Disease relevance of Xrcc5

• Ku86 mutant C. elegans as well as C. elegans fed with cku86 dsRNA also display hypersensitivity to high NaCl, characterized by a reduced number of progeny and prolonged generation time in high NaCl [1].
• In this study, we demonstrate that equitoxic heat treatments at 42.5-45.5 degrees C induce a similar amount of aggregation of Ku80 in human U-1 melanoma cells [2].
• MATERIALS AND METHODS: The efficiency and fidelity of the joining of linear plasmids by DNA-PKcs-defective mouse cells (SCID) and Ku80-defective Chinese hamster ovary cells (xrs-6) was measured using either linear or circular replicating shuttle vector pZ189 [3].
• Here we show that mouse cells deficient for Ku80 display a marked increase in chromosomal aberrations, including breakage, translocations and aneuploidy [4].
• Synergistic role of Ku80 and poly(ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation [5].

High impact information on Xrcc5

• Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates [6].
• Despite the observed chromosome instabilities, Ku80-/- mice have only a slightly earlier onset of cancer [4].
• Although the importance of Ku80 in DNA double-strand break repair is well established, neither Ku80 nor other components of the non-homologous end-joining pathway are known to have a caretaker role in maintaining genomic stability [4].
• We conclude that Ku80 is a caretaker gene that maintains the integrity of the genome by a mechanism involving the suppression of chromosomal rearrangements [4].
• To determine the role of the DNA-binding subunit of DNA-PK in vivo, we targeted Ku80 in mice [7].

Biological context of Xrcc5

• Slc22a4 and another candidate, Xrcc5, have human orthologs that map to genomic regions associated with human ethanol sensitivity in genetic linkage studies [8].
• We conclude that Ku70 and Ku80 may have functions in V(D)J recombination and DNA repair that are independent of DNA-PKcs [9].
• Deletion of Ku86 causes early onset of senescence in mice [10].
• Although less severe, this phenotype is reminiscent of the one recently described for Ku86-defective cells [11].
• Here we show evidence that cells defective in Ku80 exhibit a significantly slow S phase progression following DNA damage [12].

Anatomical context of Xrcc5

• Mutant cell lines and mice with targeted deletions in Ku70 or Ku86 are severely compromised in their ability to form coding and signal joints, the products of V(D)J recombination [13].
• Ku80 null cells showed a telomere shortening associated with extensive chromosome end fusions, whereas Ku80+/- cells exhibited an intermediate level of telomere shortening [14].
• Consistent with this growth defect, fibroblasts derived from Ku80-/- embryos showed an early loss of proliferating cells, a prolonged doubling time, and intact cell-cycle checkpoints that prevented cells with damaged DNA from entering the cell-cycle [7].
• Surprisingly, in contrast to Ku80(-/-) mice in which both T and B lymphocyte development were arrested at an early stage, lack of Ku70 was compatible with T cell receptor gene recombination and the development of mature CD4+CD8- and CD4-CD8+ T cells [15].
• In addition, Ku86 deficiency rescues the male early germ cell apoptosis triggered by short telomeres in these mice [16].

Associations of Xrcc5 with chemical compounds

• Within the minimal active fragment of Ku86 necessary for subunit interaction (aa 449 to 732) and DNA binding (aa 334 to 732), a proline-rich region is the only defined motif [17].
• In addition, flavopiridol treatment (300 nM, 1 day) resulted in decreased levels of Ku70 and Ku86 proteins that play a role in DNA repair processes, suggesting that DNA repair processes may have been disrupted by this agent [18].
• Here, treatment of embryo fibroblasts (MEFs) derived from either wild-type or Ku80-null (Ku80(-/-)) mice with various stress agents revealed that hydrogen peroxide (H(2)O(2)) was markedly more cytotoxic for Ku80(-/-) MEFs and led to their long-term accumulation in the G2 phase [19].
• In an effort to improve the efficacy of antisense delivery, we evaluated polyethyleneimine (PEI, 2 kDa) alone or grafted with nonionic amphiphilic block copolymer Pluronic (P85) as a carrier for Ku86 antisense oligonucleotide (ASO) delivery [20].

Physical interactions of Xrcc5

• We have combined mutations in factors from both repair pathways, the HR protein Rad54 and the DNA-end-binding factor Ku80, which has a role in NHEJ [21].

Other interactions of Xrcc5

• Herein, we show that Ku70 and Ku80 deficiency but not DNA-PKcs deficiency results in dramatically increased death of developing embryonic neurons in mice [22].
• These results suggest that Ku80 is required for Galpha13-mediated endodermal differentiation in P19 cells [23].
• Ku80 also is a somatostatin receptor [23].
• Here, we report on genome-wide transcription in mouse G3 Terc-/-, Ku86-/- and G3 Terc-/-/Ku86-/- germ cells using high-density oligonucleotide microarrays [24].
• The double-mutant cells are impaired for the G(1)/S checkpoint due to the p53 mutation and are hypersensitive to gamma-radiation and reactive oxygen species due to the Ku80 mutation [25].

Analytical, diagnostic and therapeutic context of Xrcc5

• In additional real-time RT-PCR, the expression of Cyclin D1 gene, key regulator of cell-cycle progression, and Xrcc5 gene, DNA damage repair-related gene, was significantly increased at each time point and at week 8, respectively [26].
• Although Ku86-deficient mice are defective in coding and signal joint formation, rare recombination products have been detected by PCR [27].
• Western blot analyses revealed a 75% and 36% decrease in the nuclear expression of Ku80 and Ku70, respectively [28].
• To determine the size and tissue transcription specificity of the mouse Ku p70 and Ku p80/XRCC5 mRNA, Northern blot analysis was carried out with six mouse tissues [29].
• Western blot analyses confirmed the significant reduction of these proteins (59.4% and 57.7% reduction in optical density at 4 hours of reperfusion from the normal level of Ku70 and Ku86 bands, respectively; P<0.001) [30].

References