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

Written2012-05Sabina 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

(Note : for Links provided by Atlas : click)

Identity

Alias_names80kDa
Alias_symbol (synonym)KU80
KARP-1
Ku86
KUB2
HGNC (Hugo) XRCC5
LocusID (NCBI) 7520
Atlas_Id 337
Location 2q35  [Link to chromosome band 2q35]
Location_base_pair Starts at 216974020 and ends at 217071016 bp from pter ( according to hg19-Feb_2009)  [Mapping XRCC5.png]
Fusion genes
(updated 2016)
CEP95 (17q23.3) / XRCC5 (2q35)GIGYF2 (2q37.1) / XRCC5 (2q35)GSTP1 (11q13.2) / XRCC5 (2q35)
SERPINE2 (2q36.1) / XRCC5 (2q35)WDR7 (18q21.31) / XRCC5 (2q35)XRCC5 (2q35) / ACADL (2q34)
XRCC5 (2q35) / HTR2B (2q37.1)XRCC5 (2q35) / MYO5A (15q21.2)XRCC5 (2q35) / PTGR1 (9q31.3)

DNA/RNA

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

Protein

Description Two isoforms of Ku80 encoded by the same genes, namely Ku80 and Karp-1 are expressed and function in primate cells.
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.
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.

Implicated in

Note
Entity 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).
  

Bibliography

DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation.
Difilippantonio MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC, Max EE, Ried T, Nussenzweig A.
Nature. 2000 Mar 30;404(6777):510-4.
PMID 10761921
 
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, Yutoku Y, Koike A.
Exp Cell Res. 2011 Oct 1;317(16):2267-75. Epub 2011 Jul 2.
PMID 21756904
 
The 86-kDa subunit of autoantigen Ku is a somatostatin receptor regulating protein phosphatase-2A activity.
Le Romancer M, Reyl-Desmars F, Cherifi Y, Pigeon C, Bottari S, Meyer O, Lewin MJ.
J Biol Chem. 1994 Jul 1;269(26):17464-8.
PMID 8021251
 
CLU and colon cancer. The dual face of CLU: from normal to malignant phenotype.
Mazzarelli P, Pucci S, Spagnoli LG.
Adv Cancer Res. 2009;105:45-61. (REVIEW)
PMID 19879422
 
Cell surface expression of the 70-kD component of Ku, a DNA-binding nuclear autoantigen.
Prabhakar BS, Allaway GP, Srinivasappa J, Notkins AL.
J Clin Invest. 1990 Oct;86(4):1301-5.
PMID 2212014
 
Clusterin in stool: a new biomarker for colon cancer screening?
Pucci S, Bonanno E, Sesti F, Mazzarelli P, Mauriello A, Ricci F, Zoccai GB, Rulli F, Galata G, Spagnoli LG.
Am J Gastroenterol. 2009a Nov;104(11):2807-15. Epub 2009 Jul 21.
PMID 19623170
 
CLU "in and out": looking for a link.
Pucci S, Mazzarelli P, Nucci C, Ricci F, Spagnoli LG.
Adv Cancer Res. 2009c;105:93-113. (REVIEW)
PMID 19879425
 
Structural model of full-length human Ku70-Ku80 heterodimer and its recognition of DNA and DNA-PKcs.
Rivera-Calzada A, Spagnolo L, Pearl LH, Llorca O.
EMBO Rep. 2007 Jan;8(1):56-62. Epub 2006 Dec 8.
PMID 17159921
 

Citation

This paper should be referenced as such :
Pucci, S ; Fisco, T ; Zonetti, MJ
XRCC5 (X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining))
Atlas Genet Cytogenet Oncol Haematol. 2012;16(11):844-847.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/XRCC5ID337ch2q35.html


External links

Nomenclature
HGNC (Hugo)XRCC5   12833
Cards
AtlasXRCC5ID337ch2q35
Entrez_Gene (NCBI)XRCC5  7520  X-ray repair complementing defective repair in Chinese hamster cells 5
AliasesKARP-1; KARP1; KU80; KUB2; 
Ku86; NFIV
GeneCards (Weizmann)XRCC5
Ensembl hg19 (Hinxton)ENSG00000079246 [Gene_View]  chr2:216974020-217071016 [Contig_View]  XRCC5 [Vega]
Ensembl hg38 (Hinxton)ENSG00000079246 [Gene_View]  chr2:216974020-217071016 [Contig_View]  XRCC5 [Vega]
ICGC DataPortalENSG00000079246
TCGA cBioPortalXRCC5
AceView (NCBI)XRCC5
Genatlas (Paris)XRCC5
WikiGenes7520
SOURCE (Princeton)XRCC5
Genetics Home Reference (NIH)XRCC5
Genomic and cartography
GoldenPath hg19 (UCSC)XRCC5  -     chr2:216974020-217071016 +  2q35   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)XRCC5  -     2q35   [Description]    (hg38-Dec_2013)
EnsemblXRCC5 - 2q35 [CytoView hg19]  XRCC5 - 2q35 [CytoView hg38]
Mapping of homologs : NCBIXRCC5 [Mapview hg19]  XRCC5 [Mapview hg38]
OMIM194364   
Gene and transcription
Genbank (Entrez)AK026166 AK096408 AK222603 AK290740 BC019027
RefSeq transcript (Entrez)NM_021141
RefSeq genomic (Entrez)NC_000002 NC_018913 NG_029780 NT_005403 NW_004929305
Consensus coding sequences : CCDS (NCBI)XRCC5
Cluster EST : UnigeneHs.388739 [ NCBI ]
CGAP (NCI)Hs.388739
Alternative Splicing GalleryENSG00000079246
Gene ExpressionXRCC5 [ NCBI-GEO ]   XRCC5 [ EBI - ARRAY_EXPRESS ]   XRCC5 [ SEEK ]   XRCC5 [ MEM ]
Gene Expression Viewer (FireBrowse)XRCC5 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7520
GTEX Portal (Tissue expression)XRCC5
Protein : pattern, domain, 3D structure
UniProt/SwissProtP13010   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP13010  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP13010
Splice isoforms : SwissVarP13010
Catalytic activity : Enzyme3.6.4.- [ Enzyme-Expasy ]   3.6.4.-3.6.4.- [ IntEnz-EBI ]   3.6.4.- [ BRENDA ]   3.6.4.- [ KEGG ]   
PhosPhoSitePlusP13010
Domains : Interpro (EBI)Ku70/Ku80_beta-barrel_dom    Ku80    Ku_C    Ku_N    Ku_PK_bind    SPOC-like_C_dom    VWF_A   
Domain families : Pfam (Sanger)Ku (PF02735)    Ku_C (PF03730)    Ku_N (PF03731)    Ku_PK_bind (PF08785)   
Domain families : Pfam (NCBI)pfam02735    pfam03730    pfam03731    pfam08785   
Domain families : Smart (EMBL)Ku78 (SM00559)  VWA (SM00327)  
Conserved Domain (NCBI)XRCC5
DMDM Disease mutations7520
Blocks (Seattle)XRCC5
PDB (SRS)1JEQ    1JEY    1Q2Z    1RW2    3RZ9   
PDB (PDBSum)1JEQ    1JEY    1Q2Z    1RW2    3RZ9   
PDB (IMB)1JEQ    1JEY    1Q2Z    1RW2    3RZ9   
PDB (RSDB)1JEQ    1JEY    1Q2Z    1RW2    3RZ9   
Structural Biology KnowledgeBase1JEQ    1JEY    1Q2Z    1RW2    3RZ9   
SCOP (Structural Classification of Proteins)1JEQ    1JEY    1Q2Z    1RW2    3RZ9   
CATH (Classification of proteins structures)1JEQ    1JEY    1Q2Z    1RW2    3RZ9   
SuperfamilyP13010
Human Protein AtlasENSG00000079246
Peptide AtlasP13010
HPRD08935
IPIIPI00220834   IPI00012911   IPI00871391   IPI00926445   
Protein Interaction databases
DIP (DOE-UCLA)P13010
IntAct (EBI)P13010
FunCoupENSG00000079246
BioGRIDXRCC5
STRING (EMBL)XRCC5
ZODIACXRCC5
Ontologies - Pathways
QuickGOP13010
Ontology : AmiGOtelomere maintenance  nuclear telomere cap complex  nuclear chromosome, telomeric region  DNA binding  damaged DNA binding  double-stranded DNA binding  double-stranded telomeric DNA binding  ATP-dependent DNA helicase activity  protein binding  ATP binding  nucleus  nucleoplasm  nucleoplasm  nucleolus  cytosol  plasma membrane  double-strand break repair  double-strand break repair via nonhomologous end joining  double-strand break repair via nonhomologous end joining  DNA recombination  transcription, DNA-templated  protein C-terminus binding  cell proliferation  membrane  ubiquitin protein ligase binding  positive regulation of type I interferon production  DNA duplex unwinding  DNA duplex unwinding  telomeric DNA binding  telomeric DNA binding  Ku70:Ku80 complex  transcription regulatory region DNA binding  poly(A) RNA binding  macromolecular complex binding  negative regulation of transcription, DNA-templated  regulation of smooth muscle cell proliferation  positive regulation of neurogenesis  5'-deoxyribose-5-phosphate lyase activity  hematopoietic stem cell differentiation  nonhomologous end joining complex  cellular response to gamma radiation  cellular response to X-ray  establishment of integrated proviral latency  negative regulation of t-circle formation  
Ontology : EGO-EBItelomere maintenance  nuclear telomere cap complex  nuclear chromosome, telomeric region  DNA binding  damaged DNA binding  double-stranded DNA binding  double-stranded telomeric DNA binding  ATP-dependent DNA helicase activity  protein binding  ATP binding  nucleus  nucleoplasm  nucleoplasm  nucleolus  cytosol  plasma membrane  double-strand break repair  double-strand break repair via nonhomologous end joining  double-strand break repair via nonhomologous end joining  DNA recombination  transcription, DNA-templated  protein C-terminus binding  cell proliferation  membrane  ubiquitin protein ligase binding  positive regulation of type I interferon production  DNA duplex unwinding  DNA duplex unwinding  telomeric DNA binding  telomeric DNA binding  Ku70:Ku80 complex  transcription regulatory region DNA binding  poly(A) RNA binding  macromolecular complex binding  negative regulation of transcription, DNA-templated  regulation of smooth muscle cell proliferation  positive regulation of neurogenesis  5'-deoxyribose-5-phosphate lyase activity  hematopoietic stem cell differentiation  nonhomologous end joining complex  cellular response to gamma radiation  cellular response to X-ray  establishment of integrated proviral latency  negative regulation of t-circle formation  
Pathways : BIOCARTATelomeres, Telomerase, Cellular Aging, and Immortality [Genes]   
Pathways : KEGGNon-homologous end-joining   
REACTOMEP13010 [protein]
REACTOME PathwaysR-HSA-73889 Nonhomologous End-Joining (NHEJ) [pathway]
REACTOME PathwaysR-HSA-1834949 Cytosolic sensors of pathogen-associated DNA [pathway]
REACTOME PathwaysR-HSA-75924 Processing of DNA ends prior to end rejoining [pathway]
REACTOME PathwaysR-HSA-164843 2-LTR circle formation [pathway]
REACTOME PathwaysR-HSA-3270619 IRF3-mediated induction of type I IFN [pathway]
NDEx NetworkXRCC5
Atlas of Cancer Signalling NetworkXRCC5
Wikipedia pathwaysXRCC5
Orthology - Evolution
OrthoDB7520
GeneTree (enSembl)ENSG00000079246
Phylogenetic Trees/Animal Genes : TreeFamXRCC5
HOVERGENP13010
HOGENOMP13010
Homologs : HomoloGeneXRCC5
Homology/Alignments : Family Browser (UCSC)XRCC5
Gene fusions - Rearrangements
Fusion: TCGAXRCC5 2q35 ACADL 2q34 PRAD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerXRCC5 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)XRCC5
dbVarXRCC5
ClinVarXRCC5
1000_GenomesXRCC5 
Exome Variant ServerXRCC5
ExAC (Exome Aggregation Consortium)XRCC5 (select the gene name)
Genetic variants : HAPMAP7520
Genomic Variants (DGV)XRCC5 [DGVbeta]
DECIPHER (Syndromes)2:216974020-217071016  ENSG00000079246
CONAN: Copy Number AnalysisXRCC5 
Mutations
ICGC Data PortalXRCC5 
TCGA Data PortalXRCC5 
Broad Tumor PortalXRCC5
OASIS PortalXRCC5 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICXRCC5  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDXRCC5
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch XRCC5
DgiDB (Drug Gene Interaction Database)XRCC5
DoCM (Curated mutations)XRCC5 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)XRCC5 (select a term)
intoGenXRCC5
NCG5 (London)XRCC5
Cancer3DXRCC5(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM194364   
Orphanet
MedgenXRCC5
Genetic Testing Registry XRCC5
NextProtP13010 [Medical]
TSGene7520
GENETestsXRCC5
Huge Navigator XRCC5 [HugePedia]
snp3D : Map Gene to Disease7520
BioCentury BCIQXRCC5
ClinGenXRCC5
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD7520
Chemical/Pharm GKB GenePA37425
Clinical trialXRCC5
Miscellaneous
canSAR (ICR)XRCC5 (select the gene name)
Probes
Litterature
PubMed354 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineXRCC5
EVEXXRCC5
GoPubMedXRCC5
iHOPXRCC5
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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