Disease relevance of XRCC5

• In this study, we found that heating at 45.5 degrees C causes a decreased extractability of XRCC5 from the nuclei of human U-1 melanoma or HeLa cells [1].
• These facts, together with the demonstration of the ability of doxazosin to bind DNA, allowed us to propose a novel mechanism of action for doxazosin in prostate cancer cells that implies DNA-damage mediated apoptosis by down-regulation of XRCC5 and PRKDC genes [2].
• Linkage and association analysis of radiation damage repair genes XRCC3 and XRCC5 with nevus density in adolescent twins [3].
• 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 [4].
• 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 [5].

Psychiatry related information on XRCC5

• We investigated the psychological sequelae of incest through the use of the Draw-A-Person Questionnaire (DAPQ; Karp, 1990), a projective technique with an objective component [6].
• First- and third-grade black children were administered Kagan's Matching Familiar Figures Test, Karp and Konstadt's Children's Embedded Figures Test (CEFT), and Shore, Milgram, and Malasky's Locus of Control Interview (LCI) [7].

High impact information on XRCC5

• Ku70 and Ku80 share a common topology and form a dyad-symmetrical molecule with a preformed ring that encircles duplex DNA [8].
• The discovery of homologues from the yeast Saccharomyces cerevisiae of the human Ku DNA-end-binding proteins (HDF1 and KU80) has established that this organism is capable of non-homologous double-strand end joining (NHEJ), a form of DNA double-strand break repair (DSBR) active in mammalian V(D)J recombination [9].
• Ku80: product of the XRCC5 gene and its role in DNA repair and V(D)J recombination [10].
• Three-dimensional structure of the human DNA-PKcs/Ku70/Ku80 complex assembled on DNA and its implications for DNA DSB repair [11].
• Consistent with this observation, we observed that human cell lines stably expressing dominant-negative constructs of KARP-1 resulted in diminished DNA-PK activity and X-ray hypersensitivity and that a KARP-1 antibody significantly neutralized DNA-PK activity in vitro [12].

Chemical compound and disease context of XRCC5

• An antisense oligonucleotide targeted to human Ku86 messenger RNA sensitizes M059K malignant glioma cells to ionizing radiation, bleomycin, and etoposide but not DNA cross-linking agents [13].
• The optimal conditions for the determination of exposure to scrub typhus by the whole blood lymphocyte transformation assay was 7 days culture of 10% blood in RPMI 1640 medium supplemented with 10% human AB-negative serum and L-glutamine with 50-200 micrograms protein/ml of Karp, Kato, or Gilliam strain membrane antigen [14].

Biological context of XRCC5

• The human XRCC5 DNA repair gene, which complements this mutant, is shown here through genetic and biochemical evidence to be the 80-kilodalton subunit of the Ku protein [10].
• These data show that the gene defective in xrs cells, XRCC5, which is involved in double-strand break rejoining, is located on human chromosome 2q [15].
• In contrast, the other mutants defective in NER activities, the XRCC2 and XRCC3 mutants, and the XRCC5 mutant all showed normal unhooking kinetics [16].
• Assignment of a human DNA double-strand break repair gene (XRCC5) to chromosome 2 [17].
• Discordancies between some chromosome 2 markers and the radiation resistance phenotype in some of the hybrid cells suggested the location of the X-ray repair cross complementing 5 (XRCC5) gene on the p arm of chromosome 2 [17].

Anatomical context of XRCC5

• Recently, one of the DSB repair genes, XRCC5, has been mapped on human chromosome 2 by concordance analysis of somatic cell hybrids and by the microcell-mediated chromosome transfer approach [18].
• A YAC contig encompassing the XRCC5 (Ku80) DNA repair gene and complementation of defective cells by YAC protoplast fusion [19].
• There was no difference in the expression of XRCC5 and RAD52 mRNA between N10 and KB cells in both unirradiated and irradiated conditions [20].
• 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 [21].
• In a previous study, by means of somatic gene targeting, we generated human cell lines deficient in Ku86 (XRCC5) [22].

Associations of XRCC5 with chemical compounds

• Strikingly, we found that doxazosin induces deregulation of genes implicated in DNA replication and repair, such as GADD45A, XRCC5 and PRKDC [2].
• Nuclear XRCC5 is normally extractable with non-ionic detergent; it is found in the soluble cytoplasmic fraction after nuclear isolation with Triton X-100 [1].
• 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 [23].
• 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 [24].
• The KARP-1-specific domain encodes interdigitating hexa- and penta-heptad repeats of leucine residues flanked by a very basic region [12].

Physical interactions of XRCC5

• The atomic structure of a truncated Ku70-Ku80 was determined; however, the subunit-specific carboxy-terminal domain of Ku80-essential for binding to DNA-PKcs-was determined only in isolation, and the C-terminal domain of Ku70 was not resolved in its DNA-bound conformation [25].
• In addition, our data indicate that the region of Ku80 between amino acids 215 and 276 is necessary for binding to WRN [26].
• These results indicate that the ATM protein is recruited to the site of DNA damage and it recognizes double strand breaks by itself or through an association with other DNA-binding protein other than DNA-PK and Ku80 proteins [27].

Regulatory relationships of XRCC5

• Ku70 and Ku80 have been shown to form a heterodimeric complex that can bind tightly to free DNA ends and activate the protein kinase DNA-PKcs [28].
• KARP-1: a novel leucine zipper protein expressed from the Ku86 autoantigen locus is implicated in the control of DNA-dependent protein kinase activity [12].
• Although the specific binding of Ku to EBVRE was not demonstrated, dominant negative Ku80 suppressed IL-4 + anti-CD40-driven CD23 expression [29].
• Our findings are consistent with the hypothesis that somatostatin controls cell cycle progression and DNA repair through a new signalling pathway that involves the regulation of Ku86 level and modulates the Ku70/86 activity in the nucleus [30].

Other interactions of XRCC5

• Based on the analysis of the structure-function of Ku70 and the crystal structure of Ku70/Ku80 heterodimer, we designed and identified a candidate dominant negative fragment involving an NH(2)-terminal deletion, and designated it as DNKu70 [23].
• DNA-PK comprises the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs [31].
• No significant association was found between the repeat length at any of the microsatellites in XRCC1, XRCC3 or XRCC5 and the incidence of late radiotherapy complications [32].
• Surprisingly, however, even in a p53-null genetic background, the absence of Ku86 proved lethal [22].
• When specific numbers of repeats were examined, no significant correlation was found between the microsatellite repeat length in XRCC1 and XRCC5 and cancer incidence [32].

Analytical, diagnostic and therapeutic context of XRCC5

• By using fluorescence in situ hybridization, chromosome banding, and physical mapping of these X-ray hybrids, we have localized the human XRCC5 locus to 2q35 [18].
• Chromatin immunoprecipitation experiments demonstrated that both Ku70 and Ku80 interact with the prostate-specific antigen promoter in an androgen-dependant manner [5].
• To determine the distribution of DNA-PK in human tissues, we assayed paraffin-embedded sections of normal and cancerous tissues for DNA-PKcs and Ku80 by immunohistochemistry [33].
• Transcripts of Ku70 and Ku86 genes were also detected by the reverse transcriptase-polymerase chain reaction (RT-PCR), and Ku protein was shown to be localized in the nucleus of neutrophils as a heterodimer [34].
• 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 [35].

References