):

Position	Phenotype
331	does not affect ability mediate double-strand break repair.
332	does not affect ability mediate double-strand break repair.
333	does not affect ability mediate double-strand break repair.
334	does not affect ability mediate double-strand break repair.
4	abolished interaction with nhej1/xlf; when associated with e-99.
26	abolished interaction with nhej1/xlf; when associated with e-99.
55	abolished interaction with nhej1/xlf.
58	abolished interaction with nhej1/xlf.
61	abolished interaction with nhej1/xlf.
62	does not affect interaction with nhej1/xlf.
65	strongly decreased interaction with nhej1/xlf. abolished interaction with nhej1/xlf; when associated with e-99. abolishe
69	does not affect interaction with nhej1/xlf.
71	abolished interaction with nhej1/xlf; when associated with e-99.
72	abolished interaction with nhej1/xlf; when associated with e-99. abolished ability to bridge dna; when associated with e
90	abolished ability to bridge dna; when associated with e-72 and e-99.
99	abolished interaction with nhej1/xlf; when associated with e-4 or e-26 or e-65 or e-71 or e-72. abolished ability to bri
102	abolished interaction with nhej1/xlf; when associated with e-65.
106	abolished interaction with nhej1/xlf.
140	no change in sumoylation.
170	abolished dna-binding.
192	abolished dna-binding.
193	in xrcc4-ala mutant; abolished phosphorylation by prkdc; does not affect ability to bridge dna when associated with nhej
193	in xrcc4-asp mutant; phospho-mimetic mutant; abolished ability to bridge dna when associated with nhej1/xlf phospho-mime
210	abolishes sumoylation. 5-fold decrease in recombination efficiency. does not affect nuclear localization of xrcc4 and li
233	abolished phosphorylation by ck2, leading to strongly reduced interaction with pnkp.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-164843	2-LTR circle formation
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)

MSigDB gene sets: 383 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, YAGI_AML_WITH_INV_16_TRANSLOCATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_INTEGRATION_OF_PROVIRUS, GOBP_CHROMOSOME_LOCALIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_PLASMA_MEMBRANE_ORGANIZATION, KAUFFMANN_DNA_REPAIR_GENES, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_POSITIVE_REGULATION_OF_LIPID_TRANSPORT, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, REACTOME_HIV_INFECTION

GO Biological Process (12): base-excision repair (GO:0006284), double-strand break repair (GO:0006302), double-strand break repair via nonhomologous end joining (GO:0006303), response to X-ray (GO:0010165), immunoglobulin V(D)J recombination (GO:0033152), positive regulation of ligase activity (GO:0051351), cellular response to lithium ion (GO:0071285), protein localization to site of double-strand break (GO:1990166), DNA double-strand break attachment to nuclear envelope (GO:1990683), DNA repair (GO:0006281), DNA recombination (GO:0006310), DNA damage response (GO:0006974)

GO Molecular Function (6): DNA binding (GO:0003677), enzyme binding (GO:0019899), protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), FHA domain binding (GO:0070975), protein binding (GO:0005515)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), DNA-dependent protein kinase-DNA ligase 4 complex (GO:0005958), DNA ligase IV complex (GO:0032807), site of double-strand break (GO:0035861), nonhomologous end joining complex (GO:0070419), chromosome (GO:0005694), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Integration of provirus	1
SUMO E3 ligases SUMOylate target proteins	1
DNA Double-Strand Break Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cellular anatomical structure	3
DNA repair	2
DNA metabolic process	2
nonhomologous end joining complex	2
nuclear protein-containing complex	2
double-strand break repair	1
response to ionizing radiation	1
somatic recombination of immunoglobulin gene segments	1
V(D)J recombination	1
ligase activity	1
positive regulation of catalytic activity	1
response to lithium ion	1
cellular response to metal ion	1
protein localization to chromosome	1
chromosome attachment to the nuclear envelope	1
DNA damage response	1
cellular response to stress	1
nucleic acid binding	1
molecular adaptor activity	1
protein domain specific binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
site of DNA damage	1
intracellular protein-containing complex	1
DNA repair complex	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1116 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XRCC4	PRKDC	P78527	999
XRCC4	NHEJ1	Q9H9Q4	999
XRCC4	XRCC6	P12956	999
XRCC4	XRCC5	P13010	999
XRCC4	LIG4	P49917	999
XRCC4	APLF	Q8IW19	997
XRCC4	PAXX	Q9BUH6	995
XRCC4	APTX	Q7Z2E3	994
XRCC4	PNKP	Q96T60	971
XRCC4	LIG3	P49916	941
XRCC4	XRCC1	P18887	909
XRCC4	POLL	Q9UGP5	899
XRCC4	LIG1	P18858	839
XRCC4	POLM	Q9NP87	839
XRCC4	TP53BP1	Q12888	827

IntAct

171 interactions, top by confidence:

A	B	Type	Score
LIG4	XRCC4	psi-mi:“MI:0915”(physical association)	0.970
XRCC4	LIG4	psi-mi:“MI:0407”(direct interaction)	0.970
XRCC4	LIG4	psi-mi:“MI:0915”(physical association)	0.970
LIG4	XRCC4	psi-mi:“MI:0914”(association)	0.970
XRCC4	LIG4	psi-mi:“MI:0914”(association)	0.970
XRCC4	PNKP	psi-mi:“MI:0915”(physical association)	0.950
PNKP	XRCC4	psi-mi:“MI:2364”(proximity)	0.950
PNKP	XRCC4	psi-mi:“MI:0915”(physical association)	0.950
PNKP	XRCC4	psi-mi:“MI:0914”(association)	0.950
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
CSNK1A1	FAM83G	psi-mi:“MI:0914”(association)	0.900

BioGRID (207): BIN1 (Protein-peptide), XRCC4 (Reconstituted Complex), XRCC4 (Two-hybrid), XRCC4 (Two-hybrid), XRCC4 (Two-hybrid), ASTE1 (Two-hybrid), FAM9B (Two-hybrid), ALDH7A1 (Affinity Capture-MS), APTX (Affinity Capture-MS), LIG4 (Affinity Capture-MS), IFFO2 (Affinity Capture-MS), IFFO1 (Affinity Capture-MS), NFKB1 (Affinity Capture-MS), APPBP2 (Affinity Capture-MS), PNKP (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8ENT6, D2HNY3, G3HKI1, O18737, O60934, O75665, P0C219, P28715, P35689, P97817, Q01850, Q13137, Q13426, Q3B8D4, Q3KNJ2, Q3UKU1, Q3ZBK8, Q4KMA0, Q4R3X1, Q4R914, Q5EAN7, Q5M834, Q5R7H1, Q5RCV3, Q5RD40, Q5ZKM0, Q682V0, Q68F60, Q6AYI4, Q6NV18, Q6TLH3, Q76CY8, Q7L4P6, Q7TN31, Q8BGX7, Q8C6D4, Q8CG73, Q8NA72, Q91VL8, Q924T3

Diamond homologs: G3HKI1, Q13426, Q924T3

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
CHD2	“up-regulates quantity”	XRCC4	relocalization
XRCC4	up-regulates	DNA_repair
PRKDC	“up-regulates activity”	XRCC4	phosphorylation
SCF-FBW7	“up-regulates activity”	XRCC4	ubiquitination
XRCC4	“up-regulates activity”	DNA-PK	binding
XRCC4	“form complex”	“Lig4-Xrcc4 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Nonhomologous End-Joining (NHEJ)	5	16.1×	2e-03
Transcriptional regulation of white adipocyte differentiation	5	12.5×	3e-03
MHC class II antigen presentation	6	10.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair via nonhomologous end joining	11	61.0×	8e-15
positive regulation of transcription initiation by RNA polymerase II	5	17.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	6
Uncertain significance	92
Likely benign	52
Benign	14

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1329084	NM_003401.5(XRCC4):c.127T>A (p.Trp43Arg)	Pathogenic
1962334	NM_003401.5(XRCC4):c.179del (p.Ala60fs)	Pathogenic
1985165	NM_003401.5(XRCC4):c.189del (p.Lys65fs)	Pathogenic
208516	NM_003401.5(XRCC4):c.823C>T (p.Arg275Ter)	Pathogenic
208517	NM_003401.5(XRCC4):c.-10-1G>T	Pathogenic
208518	NM_003401.5(XRCC4):c.673C>T (p.Arg225Ter)	Pathogenic
208520	NM_003401.5(XRCC4):c.246T>G (p.Asp82Glu)	Pathogenic
208521	NM_003401.5(XRCC4):c.482G>A (p.Arg161Gln)	Pathogenic
2133924	NM_003401.5(XRCC4):c.452_455del (p.Leu151fs)	Pathogenic
2426743	NC_000005.9:g.(?82491569)(82554516_?)del	Pathogenic
3246531	NC_000005.9:g.(?82400739)(82407042_?)del	Pathogenic
3246532	NC_000005.9:g.(?82400739)(82554516_?)del	Pathogenic
3383436	NM_003401.5(XRCC4):c.37G>T (p.Glu13Ter)	Pathogenic
3383437	NM_003401.5(XRCC4):c.613C>T (p.Arg205Ter)	Pathogenic
4075919	GRCh37/hg19 5q14.2(chr5:82414269-82522832)x1	Pathogenic
4537240	NC_000005.9:g.(82373435_82400728)_(82407023_82491588)del	Pathogenic
988442	NM_003401.5(XRCC4):c.859del (p.Ala287fs)	Pathogenic
1179135	NM_003401.5(XRCC4):c.265del (p.Ser89fs)	Likely pathogenic
208522	NM_003401.5(XRCC4):c.760del (p.Asp254fs)	Likely pathogenic
2582370	NM_003401.5(XRCC4):c.140-2A>G	Likely pathogenic
3592798	NM_003401.5(XRCC4):c.445G>T (p.Glu149Ter)	Likely pathogenic
4533235	NM_003401.5(XRCC4):c.-10-1G>C	Likely pathogenic
667362	NM_003401.5(XRCC4):c.628A>T (p.Lys210Ter)	Likely pathogenic

SpliceAI

2527 predictions. Top by Δscore:

Variant	Effect	Δscore
5:83077626:G:GT	donor_gain	1.0000
5:83105055:ACAG:A	donor_loss	1.0000
5:83105056:CAGG:C	donor_loss	1.0000
5:83105057:AGG:A	donor_loss	1.0000
5:83105058:GGTAA:G	donor_loss	1.0000
5:83105059:G:A	donor_loss	1.0000
5:83105060:T:A	donor_loss	1.0000
5:83111026:A:AG	acceptor_gain	1.0000
5:83111027:G:GC	acceptor_gain	1.0000
5:83111027:GT:G	acceptor_gain	1.0000
5:83111200:CTCAG:C	donor_loss	1.0000
5:83111201:TCAG:T	donor_loss	1.0000
5:83111202:CAGT:C	donor_loss	1.0000
5:83111203:AG:A	donor_loss	1.0000
5:83111204:G:C	donor_loss	1.0000
5:83111204:G:GG	donor_gain	1.0000
5:83111205:T:G	donor_loss	1.0000
5:83111206:AA:A	donor_loss	1.0000
5:83195768:A:AG	acceptor_gain	1.0000
5:83195769:G:GT	acceptor_gain	1.0000
5:83195769:GTTC:G	acceptor_gain	1.0000
5:83195769:GTTCA:G	acceptor_gain	1.0000
5:83195904:GCTTC:G	donor_gain	1.0000
5:83195932:GGACG:G	donor_gain	1.0000
5:83195933:G:GT	donor_gain	1.0000
5:83195934:A:T	donor_gain	1.0000
5:83195958:G:GA	donor_gain	1.0000
5:83203551:GATTT:G	acceptor_gain	1.0000
5:83203644:G:GT	donor_gain	1.0000
5:83203691:G:GT	donor_gain	1.0000

AlphaMissense

2218 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:83203607:T:C	F180L	0.996
5:83203609:T:A	F180L	0.996
5:83203609:T:G	F180L	0.996
5:83104978:T:C	L20P	0.989
5:83203608:T:C	F180S	0.989
5:83105026:T:C	L36P	0.986
5:83111054:G:C	A56P	0.985
5:83195770:T:C	F106L	0.985
5:83195772:C:A	F106L	0.985
5:83195772:C:G	F106L	0.985
5:83203630:G:C	K187N	0.984
5:83203630:G:T	K187N	0.984
5:83111097:T:C	L70P	0.983
5:83105046:T:A	W43R	0.981
5:83105046:T:C	W43R	0.981
5:83203620:T:C	L184S	0.981
5:83203596:T:C	L176P	0.980
5:83203605:G:C	R179P	0.977
5:83203617:T:A	V183E	0.977
5:83195771:T:C	F106S	0.975
5:83203641:T:C	I191T	0.975
5:83104974:T:C	F19L	0.974
5:83104976:T:A	F19L	0.974
5:83104976:T:G	F19L	0.974
5:83203632:A:T	K188I	0.973
5:83195906:T:C	L151P	0.972
5:83105013:T:C	F32L	0.971
5:83105015:T:A	F32L	0.971
5:83105015:T:G	F32L	0.971
5:83203628:A:C	K187Q	0.971

dbSNP variants (sampled 300 via entrez): RS1000005667 (5:83216921 T>C), RS1000009700 (5:83313658 C>T), RS1000028975 (5:83087884 G>C,T), RS1000037866 (5:83185162 A>G), RS1000038716 (5:83374871 G>A), RS1000050578 (5:83224005 C>A,G,T), RS1000056274 (5:83306863 A>G), RS1000063895 (5:83132446 A>G), RS1000078105 (5:83262253 T>A), RS1000081415 (5:83325856 C>T), RS1000107421 (5:83166834 G>C), RS1000108255 (5:83230749 A>G), RS1000115336 (5:83368366 C>A,G), RS1000126307 (5:83257786 C>G,T), RS1000143605 (5:83183889 T>C)

Disease associations

OMIM: gene MIM:194363 | disease phenotypes: MIM:616541, MIM:262400

GenCC curated gene-disease

Disease	Classification	Inheritance
short stature, microcephaly, and endocrine dysfunction	Definitive	Autosomal recessive
microcephalic primordial dwarfism-insulin resistance syndrome	Supportive	Autosomal recessive
hereditary nonpolyposis colon cancer	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary nonpolyposis colon cancer	Limited	AD

Mondo (4): short stature, microcephaly, and endocrine dysfunction (MONDO:0014686), isolated growth hormone deficiency type IA (MONDO:0009876), hereditary nonpolyposis colon cancer (MONDO:0018630), (MONDO:0018575)

Orphanet (3): Microcephalic primordial dwarfism-insulin resistance syndrome (Orphanet:436182), Isolated growth hormone deficiency type IA (Orphanet:231662), Non-acquired isolated growth hormone deficiency (Orphanet:631)

HPO phenotypes

94 total (30 of 94 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000122	Unilateral renal agenesis
HP:0000233	Thin vermilion border
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000320	Bird-like facies
HP:0000325	Triangular face
HP:0000331	Short chin
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000444	Convex nasal ridge
HP:0000455	Broad nasal tip
HP:0000490	Deeply set eye
HP:0000506	Telecanthus
HP:0000518	Cataract
HP:0000541	Retinal detachment
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST002540_4	Osteoarthritis biomarkers	1.000000e-06
GCST002595_17	Clozapine-induced agranulocytosis	5.000000e-06
GCST002806_17	Type 2 diabetes	7.000000e-06
GCST002875_12	Diisocyanate-induced asthma	9.000000e-06
GCST004750_74	Squamous cell lung carcinoma	5.000000e-06
GCST004750_75	Squamous cell lung carcinoma	7.000000e-06
GCST006063_1	White matter integrity (fractional anisotropy)	5.000000e-10
GCST006064_1	White matter integrity (mean diffusivity)	6.000000e-13
GCST006979_112	Heel bone mineral density	6.000000e-10
GCST009724_46	Vertical cup-disc ratio (multi-trait analysis)	2.000000e-09
GCST010796_5165	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_5166	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_5167	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_5168	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-10
GCST010796_5198	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_5199	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_5200	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005890	osteoarthritis biomarker measurement
EFO:0006995	response to diisocyanate
EFO:0004641	white matter integrity
EFO:0009270	heel bone mineral density
EFO:0006939	cup-to-disc ratio measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537404	Pituitary dwarfism 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296097 (PROTEIN COMPLEX)

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10040363	Efficacy	3	fluorouracil;Platinum compounds;radiotherapy	Stomach Neoplasms
rs1382368	Dosage	3	docetaxel	Non-Small Cell Lung Carcinoma
rs2075685	Efficacy	3	fluorouracil;Platinum compounds;radiotherapy	Stomach Neoplasms

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1382368	XRCC4	3	0.25	1	docetaxel
rs10040363	XRCC4	3	3.00	1	fluorouracil;Platinum compounds;radiotherapy
rs2075685	TMEM167A, XRCC4	3	3.00	1	fluorouracil;Platinum compounds;radiotherapy
rs1478486	XRCC4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	6
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
Camptothecin	increases methylation, decreases response to substance	2
Cisplatin	decreases expression, increases reaction, decreases response to substance, affects cotreatment	2
Etoposide	decreases response to substance, decreases reaction, increases expression	2
Lead	affects expression, affects response to substance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
taxifolin	increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases reaction, increases expression	1
selenocystine	affects cotreatment, decreases expression, increases reaction	1
nickel chloride	affects expression, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression, decreases reaction	1
coumarin	decreases phosphorylation	1
3-chlorophenol	increases expression	1
epigallocatechin gallate	decreases reaction, affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
monomethylarsonous acid	decreases expression	1
jinfukang	decreases expression	1
incobotulinumtoxinA	decreases expression	1
riccardin D	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Irinotecan	decreases expression	1
Arsenic Trioxide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4142330	Binding	Inhibition of human DNA Lig4/XRCCR at 10 uM using double strand nicked DNA as substrate after 30 mins in presence of ATP by acrylamide-based fluorescence-assay	Synthesis and bio-evaluation of indole-chalcone based benzopyrans as promising antiligase and antiproliferative agents. — Eur J Med Chem

Cellosaurus cell lines

11 cell lines: 7 cancer cell line, 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7Y4	SEES3-1V human XRCC4, clone1	Embryonic stem cell	Male
CVCL_A7Y5	SEES3-1V human XRCC4, clone2	Embryonic stem cell	Male
CVCL_A7Y6	SEES3-1V human XRCC4, clone3	Embryonic stem cell	Male
CVCL_DX07	HAP1 XRCC4 (-) 2	Cancer cell line	Male
CVCL_DX10	HAP1 PRKDC (-) XRCC4 (-)	Cancer cell line	Male
CVCL_E2Q3	HyCyte HEK293T hXRCC4_p.D103H_c.307G>C	Transformed cell line	Female
CVCL_HE00	HCT 116 XRCC4(-/-)	Cancer cell line	Male
CVCL_KU29	HeLa SilenciX XRCC4	Cancer cell line	Female
CVCL_T772	HCT116-XRCC4(+/-)	Cancer cell line	Male
CVCL_T773	HCT116-XRCC4(-/-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00141466	Not specified	UNKNOWN	Implementation of a New Strategy to Identify HNPCC Patients
NCT00262171	Not specified	UNKNOWN	Hereditary Nonpolyposis Colorectal Cancer in Taiwan-Related Genetic Study and Clinical Applications
NCT00341575	Not specified	COMPLETED	Psychosocial Aspects of Genetic Testing for Hereditary Nonpolyposis Colon Cancer
NCT00508573	Not specified	COMPLETED	Registry for Women Who Are At Risk Or May Have Lynch Syndrome
NCT01216930	Not specified	COMPLETED	Molecular Screening for Lynch Syndrome in Southern Denmark
NCT01646112	Not specified	COMPLETED	Uncertain Genetic Test Results for Lynch Syndrome
NCT01823471	Not specified	COMPLETED	I-Scan For Colon Polyp Detection In HNPCC
NCT01845753	Not specified	COMPLETED	Molecular Screening for Lynch Syndrome in Denmark
NCT02198092	Not specified	COMPLETED	Preliminary Evaluation of Septin9 in Patients With Hereditary Colon Cancer Syndromes
NCT02206360	Not specified	ACTIVE_NOT_RECRUITING	Pancreatic Cancer Early Detection Program
NCT03303833	Not specified	RECRUITING	The GEOLynch Cohort Study
NCT06426927	Not specified	COMPLETED	PeLear CCC: Proyecto Latino Contra Cancer Colorrectal
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06989814	Not specified	RECRUITING	Smart Measurement of Circulating Tumor DNA