Disease relevance of XRCC6

• These results demonstrate that Ku70 and Ku80 expression is mediated by constitutively activated NF-kappaB and constitutively expressed COX-2 in gastric cancer cells and that the high Ku DNA end-binding activity contributes to cell proliferation [1].
• Identification and biochemical characterization of a Werner's syndrome protein complex with Ku70/80 and poly(ADP-ribose) polymerase-1 [2].
• Interactions of apoJ/XIP8 or KUB3 with Ku70 were confirmed by co-immunoprecipitation analyses in MCF-7:WS8 breast cancer or IMR-90 normal lung fibroblast cells, respectively [3].
• Expression and heterodimer-binding activity of Ku70 and Ku80 in human non-melanoma skin cancer [4].
• Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii [5].

Psychiatry related information on XRCC6

• Measurements of regional or local cerebral blood flow (CBF) by the xenon-133 inhalation method and stable xenon computerized tomography CBF (CTCBF) method were made during relaxed wakefulness and different stages of REM and non-REM sleep in normal age-matched volunteers, narcoleptics, and sleep apneics [6].

High impact information on XRCC6

• Bacterial invasion is dependent on the presence of cholesterol-enriched microdomains containing Ku70 [5].
• Moreover, we show that irradiated cells deficient for Ku70 are incapable of targeting Mre11 to subnuclear foci that may represent DNA-repair complexes [7].
• Nevertheless, Ku70 and Mre11 were differentially expressed during meiosis [7].
• In early meiotic prophase, however, when meiotic recombination is most probably initiated, Mre11 was abundant, whereas Ku70 was not detectable [7].
• Ku70 and Ku80 share a common topology and form a dyad-symmetrical molecule with a preformed ring that encircles duplex DNA [8].

Chemical compound and disease context of XRCC6

• AR directly interacts with both Ku70 and Ku80 in vivo and in vitro, as shown by co-immunoprecipitation, glutathione S-transferase pull-down, and Sf9 cell/baculovirus expression [9].
• Ectopic expression of Bcl-XL or Ku70 protects human colon cancer cells (SW480) against curcumin-induced apoptosis while their down-regulation potentiates it [10].

Biological context of XRCC6

• The common promoter region of the human collagen type IV genes COL4A1 and COL4A2 comprises a C5TC7 sequence ('CTC box') which is specifically recognized by the recently identified transcription factor CTC box binding factor (CTCBF) involved in the control of divergent transcription of the two genes [11].
• Nuclear clusterin/XIP8, an x-ray-induced Ku70-binding protein that signals cell death [12].
• Overexpression of nuclear CLU/XIP8 or its minimal Ku70 binding domain (120 aa of CLU/XIP8 C terminus) in nonirradiated MCF-7:WS8 cells dramatically reduced cell growth and colony-forming ability concomitant with increased G(1) cell cycle checkpoint arrest and increased cell death [12].
• Our data suggest that Ku can affect the susceptibility to anticancer drug-induced apoptosis [13].
• Ku70 is one component of a protein complex, the Ku70/Ku80 heterodimer, which binds to DNA double-strand breaks and activates DNA-dependent protein kinase (DNA-PK), leading to DNA damage repair [14].

Anatomical context of XRCC6

• Here we show that the IR repair, DNA end binding and DNA-PK defects in Ku70-/- embryonic stem cells can be counteracted by introducing epitope-tagged wild-type Ku70 cDNA [15].
• Interestingly, YY1 interacts with Ku70 and Ku80 in HeLa cells [16].
• Ku-null mutant cell lines Ku70-/- and Ku80-/- were highly sensitive to anticancer drugs, compared with their wild-type cells [13].
• Accordingly, in resting human IgM+IgD+ B cells, HoxC4, Oct-1, and Ku70/Ku86 can be readily identified as bound to the Igamma and Iepsilon promoters but not the Ialpha1/Ialpha2 promoters [17].
• We found that tumour-transformed tissue shows positive immunostaining of DNA-PKcs, Ku86 and Ku70, while non-neoplastic squamous epithelium and tumour-free cervix glands show negative immunoreactivity [18].

Associations of XRCC6 with chemical compounds

• We find that Ku70 is phosphorylated at a single serine residue, serine 6, located in the putative transcriptional activation domain, and Ku80 is phosphorylated at serines 577 and 580 and at threonine 715 [19].
• Western blot analysis demonstrated that celecoxib downregulated the expression of Ku70 protein and inhibited the kinase activity of DNA-PKcs, which are involved in the double-stranded DNA-break repair machinery [20].
• A detailed examination of the involvement of the DNA repair pathway following Vorinostat treatment showed that Vorinostat reduced the expression of the repair-related genes Ku70, Ku80, and Rad50 in A375 cells as detected by Western blot analysis [21].
• By using glutathione S-transferase fusion proteins derived from Ku-70 and coimmunoprecipitation experiments with lysates prepared from human thymocytes and Jurkat and UT7 cells, we show that Vav associates with Ku-70 [22].
• A proline-to-leucine mutation in the carboxy SH3 of Vav that blocks interaction with proline-rich sequences does not modify the binding of Ku-70, which lacks this motif [22].

Physical interactions of XRCC6

• First, using various WRN deletion mutants we show that 50 amino acids at the amino terminus are required and sufficient to interact with Ku70/80 [23].
• Recently we have demonstrated that Ku70 interacted with TRF2, a mammalian telomere-binding protein [24].
• The Ku70 autoantigen interacts with p40phox in B lymphocytes [25].
• In vitro translated Ku70 interacted with HSF1 by binding to and displacing it from HSE [26].
• CONCLUSION: The candidates, poly(ADP-ribose)polymerase-1 (PARP-1) and the heterodimeric complex Ku70/Ku80, are known to participate in inflammatory disorders as well as tumorgenesis [27].

Co-localisations of XRCC6

• The transfected TFR2 colocalized with Ku70 [28].

Regulatory relationships of XRCC6

• Moreover, we demonstrated that Ku70/80 strongly stimulates and alters WRN exonuclease activity [23].
• Furthermore, electroporation of neutralizing anti-Ku70, Ku 80 and Ku70/80 antibodies into A549 cells totally suppressed IL-13 and IL-4-stimulated 15-LO-1 induction in these cells [29].
• Junctions were repaired in the same manner in MO59K extracts in which accurate NHEJ was inactivated by inhibition of Ku70 or DNA-PK(cs) [30].

Other interactions of XRCC6

• Here we identify Ku70 and Ku86 as proteins that interact with WRNp [31].
• Mutations in any of the three subunits of this protein kinase (Ku70, Ku80 and DNA-PKcs) lead to sensitivity to ionizing radiation (IR) and to DNA double-strand breaks, and V(D)J recombination product formation defects [15].
• Through peptide mass spectrometry, we identified this binding activity to be a heterodimer of Ku70 and Ku80 [16].
• Moreover, overexpression of Ku70/80 decreases alphaMyHC mRNA expression and increases skeletal alpha-actin [16].
• Ionizing radiation exposure results in up-regulation of Ku70 via a p53/ataxia-telangiectasia-mutated protein-dependent mechanism [32].

Analytical, diagnostic and therapeutic context of XRCC6

• Biochemical fractionation studies and immunoprecipitation assays and studies confirmed that endogenous WRN is associated with subpopulations of PARP-1 and Ku70/80 in the cell [2].
• Matrix assisted laser desorption ionization mass spectrometry (MALDI-MS) of the tryptic digests of these proteins, identified one as the 86 kDA Lupus KU autoantigen protein P86 and the second as the 70 kDa Lupus KU autoantigen protein P70 [29].
• METHODS: Levels of Ku70 and Ku80 proteins were determined by immunohistochemical analysis and Ku70-Ku80 heterodimer-binding activity by electrophoretic mobility shift assay [4].
• Molecular cloning and sequencing of cDNAs encoding homologues of human Ku70 and Ku80 autoantigen from Xenopus and their expression in various Xenopus tissues [33].
• An affinity chromatography approach identified the rickettsial protein rOmpB as a ligand for Ku70 [5].

References