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Gene Review

Xrcc5  -  X-ray repair complementing defective...

Mus musculus

Synonyms: AI314015, ATP-dependent DNA helicase 2 subunit 2, ATP-dependent DNA helicase II 80 kDa subunit, CTC box-binding factor 85 kDa subunit, CTC85, ...
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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


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


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].


  1. Ku86 preserves chromatin integrity in cells adapted to high NaCl. Dmitrieva, N.I., Celeste, A., Nussenzweig, A., Burg, M.B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. The non-homologous end-joining pathway is not involved in the radiosensitization of mammalian cells by heat shock. Dynlacht, J.R., Bittner, M.E., Bethel, J.A., Beck, B.D. J. Cell. Physiol. (2003) [Pubmed]
  3. Reduced joining of DNA double strand breaks with an abnormal mutation spectrum in rodent mutants of DNA-PKcs and Ku80. Tzung, T.Y., Rünger, T.M. Int. J. Radiat. Biol. (1998) [Pubmed]
  4. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Difilippantonio, M.J., Zhu, J., Chen, H.T., Meffre, E., Nussenzweig, M.C., Max, E.E., Ried, T., Nussenzweig, A. Nature (2000) [Pubmed]
  5. Synergistic role of Ku80 and poly(ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation. Tong, W.M., Cortes, U., Hande, M.P., Ohgaki, H., Cavalli, L.R., Lansdorp, P.M., Haddad, B.R., Wang, Z.Q. Cancer Res. (2002) [Pubmed]
  6. Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates. Zhu, C., Bogue, M.A., Lim, D.S., Hasty, P., Roth, D.B. Cell (1996) [Pubmed]
  7. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nussenzweig, A., Chen, C., da Costa Soares, V., Sanchez, M., Sokol, K., Nussenzweig, M.C., Li, G.C. Nature (1996) [Pubmed]
  8. Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs. MacLaren, E.J., Bennett, B., Johnson, T.E., Sikela, J.M. Mamm. Genome (2006) [Pubmed]
  9. A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Gao, Y., Chaudhuri, J., Zhu, C., Davidson, L., Weaver, D.T., Alt, F.W. Immunity (1998) [Pubmed]
  10. Deletion of Ku86 causes early onset of senescence in mice. Vogel, H., Lim, D.S., Karsenty, G., Finegold, M., Hasty, P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  11. The absence of the dna-dependent protein kinase catalytic subunit in mice results in anaphase bridges and in increased telomeric fusions with normal telomere length and G-strand overhang. Goytisolo, F.A., Samper, E., Edmonson, S., Taccioli, G.E., Blasco, M.A. Mol. Cell. Biol. (2001) [Pubmed]
  12. A positive role for the Ku complex in DNA replication following strand break damage in mammals. Park, S.J., Ciccone, S.L., Freie, B., Kurimasa, A., Chen, D.J., Li, G.C., Clapp, D.W., Lee, S.H. J. Biol. Chem. (2004) [Pubmed]
  13. Analysis of variable (diversity) joining recombination in DNAdependent protein kinase (DNA-PK)-deficient mice reveals DNA-PK-independent pathways for both signal and coding joint formation. Bogue, M.A., Jhappan, C., Roth, D.B. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  14. DNA repair factors and telomere-chromosome integrity in mammalian cells. Hande, M.P. Cytogenet. Genome Res. (2004) [Pubmed]
  15. Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination In vivo. Ouyang, H., Nussenzweig, A., Kurimasa, A., Soares, V.C., Li, X., Cordon-Cardo, C., Li, W., Cheong, N., Nussenzweig, M., Iliakis, G., Chen, D.J., Li, G.C. J. Exp. Med. (1997) [Pubmed]
  16. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. Espejel, S., Franco, S., Rodríguez-Perales, S., Bouffler, S.D., Cigudosa, J.C., Blasco, M.A. EMBO J. (2002) [Pubmed]
  17. Protein-protein and protein-DNA interaction regions within the DNA end-binding protein Ku70-Ku86. Wu, X., Lieber, M.R. Mol. Cell. Biol. (1996) [Pubmed]
  18. Flavopiridol, a cyclin-dependent kinase inhibitor, enhances radiosensitivity of ovarian carcinoma cells. Raju, U., Nakata, E., Mason, K.A., Ang, K.K., Milas, L. Cancer Res. (2003) [Pubmed]
  19. Enhanced sensitivity and long-term G2 arrest in hydrogen peroxide-treated Ku80-null cells are unrelated to DNA repair defects. Arrington, E.D., Caldwell, M.C., Kumaravel, T.S., Lohani, A., Joshi, A., Evans, M.K., Chen, H.T., Nussenzweig, A., Holbrook, N.J., Gorospe, M. Free Radic. Biol. Med. (2000) [Pubmed]
  20. Polyethyleneimine grafted with pluronic P85 enhances Ku86 antisense delivery and the ionizing radiation treatment efficacy in vivo. Belenkov, A.I., Alakhov, V.Y., Kabanov, A.V., Vinogradov, S.V., Panasci, L.C., Monia, B.P., Chow, T.Y. Gene Ther. (2004) [Pubmed]
  21. Collaboration of homologous recombination and nonhomologous end-joining factors for the survival and integrity of mice and cells. Couëdel, C., Mills, K.D., Barchi, M., Shen, L., Olshen, A., Johnson, R.D., Nussenzweig, A., Essers, J., Kanaar, R., Li, G.C., Alt, F.W., Jasin, M. Genes Dev. (2004) [Pubmed]
  22. Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. Gu, Y., Sekiguchi, J., Gao, Y., Dikkes, P., Frank, K., Ferguson, D., Hasty, P., Chun, J., Alt, F.W. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  23. Ku80 is required but not sufficient for Galpha13-mediated endodermal differentiation in P19 embryonic carcinoma cells. Kanungo, J., Wang, H.Y., Malbon, C.C. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  24. Effectors of mammalian telomere dysfunction: a comparative transcriptome analysis using mouse models. Franco, S., Canela, A., Klatt, P., Blasco, M.A. Carcinogenesis (2005) [Pubmed]
  25. Analysis of ku80-mutant mice and cells with deficient levels of p53. Lim, D.S., Vogel, H., Willerford, D.M., Sands, A.T., Platt, K.A., Hasty, P. Mol. Cell. Biol. (2000) [Pubmed]
  26. Molecular pathological analysis for determining the possible mechanism of piperonyl butoxide-induced hepatocarcinogenesis in mice. Muguruma, M., Nishimura, J., Jin, M., Kashida, Y., Moto, M., Takahashi, M., Yokouchi, Y., Mitsumori, K. Toxicology (2006) [Pubmed]
  27. V(D)J recombination in Ku86-deficient mice: distinct effects on coding, signal, and hybrid joint formation. Bogue, M.A., Wang, C., Zhu, C., Roth, D.B. Immunity (1997) [Pubmed]
  28. Decreased origin usage and initiation of DNA replication in haploinsufficient HCT116 Ku80+/- cells. Sibani, S., Price, G.B., Zannis-Hadjopoulos, M. J. Cell. Sci. (2005) [Pubmed]
  29. Chromosomal localization of the mouse and rat DNA double-strand break repair genes Ku p70 and Ku p80/XRCC5 and their mRNA expression in various mouse tissues. Koike, M., Matsuda, Y., Mimori, T., Harada, Y.N., Shiomi, N., Shiomi, T. Genomics (1996) [Pubmed]
  30. Early decrease in dna repair proteins, Ku70 and Ku86, and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Kim, G.W., Noshita, N., Sugawara, T., Chan, P.H. Stroke (2001) [Pubmed]
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