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 

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

Identity

HGNC
LOCATION
2q35
LOCUSID
ALIAS
KARP-1,KARP1,KU80,KUB2,Ku86,NFIV
FUSION GENES

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).
Atlas Image
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.
Atlas Image
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).

Bibliography

Pubmed IDLast YearTitleAuthors
107619212000DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation.Difilippantonio MJ et al
217569042011KARP-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
80212511994The 86-kDa subunit of autoantigen Ku is a somatostatin receptor regulating protein phosphatase-2A activity.Le Romancer M et al
198794222009CLU and colon cancer. The dual face of CLU: from normal to malignant phenotype.Mazzarelli P et al
22120141990Cell surface expression of the 70-kD component of Ku, a DNA-binding nuclear autoantigen.Prabhakar BS et al
196231702009Clusterin in stool: a new biomarker for colon cancer screening?Pucci S et al
198794252009CLU "in and out": looking for a link.Pucci S et al
171599212007Structural 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 IDTranscript IDUniprot
ENSG00000079246ENST00000392132P13010
ENSG00000079246ENST00000392133P13010
ENSG00000079246ENST00000417391C9JZ81
ENSG00000079246ENST00000451695H7C0H9

Expression (GTEx)

0
50
100
150
200
250
300

Pathways

PathwaySourceExternal ID
Non-homologous end-joiningKEGGko03450
Non-homologous end-joiningKEGGhsa03450
DNA-PK complexKEGGhsa_M00297
DNA-PK complexKEGGM00297
DiseaseREACTOMER-HSA-1643685
Infectious diseaseREACTOMER-HSA-5663205
HIV InfectionREACTOMER-HSA-162906
HIV Life CycleREACTOMER-HSA-162587
Early Phase of HIV Life CycleREACTOMER-HSA-162594
Integration of provirusREACTOMER-HSA-162592
2-LTR circle formationREACTOMER-HSA-164843
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Cytosolic sensors of pathogen-associated DNAREACTOMER-HSA-1834949
STING mediated induction of host immune responsesREACTOMER-HSA-1834941
IRF3-mediated induction of type I IFNREACTOMER-HSA-3270619
DNA RepairREACTOMER-HSA-73894
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
Nonhomologous End-Joining (NHEJ)REACTOMER-HSA-5693571
Neutrophil degranulationREACTOMER-HSA-6798695

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA444985Multiple MyelomaDiseaseClinicalAnnotationassociatedPD21435719
PA451644thalidomideChemicalClinicalAnnotationassociatedPD21435719

References

Pubmed IDYearTitleCitations
171241662006Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4.139
201955112010Ku regulates the non-homologous end joining pathway choice of DNA double-strand break repair in human somatic cells.104
167135812006Three-dimensional structure of the human DNA-PKcs/Ku70/Ku80 complex assembled on DNA and its implications for DNA DSB repair.100
120773462002Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair.96
198930542010Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex.91
222668202012The E3 ligase RNF8 regulates KU80 removal and NHEJ repair.76
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
231785932013APLF promotes the assembly and activity of non-homologous end joining protein complexes.49
202019262010Human variation in alcohol response is influenced by variation in neuronal signaling genes.45
123777592002Human Ku70/80 associates physically with telomerase through interaction with hTERT.42

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