XRCC5 (X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining))

2012-05-01 Sabina Pucci , Tommaso Fisco , Maria José Zonetti Affiliation

Lab. of Molecular Pathology, Dept. of Biopathology University of Rome Tor Vergata, Policlinico Tor Vergata, Viale Oxford, 00133 Rome, Italy

Identity

HGNC

XRCC5

LOCATION

2q35

LOCUSID

7520

ALIAS

KARP-1,KARP1,KU80,KUB2,Ku86,NFIV

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

The Ku80 gene is composed of 21 exons. It belongs together with KU70 to the family of care taker genes.

Proteins

Expression

Ku80 expression has been demonstrated in various cell types and its localization changes during the cell-cycle progression or with a pathological state.
Ku80 in addition to its well known regulatory functions in DNA repair, revealed to behave as a somatostatin receptor in gastric carcinoma cell (Le Romancer, 1994).

Localisation

Ku was originally reported to be a nuclear protein, consistent with its function as a subunits of DNA- PK involved in DNA double strand breaks repair. However several studies have revealed the cytoplasmic or cell surface localization of ku proteins in various cell types (Prabhakar et al., 1990).
In highly infiltrative and metastatic tumors of the colon, breast and bladder, the impaired DNA-repair activity is due to the loss of Ku80 and to the Ku70 shifting from the nucleus to the cytoplasm (Pucci et al., 2001). This mechanism can be controlled by various external growth-regulating stimuli.
In normal cell Ku80 activation and translocation into nucleus could be regulated or stimulated by the induction of nuclear Clusterin (nClu)-Ku70 interactions. (Pucci et al., 2009a; Pucci et al., 2009b; Mazzarelli et al., 2009).

Function

Ku80 is one component of a protein complex, the Ku70/80 heterodimer that can bind tightly to free DNA ends and activate the DNA-PKcs.
The principal role of Ku proteins is to take care of the homeostasis of the genome being involved in telomere maintenance, regulation of apoptosis induction, specific gene transcription, DNA replication and cell-cycle regulation. The function of this caretaker gene is to suppress chromosomal aberrations translocation and aneuploidy.
It has been demonstrated that Ku80 may act as a caretaker gene that maintains the integrity of the genoma by a mechanism involving the suppression of chromosomal rearrangements (Difilippantonio et al., 2000).

A. Ku80 is localized in the nucleus in normal, undamaged cell interacting with the Ku70 protein. sCLU stabilizes the Ku70-Bax interaction in the cytoplasm acting as cytoprotectant. B. After DNA damage inducing DNA double-strand breaks repair (UV treatment, ionizing radiation, etc.) Ku70 allows the translocation of Bax to the mitochondria inducing apoptosis (Mazzarelli et al., 2009). C. The differential shift of clusterin isoform production, the loss of Ku80, and the cytoplasmic relocalization of Ku70 are related to cell death inhibition and cancer progression.

Description

Karp-1 has some biochemical properties, which resemble those of Ku80, and the function of Karp-1 could partially replace that of Ku80 in DSB repair (Koibe et al., 2011). However the role in the cells of this isoform is still unclear.
The Ku80 protein is 732 amino acid long and its molecular weight is 83 kDa. It is composed of 3 domains: an amino (N) terminal alpha/beta domain, a central beta-barrel domain and a helical-C terminal arm. The 19 kDa C-terminal region of Ku80 is implicated in the recruitment of DNA-PKcs by Ku to sites of damage (Rivera-Calzada et al., 2007). Moreover it belongs to the "Care Taker gene", detecting double strands breaks.

Implicated in

Entity name

Cancer insurgence and progression

Note

The changes in Ku70 and Ku80 expression and localization are related to tumor progression. In normal cell they usually are placed in the nucleus, where they cooperate to repair double strands breaks that could occur during DNA replication. In breast, bladder, and colon cancers (Pucci et al., 2004a; Pucci et al., 2009c) DNA repair is inhibited in high infiltrative carcinomas through the loss of Ku80 and the Ku70 cell compartment shifting from nucleus to the cytoplasm. Ku70 shifts from the nucleus to the cytoplasm and binds, together with sCLU, Bax inhibiting its homodimerization and translocation to the mitochondria preventing apoptosis induction.
Somatostatin treatment to a colon carcinoma cell line (Caco-2) strongly modulates the activation of Ku70/80 heterodimer and the level of Ku80 in the nucleus by increasing its specific mRNA level (Pucci et al., 2004b). Ku80 could be a signal transducer and activator factor behaving as the intermediate of the SST transduction pathway by the internalization and the migration from the cell membrane to the nucleus.

Tumor-specific modulation of Ku70/80 in human colon cancer. Ku70 staining was strongly positive in the nuclei of normal mucosa. In node-negative carcinomas (pT3N0) Ku70 expression slightly decreased and it localized mainly in the nucleus. In node-positive carcinomas (pT3N1) Ku70 staining was distributed mainly in cytoplasm. The expression of Ku80 was positive in the nuclei of control tissues (normal mucosa). Nuclear Ku80 expression was strongly decreased in node-negative tumors (pT3N0). No staining for Ku80 was found in the nucleus or in the cytoplasm of node-positive carcinomas (pT3N1).

Article Bibliography

Pubmed ID	Last Year	Title	Authors
10761921	2000	DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation.	Difilippantonio MJ et al
21756904	2011	KARP-1 works as a heterodimer with Ku70, but the function of KARP-1 cannot perfectly replace that of Ku80 in DSB repair.	Koike M et al
8021251	1994	The 86-kDa subunit of autoantigen Ku is a somatostatin receptor regulating protein phosphatase-2A activity.	Le Romancer M et al
19879422	2009	CLU and colon cancer. The dual face of CLU: from normal to malignant phenotype.	Mazzarelli P et al
2212014	1990	Cell surface expression of the 70-kD component of Ku, a DNA-binding nuclear autoantigen.	Prabhakar BS et al
19623170	2009	Clusterin in stool: a new biomarker for colon cancer screening?	Pucci S et al
19879425	2009	CLU "in and out": looking for a link.	Pucci S et al
17159921	2007	Structural model of full-length human Ku70-Ku80 heterodimer and its recognition of DNA and DNA-PKcs.	Rivera-Calzada A et al

Other Information

Locus ID:

NCBI: 7520
MIM: 194364
HGNC: 12833
Ensembl: ENSG00000079246

Variants:

dbSNP: 7520
ClinVar: 7520
TCGA: ENSG00000079246
COSMIC: XRCC5

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000079246	ENST00000392132	P13010
ENSG00000079246	ENST00000392133	P13010
ENSG00000079246	ENST00000417391	C9JZ81
ENSG00000079246	ENST00000451695	H7C0H9

Expression (GTEx)

100

150

200

250

300

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Non-homologous end-joining	KEGG	ko03450
Non-homologous end-joining	KEGG	hsa03450
DNA-PK complex	KEGG	hsa_M00297
DNA-PK complex	KEGG	M00297
Disease	REACTOME	R-HSA-1643685
Infectious disease	REACTOME	R-HSA-5663205
HIV Infection	REACTOME	R-HSA-162906
HIV Life Cycle	REACTOME	R-HSA-162587
Early Phase of HIV Life Cycle	REACTOME	R-HSA-162594
Integration of provirus	REACTOME	R-HSA-162592
2-LTR circle formation	REACTOME	R-HSA-164843
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
Cytosolic sensors of pathogen-associated DNA	REACTOME	R-HSA-1834949
STING mediated induction of host immune responses	REACTOME	R-HSA-1834941
IRF3-mediated induction of type I IFN	REACTOME	R-HSA-3270619
DNA Repair	REACTOME	R-HSA-73894
DNA Double-Strand Break Repair	REACTOME	R-HSA-5693532
Nonhomologous End-Joining (NHEJ)	REACTOME	R-HSA-5693571
Neutrophil degranulation	REACTOME	R-HSA-6798695

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PK	PD	PMIDs
PA444985	Multiple Myeloma	Disease	ClinicalAnnotation	associated		PD	21435719
PA451644	thalidomide	Chemical	ClinicalAnnotation	associated		PD	21435719

References

Pubmed ID	Year	Title	Citations
38219597	2024	Ku80 is indispensable for repairing DNA double-strand breaks at highly methylated sites in human HCT116 cells.	0
38219597	2024	Ku80 is indispensable for repairing DNA double-strand breaks at highly methylated sites in human HCT116 cells.	0
37061192	2023	Circular RNA XRCC5 aggravates glioma progression by activating CLC3/SGK1 axis via recruiting IGF2BP2.	2
37338025	2023	SUMO2/3 promotes the progression and oxaliplatin resistance of colorectal cancer through facilitating the SUMOylation at Ku80-K307.	1
37429610	2023	RUSC1-AS1 promotes the malignant progression of breast cancer depending on the regulation of the miR-326/XRCC5 pathway.	1
37728466	2023	Nuclear expression of Ku70/80 is associated with CHEK2 germline mutations in breast cancer.	0
37061192	2023	Circular RNA XRCC5 aggravates glioma progression by activating CLC3/SGK1 axis via recruiting IGF2BP2.	2
37338025	2023	SUMO2/3 promotes the progression and oxaliplatin resistance of colorectal cancer through facilitating the SUMOylation at Ku80-K307.	1
37429610	2023	RUSC1-AS1 promotes the malignant progression of breast cancer depending on the regulation of the miR-326/XRCC5 pathway.	1
37728466	2023	Nuclear expression of Ku70/80 is associated with CHEK2 germline mutations in breast cancer.	0
35436516	2022	CircXRCC5, as a Potential Novel Biomarker, Promotes Glioma Progression via the miR-490-3p/XRCC5/CLC3 Competing Endogenous RNA Network.	3
35715658	2022	Centromeric protein K (CENPK) promotes gastric cancer proliferation and migration via interacting with XRCC5.	1
35773772	2022	[Correlation of polymorphisms of DNA double-strand break repair genes XRCC5, LIG4 and glioma].	0
35903292	2022	LINC01419 Promotes the Proliferation of Hepatoma Cells by Recruiting XRCC5 and Regulating Its Phosphorylation to Repair DNA Damage.	5
35910805	2022	DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis.	13

Citation

Sabina Pucci ; Tommaso Fisco ; Maria José Zonetti

XRCC5 (X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining))

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: http://atlasgeneticsoncology.org/gene/337/xrcc5-(x-ray-repair-complementing-defective-repair-in-chinese-hamster-cells-5-(double-strand-break-rejoining))