Disease relevance of Xrcc6

• The assignment of the mouse Ku70 gene to chromosome 15 is consistent with the syntenic relationship of this gene in human (chromosome 22q13) and mouse and adds to the comparative mapping data for the genes involved in the SCID phenotype [1].
• Ku70-deficient mice lacked mature B cells or serum immunoglobulin but, unexpectedly, reproducibly developed small populations of thymic and peripheral alpha/beta T lineage cells and had a significant incidence of thymic lymphomas [2].
• The role of the Ku70 subunit in DNA DSB repair, hypersensitivity to ionizing radiation, and V(D)J recombination was examined in mice that lack Ku70 (Ku70(-/-)) [3].

High impact information on Xrcc6

• We conclude that Ku70 and Ku80 may have functions in V(D)J recombination and DNA repair that are independent of DNA-PKcs [4].
• Targeted inactivation of the Ku70 or Ku80 genes results in elevated ionizing radiation (IR) sensitivity and inability to perform both V(D)J coding-end and signal (RS)-end joining in cells, with severe growth retardation plus immunodeficiency in mice [4].
• In association with B and T cell developmental defects, Ku70-deficient cells were severely impaired for joining of V(D)J coding and recombination signal sequences [2].
• Growth retardation and leaky SCID phenotype of Ku70-deficient mice [2].
• Our Ku70-deficient mice were about 50% the size of control littermates, and their fibroblasts were ionizing radiation sensitive and displayed premature senescence associated with the accumulation of nondividing cells [2].

Biological context of Xrcc6

• MEFs homozygous for mutations that inactivate either DNA ligase IV (Lig4) or Ku70 display dramatic genomic instability, even in the absence of exogenous DNA damaging agents [5].
• Both the human and the mouse Ku70 cDNAs have been cloned, and the human gene has been mapped to chromosome 22q13 [1].
• Function of DNA-protein kinase catalytic subunit during the early meiotic prophase without Ku70 and Ku86 [6].
• The sites within the ICR bind Ku70/80 in a sequence-specific manner and with higher affinity than previously reported binding sites [7].
• This overview will focus mainly on the role of DNA repair/recombination and DNA damage signalling molecules such as PARP-1, DNA-PKcs, Ku70/80, XRCC4 and ATM which we have been studying for the last few years [8].

Anatomical context of Xrcc6

• These unanticipated features of the Ku70-deficient phenotype with respect to lymphocyte development and V(D)J recombination may reflect differential functions of the three DNA-PK components [2].
• Mutations at multiple sites within the N-terminal two thirds of Ku80 result in loss of Ku70/80 interaction, loss of DNA end-binding activity and inability to complement Ku80 defective cell lines [9].
• Oxidative damage and defective DNA repair is linked to apoptosis of migrating neurons and progenitors during cerebral cortex development in Ku70-deficient mice [10].
• Mutational analysis of introduced Ku70 cDNAs into murine embryonic stem cells deleted for Ku70 (-/-) showed that mutants where heterodimerization and DNA binding functions of Ku were disrupted, also blocked the restoration of etoposide resistance [11].
• A single band with migration properties similar to those of Ku70 was immunoprecipitated with anti-Ku antibody, using UV cross-linked complexes formed by HeLa cell nuclear extracts and an IRES-containing RNA probe [12].

Associations of Xrcc6 with chemical compounds

• The binding required the presence of Mg(2+), implying that the sequence is a pause site for Ku70/80 translocation from a free end [7].
• 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 [13].

Physical interactions of Xrcc6

• DNA-dependent protein kinase (DNA-PK) is a DNA repair enzyme composed of a DNA-binding component called Ku70/80 and a catalytic subunit called DNA-PKcs [14].

Other interactions of Xrcc6

• Functional characterization of a novel Ku70/80 pause site at the H19/Igf2 imprinting control region [7].
• Thus, loss of Ercc1, Csb or Ku70 leads to increased fragment formation, but loss of Xrcc2 promotes exchanges between chromosomes [15].
• Ku70 is required for late B cell development and immunoglobulin heavy chain class switching [16].
• At gestational day 14.5, corresponding to the peak of neurogenesis, the Ku70(-/-) embryonic cerebral cortex displayed 25- to 30-fold more cell death than heterozygous littermates, as judged by DNA breaks, pyknosis and active caspase-3 [10].
• In contrast, antagonism of Bax by a Ku-70-derived peptide or antisense oligonucleotides prevented both apoptosis and cell death [17].

Analytical, diagnostic and therapeutic context of Xrcc6

• This report contains an analysis of the 5'-region of the mouse cDNA sequence, a characterization of the mouse Ku70 genomic structure, and fluorescence in situ hybridization data that map the mouse gene to chromosome 15 [1].
• Chromatin immunoprecipitation assays were unable to confirm that Ku70/80 binds to the ICR in vivo [7].
• Western blot analyses revealed a 75% and 36% decrease in the nuclear expression of Ku80 and Ku70, respectively [18].
• 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 [19].
• We found also that age-associated alteration of Ku70/80 was prevented or not prevented by caloric restriction (CR) in a tissue-specific manner [20].

References