XRCC5

Summary

XRCC5 (X-ray repair cross complementing 5, HGNC:12833) is a protein-coding gene on chromosome 2q35, encoding DNA repair protein Ku80 (P13010). DNA-binding protein critical for the DNA damage response, specifically in repairing double-strand breaks (DSBs) via the classical non-homologous end joining (NHEJ) pathway. It is a common-essential gene (DepMap: required in 95.0% of cancer cell lines).

The protein encoded by this gene is the 80-kilodalton subunit of the Ku heterodimer protein which is also known as ATP-dependant DNA helicase II or DNA repair protein XRCC5. Ku is the DNA-binding component of the DNA-dependent protein kinase, and it functions together with the DNA ligase IV-XRCC4 complex in the repair of DNA double-strand break by non-homologous end joining and the completion of V(D)J recombination events. This gene functionally complements Chinese hamster xrs-6, a mutant defective in DNA double-strand break repair and in ability to undergo V(D)J recombination. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity.

Source: NCBI Gene 7520 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 96 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 95.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_021141

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12833
Approved symbol	XRCC5
Name	X-ray repair cross complementing 5
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	KU80, KARP-1, Ku86, KUB2
Ensembl gene	ENSG00000079246
Ensembl biotype	protein_coding
OMIM	194364
Entrez	7520

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 21 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000392132, ENST00000392133, ENST00000417391, ENST00000429133, ENST00000451695, ENST00000460284, ENST00000471649, ENST00000476360, ENST00000485763, ENST00000493706, ENST00000893691, ENST00000893692, ENST00000893694, ENST00000893695, ENST00000893696, ENST00000893697, ENST00000893698, ENST00000939180, ENST00000939181, ENST00000939182, ENST00000939183, ENST00000939184, ENST00000939185, ENST00000939186, ENST00000947462, ENST00000947463, ENST00000947464, ENST00000947465

RefSeq mRNA: 1 — MANE Select: NM_021141 NM_021141

CCDS: CCDS2402

Canonical transcript exons

ENST00000392132 — 21 exons

Exon	Start	End
ENSE00001759320	216109348	216109457
ENSE00001800722	216205188	216206293
ENSE00003512123	216138089	216138179
ENSE00003524315	216148083	216148276
ENSE00003536230	216113016	216113129
ENSE00003538937	216161979	216162048
ENSE00003538962	216119043	216119165
ENSE00003540893	216127536	216127674
ENSE00003542498	216122062	216122253
ENSE00003554172	216125917	216126031
ENSE00003562212	216116659	216116842
ENSE00003605141	216117746	216117794
ENSE00003609869	216160068	216160161
ENSE00003616994	216192639	216192735
ENSE00003620063	216141186	216141319
ENSE00003634613	216190225	216190334
ENSE00003645092	216130875	216130987
ENSE00003675322	216204322	216204396
ENSE00003679250	216194919	216194986
ENSE00003683943	216137088	216137225
ENSE00003684949	216132325	216132387

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 265.4094 / max 4387.6396, expressed in 1828 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25190	164.7346	1828
25189	97.7074	1823
202567	1.2774	799
25194	0.8910	554
25200	0.5633	274
25199	0.1089	51
25197	0.0614	6
25196	0.0292	6
25195	0.0206	10
25198	0.0156	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
embryo	UBERON:0000922	99.18	gold quality
ganglionic eminence	UBERON:0004023	99.18	gold quality
cortical plate	UBERON:0005343	99.05	gold quality
ventricular zone	UBERON:0003053	99.00	gold quality
islet of Langerhans	UBERON:0000006	98.69	gold quality
stromal cell of endometrium	CL:0002255	98.64	gold quality
bone marrow	UBERON:0002371	98.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.36	gold quality
bone marrow cell	CL:0002092	98.36	gold quality
calcaneal tendon	UBERON:0003701	98.36	gold quality
adrenal tissue	UBERON:0018303	98.17	gold quality
smooth muscle tissue	UBERON:0001135	98.13	gold quality
monocyte	CL:0000576	98.08	gold quality
rectum	UBERON:0001052	98.07	gold quality
mononuclear cell	CL:0000842	98.06	gold quality
vermiform appendix	UBERON:0001154	98.06	gold quality
leukocyte	CL:0000738	98.03	gold quality
tonsil	UBERON:0002372	98.00	gold quality
caecum	UBERON:0001153	97.84	gold quality
gall bladder	UBERON:0002110	97.83	gold quality
trabecular bone tissue	UBERON:0002483	97.77	gold quality
lymph node	UBERON:0000029	97.76	gold quality
ectocervix	UBERON:0012249	97.76	gold quality
tongue squamous epithelium	UBERON:0006919	97.73	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	97.64	gold quality
type B pancreatic cell	CL:0000169	97.64	gold quality
endometrium	UBERON:0001295	97.64	gold quality
thymus	UBERON:0002370	97.60	gold quality
ovary	UBERON:0000992	97.56	gold quality
pancreas	UBERON:0001264	97.54	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	5.26
E-MTAB-6819	no	1463.77
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
ALOX15
CD40	Unknown
ERBB2	Unknown
ETS1	Repression
TFRC

Upstream regulators (CollecTRI, top): FLT3, MYC, SP1, TP53

miRNA regulators (miRDB)

69 targeting XRCC5, 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-340-5P	100.00	72.50	4437
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1224-5P	99.48	65.59	803

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 95.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• A functional interaction of Ku with Werner exonuclease facilitates digestion of DNA containing 8-oxoadenine and 8-oxoguanine modifications. (PMID:11328876)
• transcription initiates from a CpG island and is induced by p53 through a nearby p53 response element (PMID:11937624)
• Ku80 alteration is unlikely to be involved in multiple myeloma (PMID:11985783)
• Expression of Ku70/Ku80 proteins is decreased in malignant melanomas of the oral cavity. (PMID:12017286)
• Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair. (PMID:12077346)
• Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus (PMID:12177300)
• role of expression in NF-kappaB activation and COX-2 expression (PMID:12324457)
• Ku associates with hTERT, and this interaction may function to regulate the access of telomerase to telomeric DNA ends (PMID:12377759)
• These results suggest that association of Ku with transcription sites is important for maintenance of global transcription levels. (PMID:12391174)
• The expression of Ku is upregulated in human neuroectodermal tumor cells by retroviral DNA integration (PMID:12403924)
• Transcripts of Ku70 and Ku86 genes were detected by RT-PCR and Ku protein was localized in the nucleus of neutrophils as a heterodimer (PMID:12467650)
• The mechanism that regulates for nuclear localization of Ku70 and Ku80 appears to play, at least in part, a key role in regulating the physiological function of Ku in vivo. (PMID:12518983)
• 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)
• DNA repair proteins Ku70 and Ku80 expression is lost in cell nucleus after oxidative stress (PMID:12867423)
• 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)
• binding of the Ku complex at chromosomal breaks may be necessary to maintain the sliding clamps (PCNA) on chromatin (PMID:14617623)
• Results show that Ku70/Ku80 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) modulate RAG-mediated cleavage during V(D)J recombination. (PMID:15123719)
• DNA-binding component of human OF-1 (which binds Herpes simplex virus type 1 origin of replication) contains Ku70 and Ku80 proteins (PMID:15220460)
• DNA degradation diminished the amount of Ku70 associated with gamma-H2AX but not that of nuclear DNA helicase II. (PMID:15613478)
• Ku is involved in transcriptional recycling with androgen dependent promoters (PMID:15640154)
• Ku70-binding site of Ku80 is required for the stabilization of Ku70 in the cytoplasm and for the nuclear translocation of Ku80 through its heterodimerization with Ku70. (PMID:15817152)
• Ku70/80 interacts directly with the RNA component of human telomerase, independent of the human telomerase reverse transcriptase protein. (PMID:15824061)
• Study using HCT116 haplo-insufficient cells and Orc2 hypomorphic cells demonstrates that human Ku80 and Orc2 bind to replication origins independently of each other, while Ku binding precedes that of Orc-3, -4, and -6. (PMID:15910003)
• findings suggest Ku80 as a cellular factor targeted by Tax in engendering clastogenic DNA damage. (PMID:16014171)
• The present study suggests that Ku binds IRES -(internal ribosomal entry site)elements within RNA molecules, and that Ku plays a role in the modulation of IRES mediated mRNA translation. (PMID:16448389)
• The pre-steady state binding of Ku with various DNA duplex substrates was studied and a redox-sensitive Ku-DNA interaction was identified. (PMID:16537541)
• Dimeric particles are observed in which two DNA-PKcs/Ku70/Ku80 holoenzymes interact through the N-terminal HEAT repeats. (PMID:16713581)
• Functions in nonhomologous DNA end joining. (PMID:17124166)
• The three-dimensional structure of the human full-length Ku70-Ku80 dimer at 25 A resolution, alone and in complex with DNA, by using single-particle electron microscopy was reconstructed. (PMID:17159921)
• poly(ADP-ribose)polymerase-1 and Ku70/Ku80 are transcriptional regulators of S100A9 gene expression (PMID:17187679)
• the gene encoding Ku86 (XRCC5) is an essential gene in human somatic cells, and its absence cannot be suppressed by the loss of p53 function (PMID:17214517)
• low mRNA and protein expression in the BRCA1/BRCA2 and XRCC5 genes occur in lung adenocarcinoma and squamous cell carcinoma, respectively, and promoter hypermethylation is the predominant mechanism in deregulation of these genes (PMID:17289874)
• Individuals with A allele of XRCC5 C74468A might have low risk of developing ESCC and GCA; however, individuals with G allele of XRCC5 G74582A might only have low risk of developing GCA. (PMID:17355791)
• These data support a new role for Ku in the migration of monocytes into tissues, which depends on a tightly regulated pathway of intracellular redistribution. (PMID:17496833)
• Results describe the effect of Ku80 on both provirus integration and the resulting transgene expression in cells transduced with retroviral vectors. (PMID:17507472)
• The expression and subcellular localization of Ku80 in the nucleus demonstrated the involvement of this protein in the photo-oxidative cell death pathway. (PMID:17534116)
• ATM and Ku80 did not enhance the radiosensitivity of cervical carcinoma cells. (PMID:17626748)
• potential relevance of Bin1-Ku interaction to cancer are discussed in light of these findings (PMID:17671430)
• Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma. (PMID:17901044)
• Although the different genotypes were not associated with the risk of bladder cancer, individuals not carrying the two tandem repeats allele had an increased risk of bladder cancer compared with those carrying the allele with two repeats. (PMID:17904587)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	xrcc5	ENSDARG00000099298
mus_musculus	Xrcc5	ENSMUSG00000026187
rattus_norvegicus	Xrcc5	ENSRNOG00000016105
drosophila_melanogaster	Ku80	FBGN0041627
caenorhabditis_elegans		WBGENE00000520

Paralogs (1): XRCC6 (ENSG00000196419)

Protein

Protein identifiers

DNA repair protein Ku80 — P13010 (reviewed: P13010)

Alternative names: 86 kDa subunit of Ku antigen, ATP-dependent DNA helicase 2 subunit 2, ATP-dependent DNA helicase II 80 kDa subunit, CTC box-binding factor 85 kDa subunit, DNA repair protein XRCC5, Ku80, Ku86, Lupus Ku autoantigen protein p86, Nuclear factor IV, Thyroid-lupus autoantigen, X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining), X-ray repair cross-complementing protein 5

All UniProt accessions (3): P13010, C9JZ81, H7C0H9

UniProt curated annotations — full annotation on UniProt →

Function. DNA-binding protein critical for the DNA damage response, specifically in repairing double-strand breaks (DSBs) via the classical non-homologous end joining (NHEJ) pathway. It forms a heterodimer with XRCC6 (Ku70), creating the Ku70:Ku80 heterodimer (Ku complex), which serves as a DNA end-binding complex. It primarily binds DSBs and recruits essential repair factors, assembling the core long-range NHEJ complex to facilitate the alignment and ligation of broken DNA ends. This pathway ensures the rapid repair of cytotoxic and mutagenic DSBs and contributes to the generation of diversity in T-cell receptors and antibodies through mechanisms such as V(D)J recombination. Likely acts as a 5’-deoxyribose-5-phosphate lyase (5’-dRP lyase), catalyzing the beta-elimination of the 5’-deoxyribose-5-phosphate at abasic sites near DSBs. This activity cleans the termini of abasic sites, a common form of nucleotide damage, preparing broken ends for ligation. It may also possess 3’-5’ DNA helicase activity, although this has not been confirmed in vivo, and its physiological significance remains unclear. Beyond DNA repair, the protein contributes to telomere maintenance. It is also implicated in transcriptional regulation, acting as a cofactor for various transcription factors. It plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. Can also bind RNAs and recruits PRKDC to a wide range of cellular RNAs, including the U3 small nucleolar RNA, playing a role in the biogenesis of ribosomal RNAs.

Subunit / interactions. Heterodimer composed of XRCC5/Ku80 and XRCC6/Ku70; heterodimerization stabilizes XRCC5 protein. 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. The XRCC5-XRCC6 dimer also associates with NAA15, and this complex displays DNA binding activity towards the osteocalcin FGF response element (OCFRE). In addition, XRCC5 binds to the osteoblast-specific transcription factors MSX2 and RUNX2. Interacts with ELF3. Interacts with APLF (via KBM motif). The XRCC5/XRCC6 dimer associates in a DNA-dependent manner with APEX1. Identified in a complex with DEAF1 and XRCC6. Interacts with NR4A3; the DNA-dependent protein kinase complex DNA-PK phosphorylates and activates NR4A3 and prevents NR4A3 ubiquitinylation and degradation. Interacts with RNF138. Interacts with CYREN isoform 1 (CYREN-1) and isoform 4 (CYREN-2) (via KBM motif). Interacts with WRN (via KBM motif). Interacts (via N-terminus) with HSF1 (via N-terminus); this interaction is direct and prevents XRCC5/XRCC6 heterodimeric binding and non-homologous end joining (NHEJ) repair activities induced by ionizing radiation (IR). Interacts with DHX9; this interaction occurs in a RNA-dependent manner. Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA. Interacts with ERCC6. The XRCC5-XRCC6 dimer associates with ALKBH2. Interacts with TPRN; TPRN interacts with a number of DNA damage response proteins, is recruited to sites of DNA damage and may play a role in DNA damage repair. Interacts with ERCC6L2. (Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein HBZ.

Subcellular location. Nucleus. Nucleolus. Chromosome.

Post-translational modifications. ADP-ribosylated by PARP3. Phosphorylated on serine residues. Phosphorylation by PRKDC may enhance helicase activity. Sumoylated. Ubiquitinated by RNF8 via ‘Lys-48’-linked ubiquitination following DNA damage, leading to its degradation and removal from DNA damage sites. Ubiquitinated by RNF138, leading to remove the Ku complex from DNA breaks.

Domain organisation. The EEXXXDDL motif is required for the interaction with catalytic subunit PRKDC and its recruitment to sites of DNA damage. The VWFA domain interacts with the KBM (Ku-binding motif) found in a number of DNA repair proteins. The N-terminal and C-terminal regions are not required for binding to DNA or for degradation of the protein with only the central region being required for these processes.

Induction. In osteoblasts, by FGF2.

Miscellaneous. Individuals with systemic lupus erythematosus (SLE) and related disorders produce extremely large amounts of autoantibodies to XRCC6 and XRCC5.

Similarity. Belongs to the ku80 family.

RefSeq proteins (1): NP_066964* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002035	VWF_A	Domain
IPR005160	Ku_C	Domain
IPR005161	Ku_N	Domain
IPR006164	DNA_bd_Ku70/Ku80	Domain
IPR014893	Ku_PK_bind	Domain
IPR016194	SPOC-like_C_dom_sf	Homologous_superfamily
IPR024193	Ku80	Family
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR036494	Ku_C_sf	Homologous_superfamily

Pfam: PF02735, PF03730, PF03731, PF08785

Catalyzed reactions (Rhea), 2 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)
• 2’-deoxyribonucleotide-(2’-deoxyribose 5’-phosphate)-2’-deoxyribonucleotide-DNA = a 3’-end 2’-deoxyribonucleotide-(2,3-dehydro-2,3-deoxyribose 5’-phosphate)-DNA + a 5’-end 5’-phospho-2’-deoxyribonucleoside-DNA + H(+) (RHEA:66592)

UniProt features (109 total): helix 34, strand 34, modified residue 13, sequence conflict 8, cross-link 7, turn 3, domain 2, sequence variant 2, mutagenesis site 2, initiator methionine 1, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

63 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3RZ9	X-RAY DIFFRACTION	2.29
8AG4	ELECTRON MICROSCOPY	2.46
1JEY	X-RAY DIFFRACTION	2.5
7ZYG	ELECTRON MICROSCOPY	2.68
1JEQ	X-RAY DIFFRACTION	2.7
7ZVT	ELECTRON MICROSCOPY	2.74
6ERH	X-RAY DIFFRACTION	2.8
7ZWA	ELECTRON MICROSCOPY	2.8
9CQ3	ELECTRON MICROSCOPY	2.8
9GYF	ELECTRON MICROSCOPY	2.8
9N81	ELECTRON MICROSCOPY	2.8
6ERG	X-RAY DIFFRACTION	2.9
7Z87	ELECTRON MICROSCOPY	2.91
9Q8X	ELECTRON MICROSCOPY	2.94
8ASC	X-RAY DIFFRACTION	2.95
7SGL	ELECTRON MICROSCOPY	3
6ERF	X-RAY DIFFRACTION	3.01
9CQ6	ELECTRON MICROSCOPY	3.1
9N83	ELECTRON MICROSCOPY	3.1
7AXZ	ELECTRON MICROSCOPY	3.2
7SU3	ELECTRON MICROSCOPY	3.3
9N82	ELECTRON MICROSCOPY	3.3
9IGW	ELECTRON MICROSCOPY	3.32
7Z88	ELECTRON MICROSCOPY	3.33
9HZG	ELECTRON MICROSCOPY	3.33
9Q80	ELECTRON MICROSCOPY	3.39
9CQC	ELECTRON MICROSCOPY	3.4
9IOL	ELECTRON MICROSCOPY	3.46
8AG5	ELECTRON MICROSCOPY	3.47
7ZT6	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13010-F1	83.71	0.58

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 (20): 318, 332, 535, 577, 579, 580, 660, 665, 715, 195, 532, 534, 566, 568, 669, 688, 144, 255, 258, 265

Mutagenesis-validated functional residues (2):

Position	Phenotype
720–721	abolishes interaction with prkdc and its recruitment to sites of dna damage.
726–727	abolishes interaction with prkdc and its recruitment to sites of dna damage.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-164843	2-LTR circle formation
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-3270619	IRF3-mediated induction of type I IFN
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 408 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, MORF_DNMT1, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RIBOSOME_BIOGENESIS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, REACTOME_INNATE_IMMUNE_SYSTEM, BIOCARTA_TEL_PATHWAY

GO Biological Process (26): telomere maintenance (GO:0000723), recombinational repair (GO:0000725), activation of innate immune response (GO:0002218), double-strand break repair (GO:0006302), double-strand break repair via nonhomologous end joining (GO:0006303), DNA recombination (GO:0006310), DNA damage response (GO:0006974), telomere maintenance via telomerase (GO:0007004), neurogenesis (GO:0022008), regulation of telomere maintenance (GO:0032204), small-subunit processome assembly (GO:0034462), innate immune response (GO:0045087), negative regulation of DNA-templated transcription (GO:0045892), regulation of smooth muscle cell proliferation (GO:0048660), positive regulation of neurogenesis (GO:0050769), hematopoietic stem cell differentiation (GO:0060218), protein localization to chromosome, telomeric region (GO:0070198), hematopoietic stem cell proliferation (GO:0071425), cellular response to gamma radiation (GO:0071480), negative regulation of t-circle formation (GO:1904430), cellular response to leukemia inhibitory factor (GO:1990830), immune system process (GO:0002376), DNA repair (GO:0006281), negative regulation of macromolecule biosynthetic process (GO:0010558), ribosome biogenesis (GO:0042254), positive regulation of protein kinase activity (GO:0045860)

GO Molecular Function (21): transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), DNA helicase activity (GO:0003678), damaged DNA binding (GO:0003684), double-stranded DNA binding (GO:0003690), RNA binding (GO:0003723), ATP binding (GO:0005524), enzyme activator activity (GO:0008047), ATP-dependent activity, acting on DNA (GO:0008094), ATP hydrolysis activity (GO:0016887), ubiquitin protein ligase binding (GO:0031625), U3 snoRNA binding (GO:0034511), telomeric repeat DNA binding (GO:0042162), protein-containing complex binding (GO:0044877), DNA end binding (GO:0045027), nucleotide binding (GO:0000166), double-stranded telomeric DNA binding (GO:0003691), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), 5’-deoxyribose-5-phosphate lyase activity (GO:0051575)

GO Cellular Component (21): chromosome, telomeric region (GO:0000781), nuclear telomere cap complex (GO:0000783), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), plasma membrane (GO:0005886), DNA-dependent protein kinase-DNA ligase 4 complex (GO:0005958), membrane (GO:0016020), small-subunit processome (GO:0032040), protein-containing complex (GO:0032991), protein-DNA complex (GO:0032993), secretory granule lumen (GO:0034774), Ku70:Ku80 complex (GO:0043564), DNA-dependent protein kinase complex (GO:0070418), nonhomologous end joining complex (GO:0070419), site of DNA damage (GO:0090734), ribonucleoprotein complex (GO:1990904), chromosome (GO:0005694), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	2
Integration of provirus	1
STING mediated induction of host immune responses	1
DNA Double-Strand Break Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear protein-containing complex	5
cellular anatomical structure	5
DNA binding	3
ATP-dependent activity	3
DNA metabolic process	2
DNA repair	2
nucleic acid binding	2
catalytic activity	2
binding	2
nuclear lumen	2
intracellular membraneless organelle	2
protein-containing complex	2
telomere organization	1
DNA recombination	1
activation of immune response	1
positive regulation of innate immune response	1
double-strand break repair	1
cellular response to stress	1
telomerase activity	1
RNA-templated DNA biosynthetic process	1
telomere maintenance via telomere lengthening	1
telomere-telomerase complex assembly	1
nervous system development	1
cell differentiation	1
telomere maintenance	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
protein-RNA complex assembly	1
cytosolic small ribosomal subunit assembly	1
immune response	1
defense response to symbiont	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
regulation of cell population proliferation	1
smooth muscle cell proliferation	1
positive regulation of cell development	1
neurogenesis	1
regulation of neurogenesis	1
positive regulation of nervous system development	1

Protein interactions and networks

STRING

3602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XRCC5	PRKDC	P78527	999
XRCC5	XRCC6	P12956	999
XRCC5	XRCC4	Q13426	999
XRCC5	NHEJ1	Q9H9Q4	987
XRCC5	LIG4	P49917	985
XRCC5	PARP1	P09874	968
XRCC5	ATM	Q13315	964
XRCC5	APLF	Q8IW19	957
XRCC5	PAXX	Q9BUH6	957
XRCC5	WRN	Q14191	953
XRCC5	LIG3	P49916	943
XRCC5	HOXB7	P09629	928
XRCC5	BRCA1	P38398	884
XRCC5	CYREN	Q9BWK5	878
XRCC5	XRCC1	P18887	877

IntAct

445 interactions, top by confidence:

A	B	Type	Score
XRCC6	XRCC5	psi-mi:“MI:0914”(association)	0.970
XRCC5	XRCC6	psi-mi:“MI:0914”(association)	0.970
XRCC5	XRCC6	psi-mi:“MI:0915”(physical association)	0.970
XRCC6	XRCC5	psi-mi:“MI:0915”(physical association)	0.970
PRKDC	XRCC5	psi-mi:“MI:0407”(direct interaction)	0.900
PRKDC	XRCC6	psi-mi:“MI:0217”(phosphorylation reaction)	0.900
PRKDC	XRCC5	psi-mi:“MI:2364”(proximity)	0.900
XRCC5	PARP1	psi-mi:“MI:0914”(association)	0.880
APLF	PARP1	psi-mi:“MI:0914”(association)	0.870
PARP1	XRCC6	psi-mi:“MI:0914”(association)	0.850
XRCC6	PARP1	psi-mi:“MI:0914”(association)	0.850
PARP1	XRCC6	psi-mi:“MI:0557”(adp ribosylation reaction)	0.850
RARA	NCOR1	psi-mi:“MI:0914”(association)	0.800
H3C1	HAT1	psi-mi:“MI:0914”(association)	0.770
H2AZ1	ZNHIT1	psi-mi:“MI:0914”(association)	0.770
RECQL	PARP1	psi-mi:“MI:0914”(association)	0.750
WRN	PARP1	psi-mi:“MI:0914”(association)	0.740
XPC	PARP1	psi-mi:“MI:0914”(association)	0.730
TPT1	XRCC6	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
NHEJ1	XRCC5	psi-mi:“MI:0914”(association)	0.710

BioGRID (945): XRCC5 (Affinity Capture-MS), XRCC5 (Reconstituted Complex), XRCC5 (Reconstituted Complex), XRCC5 (Affinity Capture-Western), XRCC5 (Affinity Capture-MS), XRCC5 (Reconstituted Complex), XRCC5 (Affinity Capture-Western), XRCC5 (Affinity Capture-MS), XRCC5 (Affinity Capture-MS), XRCC5 (Affinity Capture-MS), XRCC5 (Affinity Capture-Western), XRCC5 (Affinity Capture-Western), XRCC5 (Affinity Capture-Western), XRCC5 (Affinity Capture-MS), XRCC5 (Affinity Capture-MS)

ESM2 similar proteins: A6QLC7, B2RXC1, O14417, O18637, O70481, O88763, P13010, P40958, P53914, P59015, P83509, P87115, Q09305, Q0E7J8, Q13257, Q14AI0, Q3T1J9, Q54CR8, Q54XJ0, Q556Y9, Q59VQ3, Q5D891, Q5RAE0, Q5ZI89, Q66I84, Q6AX60, Q6AZN6, Q6DDS9, Q6GL75, Q6GMB0, Q6IR55, Q6PD82, Q6PF93, Q7L9L4, Q7X659, Q7Z392, Q811G0, Q8BPB0, Q8IWV7, Q8NEB9

Diamond homologs: P13010, P27641, Q6DDS9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
XRCC5	“form complex”	DNA-PK	binding
XRCC5	“down-regulates quantity by destabilization”	PDX1	binding
FLT3	“up-regulates quantity by expression”	XRCC5	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 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)	7	11.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair via nonhomologous end joining	8	26.1×	3e-07
double-strand break repair	10	15.7×	3e-07
telomere maintenance	6	12.4×	2e-03
mitochondrion organization	7	8.2×	4e-03
DNA damage response	13	5.4×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	7
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3292 predictions. Top by Δscore:

Variant	Effect	Δscore
2:216110520:G:GT	donor_gain	1.0000
2:216110520:G:T	donor_gain	1.0000
2:216113126:ACAGG:A	donor_loss	1.0000
2:216113127:CAGG:C	donor_loss	1.0000
2:216113128:AGGTA:A	donor_loss	1.0000
2:216113129:GGTA:G	donor_loss	1.0000
2:216113130:GTAAG:G	donor_loss	1.0000
2:216113131:TAA:T	donor_loss	1.0000
2:216119041:A:AG	acceptor_gain	1.0000
2:216119042:G:GG	acceptor_gain	1.0000
2:216119042:GA:G	acceptor_gain	1.0000
2:216119166:G:GG	donor_gain	1.0000
2:216122060:A:AG	acceptor_gain	1.0000
2:216122061:G:GG	acceptor_gain	1.0000
2:216125915:A:AG	acceptor_gain	1.0000
2:216125916:G:GG	acceptor_gain	1.0000
2:216127518:T:TA	acceptor_gain	1.0000
2:216127520:T:TA	acceptor_gain	1.0000
2:216127525:T:TA	acceptor_gain	1.0000
2:216127526:G:A	acceptor_gain	1.0000
2:216127530:T:G	acceptor_gain	1.0000
2:216127533:A:AG	acceptor_gain	1.0000
2:216127534:A:G	acceptor_gain	1.0000
2:216127670:TCAAG:T	donor_loss	1.0000
2:216127671:CAAGG:C	donor_loss	1.0000
2:216127674:GGTA:G	donor_loss	1.0000
2:216127675:GT:G	donor_loss	1.0000
2:216127676:T:G	donor_loss	1.0000
2:216127683:G:GG	donor_gain	1.0000
2:216130873:A:AG	acceptor_gain	1.0000

AlphaMissense

4905 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:216137155:G:C	R394P	0.996
2:216130970:T:C	F345L	0.995
2:216130972:T:A	F345L	0.995
2:216130972:T:G	F345L	0.995
2:216137146:C:A	A391D	0.995
2:216138108:T:C	L424P	0.994
2:216190318:G:C	R643P	0.993
2:216130962:T:A	V342D	0.992
2:216137152:T:A	V393D	0.992
2:216137197:C:A	A408D	0.992
2:216190237:T:C	L616P	0.992
2:216190326:G:C	A646P	0.992
2:216116693:T:A	V57D	0.990
2:216130899:T:A	V321D	0.990
2:216137113:T:C	L380P	0.990
2:216116686:G:C	A55P	0.989
2:216130971:T:C	F345S	0.988
2:216137191:G:A	G406D	0.988
2:216113094:G:C	A34P	0.987
2:216137121:G:C	A383P	0.987
2:216117766:A:C	S114R	0.986
2:216117768:C:A	S114R	0.986
2:216117768:C:G	S114R	0.986
2:216148087:T:C	L494P	0.986
2:216190293:A:C	S635R	0.986
2:216190295:C:A	S635R	0.986
2:216190295:C:G	S635R	0.986
2:216137196:G:C	A408P	0.985
2:216113031:T:C	C13R	0.983
2:216137104:T:C	L377P	0.983

dbSNP variants (sampled 300 via entrez): RS1000023818 (2:216159369 G>A), RS1000033714 (2:216159579 T>G), RS1000101478 (2:216125173 A>G), RS1000130253 (2:216143855 C>A,T), RS1000132844 (2:216137682 T>C), RS1000143273 (2:216165084 G>A), RS1000201274 (2:216205142 T>C), RS1000222419 (2:216166547 G>A), RS1000236444 (2:216143813 TCTC>T), RS1000240071 (2:216185590 A>C), RS1000253639 (2:216204933 G>A,T), RS1000256241 (2:216143302 TG>T), RS1000343395 (2:216130828 A>G,T), RS1000376515 (2:216169036 G>A,T), RS1000464560 (2:216198981 T>C)

Disease associations

OMIM: gene MIM:194364 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4106136 (PROTEIN COMPLEX), CHEMBL6066957 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1051685	Efficacy	3	thalidomide	Multiple Myeloma

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6941	XRCC5		0.00	0
rs1051685	XRCC5	3	1.50	1	thalidomide

ChEMBL bioactivities

4 potent at pChembl≥5 of 10 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.58	Kd	26.44	nM	CHEMBL3752910
7.58	ED50	26.44	nM	CHEMBL3752910
5.89	IC50	1290	nM	MOLIBRESIB
5.00	IC50	1e+04	nM	CHEMBL1795743

PubChem BioAssay actives

3 with measured affinity, of 88 total; 3 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149791: Binding affinity to human XRCC5 incubated for 45 mins by Kinobead based pull down assay	kd	0.0264	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178497: Inhibition of XRCC5 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	1.2900	uM
2-morpholin-4-ylbenzo[h][1,3]benzoxazin-4-one	1325306: Inhibition of human DNA-PK/Ku70/Ku85 using EPPLSQEAFADLWKK as substrate by HTRF assay relative to control	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, affects binding, decreases reaction, decreases expression, decreases methylation	4
sodium arsenite	increases abundance, affects binding, increases reaction, decreases expression, affects cotreatment	4
4-biphenylamine	decreases expression, decreases reaction	2
trichostatin A	increases acetylation, increases expression	2
cobaltous chloride	decreases expression	2
Vorinostat	decreases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	decreases methylation, affects expression, increases abundance	2
Arsenic	increases expression, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Caffeine	decreases expression, decreases phosphorylation	2
Cisplatin	affects expression, affects cotreatment, increases response to substance	2
Valproic Acid	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
naringenin	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
selenocystine	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
afimoxifene	decreases expression	1
fludarabine	affects cotreatment, decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
aflatoxin B2	increases methylation	1
2-hydroxyethyl disulfide	affects binding, affects cotreatment, decreases activity	1
epigallocatechin gallate	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CPG-oligonucleotide	increases expression	1

ChEMBL screening assays

44 unique, capped per target: 44 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3864780	Binding	Inhibition of human DNA-PK/Ku70/Ku85 at 10 uM using EPPLSQEAFADLWKK as substrate by HTRF assay relative to control	Synthesis of linear and angular aryl-morpholino-naphth-oxazines, their DNA-PK, PI3K, PDE3A and antiplatelet activity. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 4 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_HE13	NALM-6 XRCC5(+/-)	Cancer cell line	Male
CVCL_VU47	R7080-20	Spontaneously immortalized cell line	Male
CVCL_VU48	R7080-6	Spontaneously immortalized cell line	Male
CVCL_VU49	R80-1	Spontaneously immortalized cell line	Male
CVCL_VU50	R80-6	Spontaneously immortalized cell line	Male

Clinical trials (associated diseases)

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