Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6)

Written2010-06Sabina Pucci, Maria Josç Zonetti
Lab of Molecular Pathology, Dept of Biopathology, University of Rome Tor Vergata, Via Montpellier, 00133 Rome, Italy

(Note : for Links provided by Atlas : click)

Identity

Alias_names70kDa
G22P1
Alias_symbol (synonym)D22S731
D22S671
KU70
ML8
HGNC (Hugo) XRCC6
LocusID (NCBI) 2547
Atlas_Id 246
Location 22q13.2  [Link to chromosome band 22q13]
Location_base_pair Starts at 42017346 and ends at 42060052 bp from pter ( according to hg19-Feb_2009)  [Mapping XRCC6.png]
Fusion genes
(updated 2016)
PRR5-ARHGAP8 (22q13.31) / XRCC6 (22q13.2)XRCC6 (22q13.2) / GPX5 (6p22.1)XRCC6 (22q13.2) / POLR3H (22q13.2)
XRCC6 (22q13.2) / SIVA1 (14q32.33)

DNA/RNA

Description The KU70 gene is composed of 13 exons.
Transcription 2156 bp mRNA.

Protein

Description The Ku70 protein is 609 amino acid long and its molecular weight is 69.8 kDa. It is composed of 3 domains: an amino (N) amino-terminal alpha/beta domain, a central beta-barrel domain and a helical C-terminal arm (Rivera-Calzada et al., 2007). The C-terminal region consists of a 5 kDa SAP domain (Ku70-SAP) which involved in DNA binding during NHEJ reaction.
 
Expression Ku70 is ubiquitously expressed. Changes in Ku70 expression correlated to a pathological state.
Localisation Ku was originally reported to be a nuclear protein, consistent with its functions as a subunit 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). Recently, it has been demonstrated that the shift from the nucleus to the cytoplasm of the Ku70/Ku80 proteins in tumor cells could represents a mechanism to inhibit cell death through the Ku70-Bax-sCLU interactions, giving rise to a new chemoresistant clone with a more aggressive phenotype.
Function Ku is a heterodimeric protein composed of two subunits with molecular weight of 70 and 86 kDa. Ku forms a complex with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the full DNA-dependent protein kinase, DNA-PK, consisting of 470 kDa and required for the non-homologous end joining (NHEJ) pathway of DNA repair. The Ku heterodimer binds the ends of various types of DNA discontinuity, and is involved in the repair of DNA breaks caused by an incorrect DNA replication, V(D)J recombination, physiological oxidations, ionizing irradiation, and some chemotherapeutic drug effects (Featherstone and Jackson, 1999). The principal role of Ku proteins is to take care of the homeostasis of the genome being involved in telomere maintenance, specific gene transcription, DNA replication, cell-cycle regulation and regulation of apoptosis induction. Ku70 has been shown to bind to the pro-apoptotic protein BAX in the cytoplasm in normal, undamaged cell. After DNA damage inducing DNA double-strand breaks repair (UV treatment, ionizing radiation, etc.) Ku70 allows the translocation of Bax to the mitochondria leading to the release of death-promoting factors, such as cytochrome c, in the cytoplasmic compartment. In normal cells, after an irreversible cell damage, nCLU cooperates with Ku70 to induce apoptotic death, activating the translocation of Bax to mitochondria whereas the sCLU protein stabilizes the Ku70-Bax interaction in the cytoplasm acting as cytoprotectant. The Ku70-Bax-sCLU interaction in the cytoplasm seems to play an important role in cell survival pathways and in cell death escape, that in pathological condition could lead to the survival of the aberrant cell clone. Overall, the dynamic interactions among CLU, Ku70, and Bax seems to have an important role in both tumor insurgence and its progression (Pucci et al., 2009a; Pucci et al., 2009b).
 
  Ku70/80-CLU-Bax interactions. (A) Bax is localized inactive in the cytoplasm in normal, undamaged cell interacting with the Ku70 protein C-terminus. 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).

Implicated in

Note
Entity Colon cancer
Note The colon cancer expression and the localization of Ku70 and Ku80 are related to tumor progression in colon cancer. DNA repair is inhibited in high infiltrative colon carcinoma by Ku80 loss and Ku70 cell compartment shift (from the nucleus to the cytoplasm).
Moreover in colorectal carcinoma was demonstrated a very important role of Ku70 expression, localization, and physical interaction with CLU and Bax. In fact the Ku70-CLU-Bax colocalization in the cytoplasm and an increase in Ku70-CLU-Bax binding were observed in highly aggressive human colon cancer (Pucci et al., 2004; Pucci et al., 2009c), confirming that these interactions regulate the Bax-dependent cell death.
 
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 Ku86 was positive in the nuclei of control tissues (normal mucosa). Nuclear Ku86 expression was strongly decreased in node-negative tumors (pT3N0). No staining for Ku86 was found in the nucleus or in the cytoplasm of node-positive carcinomas (pT3N1).
 
Ku70-Bax-CLU pathological interaction. Apoptosis escaping. The shift of clusterin forms production, the loss of Ku80, and the cytoplasmic relocalization of Ku70 are related to cell death inhibition and cancer progression.
  
Entity Breast cancer
Note Experimental data further reported an inactivation of Ku DNA-binding activity, essential for genomic stability in breast and in bladder carcinomas. A dysfunction of this protective activity let the aberrant cell clone growing. In highly infiltrative and metastatic tumors of the breast and bladder, the impaired DNA-repair activity is due to the loss of Ku86 (Pucci et al., 2001) and to the Ku70 shifting from the nucleus to the cytoplasm. The shift from the nucleus to the cytoplasm of the Ku70/80 proteins in tumor cells could represents a mechanism to inhibit cell death through the cooperative interaction with sCLU, giving rise to a new chemoresistant clone with a more aggressive phenotype.
  

Bibliography

Ku, a DNA repair protein with multiple cellular functions?
Featherstone C, Jackson SP.
Mutat Res. 1999 May 14;434(1):3-15. (REVIEW)
PMID 10377944
 
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
 
Interleukin-6 affects cell death escaping mechanisms acting on Bax-Ku70-Clusterin interactions in human colon cancer progression.
Pucci S, Mazzarelli P, Sesti F, Boothman DA, Spagnoli LG.
Cell Cycle. 2009b Feb 1;8(3):473-81. Epub 2009 Feb 18.
PMID 19177010
 
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 ; Zonetti, MJ
XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(3):293-296.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/XRCC6ID246ch22q13.html


External links

Nomenclature
HGNC (Hugo)XRCC6   4055
Cards
AtlasXRCC6ID246ch22q13
Entrez_Gene (NCBI)XRCC6  2547  X-ray repair complementing defective repair in Chinese hamster cells 6
AliasesCTC75; CTCBF; G22P1; KU70; 
ML8; TLAA
GeneCards (Weizmann)XRCC6
Ensembl hg19 (Hinxton)ENSG00000196419 [Gene_View]  chr22:42017346-42060052 [Contig_View]  XRCC6 [Vega]
Ensembl hg38 (Hinxton)ENSG00000196419 [Gene_View]  chr22:42017346-42060052 [Contig_View]  XRCC6 [Vega]
ICGC DataPortalENSG00000196419
TCGA cBioPortalXRCC6
AceView (NCBI)XRCC6
Genatlas (Paris)XRCC6
WikiGenes2547
SOURCE (Princeton)XRCC6
Genetics Home Reference (NIH)XRCC6
Genomic and cartography
GoldenPath hg19 (UCSC)XRCC6  -     chr22:42017346-42060052 +  22q13.2   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)XRCC6  -     22q13.2   [Description]    (hg38-Dec_2013)
EnsemblXRCC6 - 22q13.2 [CytoView hg19]  XRCC6 - 22q13.2 [CytoView hg38]
Mapping of homologs : NCBIXRCC6 [Mapview hg19]  XRCC6 [Mapview hg38]
OMIM152690   
Gene and transcription
Genbank (Entrez)AK055786 AK293439 AK304580 AK315618 BC001583
RefSeq transcript (Entrez)NM_001288976 NM_001288977 NM_001288978 NM_001469
RefSeq genomic (Entrez)NC_000022 NC_018933 NT_011520 NW_004929430
Consensus coding sequences : CCDS (NCBI)XRCC6
Cluster EST : UnigeneHs.730702 [ NCBI ]
CGAP (NCI)Hs.730702
Alternative Splicing GalleryENSG00000196419
Gene ExpressionXRCC6 [ NCBI-GEO ]   XRCC6 [ EBI - ARRAY_EXPRESS ]   XRCC6 [ SEEK ]   XRCC6 [ MEM ]
Gene Expression Viewer (FireBrowse)XRCC6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2547
GTEX Portal (Tissue expression)XRCC6
Protein : pattern, domain, 3D structure
UniProt/SwissProtP12956   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP12956  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP12956
Splice isoforms : SwissVarP12956
Catalytic activity : Enzyme3.6.4.- [ Enzyme-Expasy ]   3.6.4.-3.6.4.- [ IntEnz-EBI ]   3.6.4.- [ BRENDA ]   3.6.4.- [ KEGG ]   
PhosPhoSitePlusP12956
Domaine pattern : Prosite (Expaxy)SAP (PS50800)   
Domains : Interpro (EBI)Ku70    Ku70/Ku80_beta-barrel_dom    Ku70_bridge/pillars_dom    Ku_C    Ku_N    SAP_dom    SPOC-like_C_dom    VWF_A   
Domain families : Pfam (Sanger)Ku (PF02735)    Ku_C (PF03730)    Ku_N (PF03731)    SAP (PF02037)   
Domain families : Pfam (NCBI)pfam02735    pfam03730    pfam03731    pfam02037   
Domain families : Smart (EMBL)Ku78 (SM00559)  SAP (SM00513)  
Conserved Domain (NCBI)XRCC6
DMDM Disease mutations2547
Blocks (Seattle)XRCC6
PDB (SRS)1JEQ    1JEY    1JJR    3RZX   
PDB (PDBSum)1JEQ    1JEY    1JJR    3RZX   
PDB (IMB)1JEQ    1JEY    1JJR    3RZX   
PDB (RSDB)1JEQ    1JEY    1JJR    3RZX   
Structural Biology KnowledgeBase1JEQ    1JEY    1JJR    3RZX   
SCOP (Structural Classification of Proteins)1JEQ    1JEY    1JJR    3RZX   
CATH (Classification of proteins structures)1JEQ    1JEY    1JJR    3RZX   
SuperfamilyP12956
Human Protein AtlasENSG00000196419
Peptide AtlasP12956
HPRD01071
IPIIPI00644712   IPI00889791   IPI00893179   IPI00893062   
Protein Interaction databases
DIP (DOE-UCLA)P12956
IntAct (EBI)P12956
FunCoupENSG00000196419
BioGRIDXRCC6
STRING (EMBL)XRCC6
ZODIACXRCC6
Ontologies - Pathways
QuickGOP12956
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  transcription factor complex  cytosol  DNA ligation  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  membrane  positive regulation of type I interferon production  DNA duplex unwinding  DNA duplex unwinding  Ku70:Ku80 complex  transcription regulatory region DNA binding  poly(A) RNA binding  macromolecular complex binding  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  regulation of smooth muscle cell proliferation  protein heterotetramerization  5'-deoxyribose-5-phosphate lyase activity  nonhomologous end joining complex  cellular response to gamma radiation  cellular response to X-ray  establishment of integrated proviral latency  double-strand break repair via classical nonhomologous end joining  
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  transcription factor complex  cytosol  DNA ligation  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  membrane  positive regulation of type I interferon production  DNA duplex unwinding  DNA duplex unwinding  Ku70:Ku80 complex  transcription regulatory region DNA binding  poly(A) RNA binding  macromolecular complex binding  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  regulation of smooth muscle cell proliferation  protein heterotetramerization  5'-deoxyribose-5-phosphate lyase activity  nonhomologous end joining complex  cellular response to gamma radiation  cellular response to X-ray  establishment of integrated proviral latency  double-strand break repair via classical nonhomologous end joining  
Pathways : BIOCARTATelomeres, Telomerase, Cellular Aging, and Immortality [Genes]   
Pathways : KEGGNon-homologous end-joining   
REACTOMEP12956 [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 NetworkXRCC6
Atlas of Cancer Signalling NetworkXRCC6
Wikipedia pathwaysXRCC6
Orthology - Evolution
OrthoDB2547
GeneTree (enSembl)ENSG00000196419
Phylogenetic Trees/Animal Genes : TreeFamXRCC6
HOVERGENP12956
HOGENOMP12956
Homologs : HomoloGeneXRCC6
Homology/Alignments : Family Browser (UCSC)XRCC6
Gene fusions - Rearrangements
Fusion : MitelmanPRR5-ARHGAP8/XRCC6 [22q13.31/22q13.2]  [t(22;22)(q13;q13)]  
Fusion : MitelmanXRCC6/GPX5 [22q13.2/6p22.1]  [t(6;22)(p22;q13)]  
Fusion: TCGAPRR5-ARHGAP8 22q13.31 XRCC6 22q13.2 LUAD
Fusion: TCGAXRCC6 22q13.2 GPX5 6p22.1 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerXRCC6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)XRCC6
dbVarXRCC6
ClinVarXRCC6
1000_GenomesXRCC6 
Exome Variant ServerXRCC6
ExAC (Exome Aggregation Consortium)XRCC6 (select the gene name)
Genetic variants : HAPMAP2547
Genomic Variants (DGV)XRCC6 [DGVbeta]
DECIPHER (Syndromes)22:42017346-42060052  ENSG00000196419
CONAN: Copy Number AnalysisXRCC6 
Mutations
ICGC Data PortalXRCC6 
TCGA Data PortalXRCC6 
Broad Tumor PortalXRCC6
OASIS PortalXRCC6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICXRCC6  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDXRCC6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch XRCC6
DgiDB (Drug Gene Interaction Database)XRCC6
DoCM (Curated mutations)XRCC6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)XRCC6 (select a term)
intoGenXRCC6
NCG5 (London)XRCC6
Cancer3DXRCC6(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM152690   
Orphanet
MedgenXRCC6
Genetic Testing Registry XRCC6
NextProtP12956 [Medical]
TSGene2547
GENETestsXRCC6
Huge Navigator XRCC6 [HugePedia]
snp3D : Map Gene to Disease2547
BioCentury BCIQXRCC6
ClinGenXRCC6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2547
Chemical/Pharm GKB GenePA28467
Clinical trialXRCC6
Miscellaneous
canSAR (ICR)XRCC6 (select the gene name)
Probes
Litterature
PubMed364 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineXRCC6
EVEXXRCC6
GoPubMedXRCC6
iHOPXRCC6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Nov 18 20:00:07 CET 2016

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.