XRCC3

Summary

XRCC3 (X-ray repair cross complementing 3, HGNC:12830) is a protein-coding gene on chromosome 14q32.33, encoding DNA repair protein XRCC3 (O43542). Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions. It is a selective cancer dependency (DepMap: 62.5% of cell lines).

This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene functionally complements Chinese hamster irs1SF, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents and is chromosomally unstable. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. Alternatively spliced transcript variants encoding the same protein have been identified.

Source: NCBI Gene 7517 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 41 total
• Phenotypes (HPO): 3
• Cancer dependency (DepMap): dependent in 62.5% of screened cell lines
• MANE Select transcript: NM_005432

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12830
Approved symbol	XRCC3
Name	X-ray repair cross complementing 3
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000126215
Ensembl biotype	protein_coding
OMIM	600675
Entrez	7517

Gene structure

Transcript identifiers

Ensembl transcripts: 69 — 62 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000352127, ENST00000553264, ENST00000553332, ENST00000553361, ENST00000553807, ENST00000554170, ENST00000554774, ENST00000554811, ENST00000554913, ENST00000554974, ENST00000555055, ENST00000555231, ENST00000555451, ENST00000555832, ENST00000555964, ENST00000556682, ENST00000556980, ENST00000557439, ENST00000881941, ENST00000881942, ENST00000881943, ENST00000881944, ENST00000881945, ENST00000881946, ENST00000881947, ENST00000881948, ENST00000881949, ENST00000881950, ENST00000881951, ENST00000881952, ENST00000920655, ENST00000920656, ENST00000920657, ENST00000920658, ENST00000920659, ENST00000920660, ENST00000920661, ENST00000920662, ENST00000920663, ENST00000920664, ENST00000920665, ENST00000920666, ENST00000920667, ENST00000920668, ENST00000920669, ENST00000920670, ENST00000920671, ENST00000920672, ENST00000920673, ENST00000920674, ENST00000920675, ENST00000920676, ENST00000920677, ENST00000920678, ENST00000920679, ENST00000920680, ENST00000920681, ENST00000920682, ENST00000920683, ENST00000920684, ENST00000920685, ENST00000920686, ENST00000920687, ENST00000920688, ENST00000920689, ENST00000920690, ENST00000920691, ENST00000920692, ENST00000950264

RefSeq mRNA: 6 — MANE Select: NM_005432 NM_001100118, NM_001100119, NM_001371229, NM_001371231, NM_001371232, NM_005432

CCDS: CCDS9984

Canonical transcript exons

ENST00000555055 — 10 exons

Exon	Start	End
ENSE00001365931	103711466	103711567
ENSE00002447933	103697617	103699017
ENSE00002458366	103715424	103715451
ENSE00002505153	103712875	103712931
ENSE00003251200	103708522	103708659
ENSE00003463205	103699133	103699179
ENSE00003572227	103699364	103699576
ENSE00003580849	103703173	103703327
ENSE00003604366	103711033	103711245
ENSE00003615237	103707003	103707215

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 93.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.9219 / max 78.3085, expressed in 1352 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145109	3.3114	1241
145108	1.6105	739

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	93.26	gold quality
endocervix	UBERON:0000458	92.78	gold quality
right uterine tube	UBERON:0001302	92.65	gold quality
ectocervix	UBERON:0012249	92.39	gold quality
right coronary artery	UBERON:0001625	92.09	gold quality
lower esophagus mucosa	UBERON:0035834	92.00	gold quality
tibial nerve	UBERON:0001323	91.95	gold quality
apex of heart	UBERON:0002098	91.73	gold quality
right ovary	UBERON:0002118	91.71	gold quality
body of uterus	UBERON:0009853	91.68	gold quality
left ovary	UBERON:0002119	91.43	gold quality
skin of leg	UBERON:0001511	91.00	gold quality
right lung	UBERON:0002167	90.72	gold quality
skin of abdomen	UBERON:0001416	90.59	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.59	gold quality
granulocyte	CL:0000094	90.48	gold quality
ascending aorta	UBERON:0001496	90.44	gold quality
spleen	UBERON:0002106	90.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.11	gold quality
thoracic aorta	UBERON:0001515	90.10	gold quality
lower esophagus	UBERON:0013473	90.09	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.97	gold quality
left lobe of thyroid gland	UBERON:0001120	89.93	gold quality
left coronary artery	UBERON:0001626	89.91	gold quality
right lobe of thyroid gland	UBERON:0001119	89.84	gold quality
mucosa of transverse colon	UBERON:0004991	89.67	gold quality
aorta	UBERON:0000947	89.63	gold quality
left uterine tube	UBERON:0001303	89.56	gold quality
popliteal artery	UBERON:0002250	89.53	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN

miRNA regulators (miRDB)

38 targeting XRCC3, 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-4692	100.00	67.32	2066
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-6529-3P	98.68	66.76	1020

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 62.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• XRCC3 promotes homology-directed repair of DNA double-strand breaks in mammalian cells (PMID:10541549)
• Mutation in XRCC3 gene may be associated with increased risk of squamous cell carcinoma of head and neck neoplasms (PMID:12115490)
• no evidence seen that XRCC3 241Met variant significantly associated with increased risk of cutaneous malignant melanoma in case-control study (PMID:12376526)
• The genotype distribution of the XRCC3 gene does not indicate a role for base excision repair in the development of therapy-related acute myeloblastic leukemia (PMID:12393447)
• Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer. (PMID:12565173)
• The XRCC3 T241M polymorphism is associated with risk of breast cancer. XRCC3 participates in the repair of DNA damage. (PMID:12815008)
• frequency of flat or raised moles is associated with polymorphism at or near this DNA repair gene and certain alleles are associated with less efficient DNA repair and greater nevus density (PMID:14511439)
• no evidence therefore that the T allele of this XRCC3 polymorphism is indicative of susceptibility to melanoma but there was a marginal relationship with nevus phenotype (PMID:15009726)
• Finds no association between XRCC3 T241M and two intronic XRCC3 polymorphisms and risk of colorectal adenoma. (PMID:15184273)
• The level of XRCC3 protein was sharply reduced in Rad51C-depleted HeLa cells, suggesting that XRCC3 is dependent for its stability upon heterodimerization with Rad51C (PMID:15292210)
• Polymorphism of XRCC3 is associated with colorectal cancer (PMID:15354414)
• Xrcc3 forms distinct foci in human cells and that nuclear Xrcc3 begins to localize at sites of DNA damage within 10 min after radiation treatment. (PMID:15372620)
• The role of a genetic polymorphism of the XRCC3 gene in risk for colorectal cancer was investigated. (PMID:15679883)
• Xrcc3 overexpression is associated with increased Rad51C protein levels consistent with the known interaction of these two proteins (PMID:15843498)
• the XRCC1 280His and XRCC3 241Met alleles affect individual chromosomal aberration levels, most probably via influencing the DNA repair phenotype (PMID:15971256)
• XRCC3 T241M polymorphism and family history of cancer may be risk factors for colorectal cancer, and the XRCC3 241Met allele may be an effective biomarker for genetic susceptibility. (PMID:16271954)
• polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers (PMID:16492913)
• Mitotic defects in XRCC3 variants T241M and D213N and their relation to cancer susceptibility (PMID:16505003)
• XRCC1, XRCC3, GSTM1 and GSTT1 polymorphisms and chromosome damage are higher in welders than in a control group (PMID:16551674)
• FANCG was found to interact with XRCC3, and this interaction was disrupted by the FA-G patient derived mutation L71P. (PMID:16621732)
• Our meta-analysis results support that the XRCC3 might represent a low-penetrance susceptible gene especially for cancer of breast, bladder, head and neck, and non-melanoma skin cancer. (PMID:16791138)
• XRCC3 variated genotype was one of the risk factors of cardia cancer while different risks of factors might exsit between cardia and non-cardia gastric cancer. (PMID:16981340)
• Our results show that the genetic variation in XRCC1, XRCC3 and NBS1 influence lung cancer susceptibility among women, and that combinations of risk alleles in the two HR genes can enhance the effects. (PMID:17034901)
• Polymorphism of XRCC3 codon 241 Thr/Met is unlikely to have a substantial overall association with increased breast cancer risk in Korean women (PMID:17063279)
• the RAD51C-XRCC3-associated Holliday junction resolvase complex associates with crossovers and may play an essential role in the resolution of recombination intermediates prior to chromosome segregation (PMID:17114795)
• XRCC1-01, XRCC3-01, and CCND1-01 may be predictive of survival outcome in patients with metastatic breast cancer treated with DNA-damaging chemotherapy (PMID:17116943)
• Increased susceptibility to genotoxic agents with polymorphisms in DNA repair genes XRCC3. (PMID:17159780)
• A decrease in the expression of XRCC3 leads to accumulation of DNA breaks and induction of cell death. (PMID:17351336)
• Patients with XRCC3 18067T variant allele are tolerant to benzene poisoning. (PMID:17535647)
• Fndings suggest that the XRCC3 Thr241Met polymorphism is likely to play a modifying role in the individual susceptibility to breast cancer among Thai women as already shown for women of European ancestry. (PMID:17701750)
• Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma. (PMID:17901044)
• Evidence that the combination of different DNA repair genes (hOGG1, XRCC1 and XRCC3) and their interaction with environmental genotoxic agents may modulate micronuclei induction. (PMID:17971348)
• polymorphism may be one of the genetic modifiers for smoking-related pancreatic cancer (PMID:17986315)
• patients heterozygous for the XRCC3 Thr241Met allele had improved post-induction disease-free survival compared to children homozygous for the major or minor allele (PMID:18033323)
• investigated the possible association of three SNPs, XRCC2 C41657T, XRCC2 G4234C and XRCC3 A17893G with susceptibility to esophageal squamous cell carcinoma and gastric cardia adenocarcinoma in a population of northern China (PMID:18046624)
• Multiplicative interaction of risk due to the MC1R variants and the common allele (high risk) of the T241M polymorphism in the XRCC3 gene. (PMID:18067130)
• There could be a correlation between polymorphisms of XRCC3 and DNA repair capacity of DNA damage induced by benzene. (PMID:18095557)
• genetic variation in SNPs in XRCC1 and XRCC2 genes, but not XRCC3, may influence breast cancer susceptibility (PMID:18188695)
• FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3. (PMID:18212739)
• XRCC3 Thr 241 Met plays an important role in the development of laryngeal and hypopharyngeal carcinoma. (PMID:18300452)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	xrcc3	ENSDARG00000017928
mus_musculus	Xrcc3	ENSMUSG00000021287
rattus_norvegicus	Xrcc3	ENSRNOG00000012141
drosophila_melanogaster	spn-B	FBGN0003480

Paralogs (6): RAD51 (ENSG00000051180), DMC1 (ENSG00000100206), RAD51C (ENSG00000108384), RAD51B (ENSG00000182185), RAD51D (ENSG00000185379), XRCC2 (ENSG00000196584)

Protein

Protein identifiers

DNA repair protein XRCC3 — O43542 (reviewed: O43542)

Alternative names: X-ray repair cross-complementing protein 3

All UniProt accessions (9): O43542, G3V2L7, G3V2P3, G3V399, G3V3C8, G3V3H9, G3V3Q2, G3V5K0, Q53XC8

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions. Part of the RAD51 paralog protein complex CX3 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, CX3 acts downstream of RAD51 recruitment; the complex binds predominantly to the intersection of the four duplex arms of the Holliday junction (HJ) and to junctions of replication forks. Involved in HJ resolution and thus in processing HR intermediates late in the DNA repair process; the function may be linked to the CX3 complex and seems to involve GEN1 during mitotic cell cycle progression. Part of a PALB2-scaffolded HR complex containing BRCA2 and RAD51C and which is thought to play a role in DNA repair by HR. Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51 and RAD51C.

Subunit / interactions. Interacts with RAD51C and RAD51. Part of the CX3 complex consisting of RAD51C and XRCC3; the complex has a ring-like structure arranged into a flat disk around a central channel; CX3 can interact with RAD51 in vitro. Forms a complex with FANCD2, BRCA2 and phosphorylated FANCG. Interacts with SWSAP1 and ZSWIM7; involved in homologous recombination repair. Interacts directly with PALB2 which may serve as a scaffold for a HR complex containing PALB2, BRCA2, RAD51C, RAD51 and XRCC3.

Subcellular location. Nucleus. Cytoplasm. Perinuclear region. Mitochondrion.

Disease relevance. Breast cancer (BC) [MIM:114480] A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Disease susceptibility is associated with variants affecting the gene represented in this entry. Melanoma, cutaneous malignant 6 (CMM6) [MIM:613972] A malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but may also involve other sites. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Variant p.Thr341Met has been reported to be associated with an increased risk for CMM6. Further studies have shown that this variant is functional in homology-directed DNA repair, and the association of XRCC3 with CMM6 has not been confirmed.

Induction. Stress-induced increase in the mitochondrial levels is seen.

Similarity. Belongs to the RecA family. RAD51 subfamily.

RefSeq proteins (6): NP_001093588, NP_001093589, NP_001358158, NP_001358160, NP_001358161, NP_005423* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013632	Rad51_C	Domain
IPR016467	DNA_recomb/repair_RecA-like	Family
IPR020588	RecA_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR047348	XRCC3-like_C	Domain
IPR058766	HHH_XRCC3_RAD51B	Domain

Pfam: PF08423, PF26169

UniProt features (7 total): sequence variant 4, chain 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
9SVY	ELECTRON MICROSCOPY	2.6
9Q29	ELECTRON MICROSCOPY	2.61
9Q2A	ELECTRON MICROSCOPY	2.67
9SVX	ELECTRON MICROSCOPY	2.7
9Q23	ELECTRON MICROSCOPY	2.84
9Q28	ELECTRON MICROSCOPY	2.84
9ZZR	ELECTRON MICROSCOPY	2.95
9SW0	ELECTRON MICROSCOPY	3
9ON2	ELECTRON MICROSCOPY	3.16
9Q2B	ELECTRON MICROSCOPY	3.2
9Q25	ELECTRON MICROSCOPY	3.24
9OMY	ELECTRON MICROSCOPY	3.25
9OMZ	ELECTRON MICROSCOPY	3.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43542-F1	87.19	0.67

Functional residue map

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

Ligand- & substrate-binding residues (1): 107–114

Post-translational modifications (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693554	Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates
R-HSA-5693579	Homologous DNA Pairing and Strand Exchange

MSigDB gene sets: 208 (showing top): PID_FANCONI_PATHWAY, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOMF_ENDONUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOMF_NUCLEASE_ACTIVITY, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_TELOMERE_ORGANIZATION, GOBP_CHROMOSOME_SEPARATION, KAUFFMANN_DNA_REPAIR_GENES, KEGG_HOMOLOGOUS_RECOMBINATION, PATIL_LIVER_CANCER, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION

GO Biological Process (13): telomere maintenance via recombination (GO:0000722), double-strand break repair via homologous recombination (GO:0000724), DNA repair (GO:0006281), DNA recombination (GO:0006310), DNA damage response (GO:0006974), regulation of centrosome duplication (GO:0010824), interstrand cross-link repair (GO:0036297), double-strand break repair via synthesis-dependent strand annealing (GO:0045003), resolution of mitotic recombination intermediates (GO:0071140), positive regulation of mitotic cell cycle spindle assembly checkpoint (GO:0090267), t-circle formation (GO:0090656), telomeric loop disassembly (GO:0090657), telomere maintenance via telomere trimming (GO:0090737)

GO Molecular Function (7): DNA binding (GO:0003677), ATP binding (GO:0005524), ATP-dependent DNA damage sensor activity (GO:0140664), nucleotide binding (GO:0000166), four-way junction DNA binding (GO:0000400), protein binding (GO:0005515), crossover junction DNA endonuclease activity (GO:0008821)

GO Cellular Component (9): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), Rad51C-XRCC3 complex (GO:0033065), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Resolution of D-Loop Structures	2
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
HDR through Homologous Recombination (HRR)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
telomere maintenance	3
cytoplasm	3
mitotic recombination	2
DNA metabolic process	2
intracellular membrane-bounded organelle	2
recombinational repair	1
double-strand break repair	1
DNA damage response	1
cellular response to stress	1
regulation of centrosome cycle	1
centrosome duplication	1
DNA repair	1
double-strand break repair via homologous recombination	1
resolution of DNA recombination intermediates	1
mitotic spindle assembly checkpoint signaling	1
positive regulation of cell cycle process	1
positive regulation of spindle checkpoint	1
regulation of mitotic cell cycle spindle assembly checkpoint	1
formation of extrachromosomal circular DNA	1
telomere maintenance via telomere trimming	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ATP-dependent activity, acting on DNA	1
DNA damage sensor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
DNA secondary structure binding	1
binding	1
DNA endonuclease activity, producing 3’-phosphomonoesters	1
chromosomal region	1
nuclear lumen	1
chromosome	1
intracellular anatomical structure	1
DNA recombinase mediator complex	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

2848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XRCC3	XRCC2	O43543	996
XRCC3	RAD51C	O43502	991
XRCC3	BRCA2	P51587	988
XRCC3	K7EN88	K7EN88	969
XRCC3	FANCG	O15287	948
XRCC3	RAD51	Q06609	930
XRCC3	FANCD2	Q9BXW9	919
XRCC3	RAD52	P43351	910
XRCC3	BRCA1	P38398	909
XRCC3	XRCC1	P18887	906
XRCC3	ERCC2	P18074	872
XRCC3	ATRX	P46100	870
XRCC3	ERCC1	P07992	861
XRCC3	WRN	Q14191	829
XRCC3	ATM	Q13315	827

IntAct

82 interactions, top by confidence:

A	B	Type	Score
RAD51C	XRCC3	psi-mi:“MI:0915”(physical association)	0.940
RAD51C	RAD51B	psi-mi:“MI:0914”(association)	0.940
XRCC3	RAD51C	psi-mi:“MI:0914”(association)	0.940
XRCC3	RAD51C	psi-mi:“MI:0915”(physical association)	0.940
RAD51	XRCC3	psi-mi:“MI:0915”(physical association)	0.730
XRCC3	RAD51	psi-mi:“MI:0915”(physical association)	0.730
TOMM22	XRCC3	psi-mi:“MI:0914”(association)	0.640
PALB2	RAD51C	psi-mi:“MI:0914”(association)	0.610
XRCC3	PALB2	psi-mi:“MI:0407”(direct interaction)	0.580
TOR1AIP2	TMEM223	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
ISLR	BCKDK	psi-mi:“MI:0914”(association)	0.530
PLAUR	XRCC3	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
XRCC3	SWSAP1	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (238): XRCC3 (Affinity Capture-MS), XRCC3 (Affinity Capture-MS), XRCC3 (Affinity Capture-MS), XRCC3 (Affinity Capture-MS), BAP1 (Two-hybrid), BCAS3 (Two-hybrid), CXCL1 (Two-hybrid), FAM84B (Two-hybrid), GREB1 (Two-hybrid), ITIH5 (Two-hybrid), MRC2 (Two-hybrid), OSGIN1 (Two-hybrid), PSMC3IP (Two-hybrid), RNF20 (Two-hybrid), SCGB3A1 (Two-hybrid)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: A2SR54, A3CWU4, A3CXI2, A3MXX9, A4FWV5, A4WN87, A4YCN4, A5UKT8, A5UMW0, A6VGG2, A8AB83, A9AA90, B0R636, B0R7Y4, B1YC14, B6YXT4, B8BM09, B8D610, C3MRI1, C3MY77, C3MZK6, C3N7M8, C3NFU5, C4KIT6, C5A2F7, C6A0N1, O27436, O27728, O28184, O29269, O42634, O43542, O57859, O58001, O73948, O74036, O77507, O93748, P0CW58, P0CW59

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
ATR	“up-regulates activity”	XRCC3	phosphorylation
XRCC3	“up-regulates quantity by stabilization”	RAD51	binding
XRCC3	“form complex”	“D1-D2-G-X3 complex”	binding
XRCC3	“up-regulates activity”	RAD51	relocalization
RAD51C	“up-regulates activity”	XRCC3	relocalization
XRCC3	“up-regulates activity”	CHEK2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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.

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair via homologous recombination	6	14.4×	1e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2884 predictions. Top by Δscore:

Variant	Effect	Δscore
14:103699358:GCTCA:G	donor_loss	1.0000
14:103699359:CTCA:C	donor_loss	1.0000
14:103699360:TCAC:T	donor_loss	1.0000
14:103699361:CACC:C	donor_loss	1.0000
14:103699362:ACCTG:A	donor_loss	1.0000
14:103700544:C:A	donor_gain	1.0000
14:103700621:C:CA	donor_gain	1.0000
14:103703168:CT:C	donor_loss	1.0000
14:103703170:C:CC	donor_loss	1.0000
14:103703171:A:AC	donor_gain	1.0000
14:103703171:A:AG	donor_loss	1.0000
14:103703172:C:CA	donor_loss	1.0000
14:103703172:C:CC	donor_gain	1.0000
14:103703172:CCA:C	donor_gain	1.0000
14:103706998:CTCA:C	donor_loss	1.0000
14:103706999:TCAC:T	donor_loss	1.0000
14:103707000:CA:C	donor_loss	1.0000
14:103707001:A:AC	donor_gain	1.0000
14:103707001:A:C	donor_loss	1.0000
14:103707001:ACCAG:A	donor_gain	1.0000
14:103707002:C:CC	donor_gain	1.0000
14:103707002:CCAG:C	donor_gain	1.0000
14:103707002:CCAGC:C	donor_gain	1.0000
14:103707211:CAGTG:C	acceptor_gain	1.0000
14:103707213:GTG:G	acceptor_gain	1.0000
14:103707214:TG:T	acceptor_gain	1.0000
14:103707216:C:CC	acceptor_gain	1.0000
14:103708520:A:C	donor_loss	1.0000
14:103708655:TTTGG:T	acceptor_gain	1.0000
14:103708656:TTGG:T	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000105326 (14:103698087 C>T), RS1000173903 (14:103697623 C>T), RS1000291275 (14:103714925 C>A,T), RS1000406236 (14:103714612 A>T), RS1000505145 (14:103698490 CT>C), RS1000528657 (14:103710928 G>T), RS1000627116 (14:103715785 C>G,T), RS1000732900 (14:103715575 C>T), RS1000878077 (14:103702484 C>T), RS1000961256 (14:103710639 G>C,T), RS1001265290 (14:103697631 A>G), RS1001394341 (14:103702174 G>A), RS1001521506 (14:103713272 G>A,T), RS1001552596 (14:103713611 G>C), RS1001750274 (14:103708393 C>G)

Disease associations

OMIM: gene MIM:600675 | disease phenotypes: MIM:114480, MIM:167000

GenCC curated gene-disease

Mondo (2): hereditary breast carcinoma (MONDO:0016419), ovarian cancer (MONDO:0008170)

Orphanet (2): Hereditary breast cancer (Orphanet:227535), Rare ovarian cancer (Orphanet:213500)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001442	Typified by somatic mosaicism
HP:0003002	Breast carcinoma

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002539_23	Schizophrenia	1.000000e-13
GCST004521_135	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_15	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_262	Autism spectrum disorder or schizophrenia	6.000000e-09
GCST005951_9	Body mass index	4.000000e-09
GCST006803_15	Schizophrenia	3.000000e-14
GCST008103_98	Bipolar disorder	2.000000e-06
GCST008129_80	Body mass index	2.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
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
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs861539	Efficacy	3	fluorouracil;irinotecan;leucovorin	Colorectal Neoplasms
rs861539	Efficacy	3	Platinum compounds	Non-Small Cell Lung Carcinoma

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs861539	KLC1, XRCC3	3	2.00	2	Platinum compounds;fluorouracil;irinotecan;leucovorin
rs1799794	XRCC3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases expression, affects cotreatment, decreases expression, increases abundance	4
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Arsenic	affects cotreatment, decreases expression, increases abundance, affects response to substance	3
Benzo(a)pyrene	increases expression, affects methylation, decreases expression	3
Cisplatin	affects response to substance, increases expression, affects cotreatment	2
Doxorubicin	decreases expression, decreases response to substance	2
aristolochic acid I	decreases expression	1
afuresertib	decreases expression	1
apocarotenal	increases expression	1
myristicin	increases expression, decreases expression	1
triphenyl phosphate	affects expression	1
4-biphenylamine	decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects cotreatment, increases expression	1
beta-lapachone	decreases expression	1
bromoacetate	decreases expression	1
potassium bromate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, decreases expression	1
CGP 52608	affects binding, increases reaction	1
CPG-oligonucleotide	decreases expression	1
ICG 001	affects expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects cotreatment, increases expression, decreases reaction	1
brevetoxin 2	increases expression	1
riccardin D	decreases expression	1
NSC 689534	affects binding, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Bortezomib	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_VR86	U2OS#18-XRCC3-6A	Cancer cell line	Female
CVCL_XX05	HEK293-DR-GFP-XRCC3-5	Transformed cell line	Female
CVCL_XX10	HEK293-DR-GFP-XRCC3-5/X3+	Transformed cell line	Female
CVCL_YL50	U2OS#18-XRCC3-6A/X3+	Cancer cell line	Female

Clinical trials (associated diseases)

300 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
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
NCT00003644	PHASE3	COMPLETED	Carboplatin Plus Paclitaxel With or Without Continued Low-Dose Paclitaxel in Treating Patients With Early-Stage Ovarian Cancer