A means to a DNA end: the many roles of Ku (original) (raw)

References

  1. Mimori, T. et al. Characterization of a high molecular weight acidic nuclear protein recognised by antibodies in sera from patients with polymyositis-scleroderma overlap. J. Clin. Invest. 68, 611–620 (1981).
    CAS PubMed PubMed Central Google Scholar
  2. Mimori, T., Hardin, J. A. & Steitz, J. A. Characterization of the DNA-binding protein antigen Ku recognized by autoantibodies from patients with rheumatic disorders. J. Biol. Chem. 261, 2274–2278 (1986).
    CAS PubMed Google Scholar
  3. Francoeur, A. M., Peebles, C. L., Gompper, P. T. & Tan, E. M. Identification of KI [KU, P70/P80] autoantigens and analysis of anti-KI autoantibody reactivity. J. Immunol. 136, 1648–1653 (1986).
    CAS PubMed Google Scholar
  4. Martin, S. G., Laroche, T., Suka, N., Grunstein, M. & Gasser, S. M. Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast. Cell 97, 621–633 (1999). This paper shows that Ku dynamically associates with sites of DNA damage in vivo.
    CAS PubMed Google Scholar
  5. Koike, M., Shiomi, T. & Koike, A. Dimerization and nuclear localization of Ku proteins. J. Biol. Chem. 276, 11167–11173 (2001).
    CAS PubMed Google Scholar
  6. McAinsh, A. D., Scott-Drew, S., Murray, J. A. H. & Jackson, S. P. DNA damage triggers disruption of telomeric silencing and Mec1p-dependent relocation of Sir3p. Curr. Biol. 9, 963–966 (1999).
    CAS PubMed Google Scholar
  7. Koike, M. Dimerization, translocation and localization of Ku70 and Ku80 proteins. J. Radiat. Res. 43, 223–236 (2002).
    CAS PubMed Google Scholar
  8. Fewell, J. W. & Kuff, E. L. Intracellular redistribution of Ku immunoreactivity in response to cell–cell contact and growth modulating components in the medium. J. Cell Sci. 109, 1937–1946 (1996).
    CAS PubMed Google Scholar
  9. Sawada, M. et al. Ku70 suppresses the apoptotic translocation of Bax to mitochrondria. Nature Cell Biol. 5, 320–329 (2003).
    CAS PubMed Google Scholar
  10. Morio, T. et al. Ku in the cytoplasm associates with CD40 in human B cells and translocates into the nucleus following incubation with IL-4 and anti-CD40 mAb. Immunity 11, 339–348 (1999).
    CAS PubMed Google Scholar
  11. Gu, Y., Jin, S., Gao, Y., Weaver, D. & Alt, F. W. Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination. Proc. Natl Acad. Sci. USA 94, 8076–8081 (1997).
    CAS PubMed PubMed Central Google Scholar
  12. Singleton, B. K. et al. Molecular and biochemical characterization of xrs mutants defective in Ku80. Mol. Cell. Biol. 17, 1264–1273 (1997).
    CAS PubMed PubMed Central Google Scholar
  13. Errami, A. et al. Ku86 defines the genetic defect and restores X-ray resistance and V(D)J recombination to complementation group 5 hamster cell mutants. Mol. Cell. Biol. 16, 1519–1526 (1996).
    CAS PubMed PubMed Central Google Scholar
  14. Gu, Y. et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7, 653–665 (1997).
    CAS PubMed Google Scholar
  15. Li, G. C. et al. Ku70: a candidate tumor suppressor gene for murine T cell lymphoma. Mol. Cell 2, 1–8 (1998).
    CAS PubMed Google Scholar
  16. Vogel, H., Lim, D. -S., Karsenty, G., Finegold, M. & Hasty, P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl Acad. Sci. USA 96, 10770–10775 (1999).
    CAS PubMed PubMed Central Google Scholar
  17. Mimori, T. & Hardin, J. A. Mechanism of interaction between Ku protein and DNA. J. Biol. Chem. 261, 10375–10379 (1986).
    CAS PubMed Google Scholar
  18. Falzon, M., Fewell, J. W. & Kuff, E. L. EBP-80, a transcription factor closely resembling the human autoantigen Ku, recognizes single- to double-strand transitions in DNA. J. Biol. Chem. 268, 10546–10552 (1993).
    CAS PubMed Google Scholar
  19. Yaneva, M., Kowalewski, T. & Lieber, M. R. Interaction of DNA-dependent protein kinase with DNA and with Ku: biochemical and atomic-force microscopy studies. EMBO J. 16, 5098–5112 (1997).
    CAS PubMed PubMed Central Google Scholar
  20. Paillard, S., & Strauss, F. Analysis of the mechanism of interaction of simian Ku protein with DNA. Nucl. Acids Res. 19, 5619–5624 (1991).
    CAS PubMed PubMed Central Google Scholar
  21. Ono, M., Tucker, P. W. & Capra, J. D. Production and characterization of recombinant human Ku antigen. Nucl. Acids Res. 22, 3918–3924 (1994).
    CAS PubMed PubMed Central Google Scholar
  22. Pang, D. L., Yoo, S., Dynan, W. S., Jung, M. & Dritschilo, A. Ku proteins join DNA fragments as shown by atomic force microscopy. Cancer Res. 57, 1412–1415 (1997).
    CAS PubMed Google Scholar
  23. Blier, P. R., Griffith, A. J., Craft, J. & Hardin, J. A. Binding of Ku protein to DNA. J. Biol. Chem. 268, 7594–7601 (1993).
    CAS PubMed Google Scholar
  24. deVries, E., Vandriel, W., Bergsma, W. G., Amberg, A. C. & Vandervliet, P. C. HeLa nuclear-protein recognizing DNA termini and translocating on DNA forming a regular DNA multimeric complex. J. Mol. Biol. 208, 65–78 (1989).
    CAS Google Scholar
  25. Chiu, C. -F., Lin, T. -Y. & Chou, W. -G. Direct transfer of Ku between DNA molecules with nonhomologous ends. Mutat. Res. 486, 185–194 (2001).
    CAS PubMed Google Scholar
  26. Dynan, W. S. & Yoo, S. Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucl. Acids Res. 26, 1551–1559 (1998). A comprehensive review of the biochemical properties of Ku and DNA-PK cs.
    CAS PubMed PubMed Central Google Scholar
  27. Gell, D. & Jackson, S. P. Mapping of protein–protein interactions within the DNA-dependent protein kinase complex. Nucl. Acids Res. 27, 3494–3502 (1999).
    CAS PubMed PubMed Central Google Scholar
  28. Aravind, L. & Koonin, E. V. Prokaryotic homologs of the eukaryotic DNA-end-binding protein Ku, novel domains in the Ku protein and prediction of a prokaryotic double-strand break repair system. Genome Res. 11, 1365–1374 (2001). This report, in addition to reference 46, identified the presence of Ku homologues in prokaryotes.
    CAS PubMed PubMed Central Google Scholar
  29. Aravind, L. & Koonin, E. V. SAP — a putative DNA-binding motif involved in chromosomal organization. Trends Biochem. Sci. 25, 112–114 (2000).
    CAS PubMed Google Scholar
  30. Walker, J. R., Corpina, R. A. & Goldberg, J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412, 607–614 (2001). Report of the crystal structure of Ku alone and bound to DNA, which provided enormous insight into the biochemical properties of Ku including the mechanism of DNA binding.
    CAS PubMed Google Scholar
  31. Wang, J., Satoh, M., Chou, C. & Reeves, W. H. Similar DNA binding properties of free p70 (KU) subunit and p70/p80 heterodimer. FEBS Lets. 351, 219–224 (1994).
    CAS Google Scholar
  32. Griffith, A. J., Blier, P. R., Mimori, T. & Hardin, J. A. Ku polypeptides synthesized in vitro assemble into complexes which recognize ends of double-stranded DNA. J. Biol. Chem. 267, 331–338 (1992).
    CAS PubMed Google Scholar
  33. Zhang, Z. et al. The three-dimensional structure of the C-terminal DNA-binding domain of human Ku70. J. Biol. Chem. 276, 38231–38236 (2001).
    CAS PubMed Google Scholar
  34. Harris, R. et al. The 3D solution structure of the C-terminal region of Ku86 (Ku86CTR). J. Mol. Biol. 335, 573–582 (2004).
    CAS PubMed Google Scholar
  35. Giffen, W. et al. Sequence-specific DNA binding by Ku autoantigen and its effects on transcription. Nature 380, 265–268 (1996).
    Google Scholar
  36. Schild-Poulter, C. et al. Differential DNA binding of Ku antigen determines its involvement in DNA replication. DNA Cell Biol. 22, 65–78 (2003).
    CAS PubMed Google Scholar
  37. Gottlieb, T. M. & Jackson, S. P. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 72, 131–142 (1993).
    CAS PubMed Google Scholar
  38. Dvir, A., Peterson, S. R., Knuth, M. W., Lu, H. & Dynan, W. S. Ku autoantigen is the regulatory component of a template-associated protein kinase that phosphorylates RNA polymerase II. Proc. Natl Acad. Sci. USA 89, 11920–11924 (1992). References 37 and 38 show that Ku is a part of the DNA-dependent protein kinase in higher eukaryotes.
    CAS PubMed PubMed Central Google Scholar
  39. Suwa, A. et al. DNA-dependent protein kinase (Ku protein–p350 complex) assembles on double-stranded DNA. Proc. Natl Acad. Sci. USA 91, 6904–6908 (1994).
    CAS PubMed PubMed Central Google Scholar
  40. Hammarsten, O. & Chu, G. DNA-dependent protein kinase: DNA binding and activation in the absence of Ku. Proc. Natl Acad. Sci. USA 95, 525–530 (1998).
    CAS PubMed PubMed Central Google Scholar
  41. Chan, D. W. & Lees-Miller, S. The DNA-dependent protein kinase is inactivated by autophosphorylation of the catalytic subunit. J. Biol. Chem. 271, 8936–8941 (1996).
    CAS PubMed Google Scholar
  42. Myung, K., He, D. M., Lee, S. E. & Hendrickson, E. A. KARP-1: a novel leucine zipper protein expressed from the Ku86 autoantigen locus is implicated in the control of DNA-dependent protein kinase activity. EMBO J. 18, 3172–3184 (1997).
    Google Scholar
  43. Hanakahi, L. A. & West, S. C. Specific interaction of IP6 with human Ku70/80, the DNA-binding subunit of DNA-PK. EMBO J. 21, 2038–2044 (2002).
    CAS PubMed PubMed Central Google Scholar
  44. Ma, Y. & Lieber, M. R. Binding of inositol hexakisphosphate (IP6) to Ku but not to DNA-PKcs. J. Biol. Chem. 277, 10756–10759 (2002).
    CAS PubMed Google Scholar
  45. Hanakahi, L. A., Bartlet-Jones, M., Chappell, C., Pappin, D. & West, S. C. Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair. Cell 102, 721–729 (2000).
    CAS PubMed Google Scholar
  46. Doherty, A. J., Jackson, S. P. & Weller, G. R. Identification of bacterial homologes of the Ku DNA-repair proteins. FEBS Lett. 500, 186–188 (2001).
    CAS PubMed Google Scholar
  47. West, S. C. Molecular views of recombination proteins and their control. Nature Rev. Mol. Cell Biol. 4, 1–11 (2003).
    Google Scholar
  48. Lieber, M. R., Ma, Y., Pannicke, U. & Schwarz, K. Mechanism and regulation of human non-homologous DNA end-joining. Nature Rev. Mol. Cell Biol. 4, 712–720 (2003). A comprehensive review of NHEJ.
    CAS Google Scholar
  49. Jeggo, P. A., Taccioli, G. E. & Jackson, S. P. Menage a trois: double strand break repair, V(D)J recombination and DNA-PK. Bioessays 17, 949–957 (1995).
    CAS PubMed Google Scholar
  50. Ferguson, D. O. & Alt, F. W. DNA double strand break repair and chromosomal translocation: lessons from animal models. Oncogene 20, 5572–5579 (2001).
    CAS PubMed Google Scholar
  51. Smith, G. C. M. & Jackson, S. P. The DNA-dependent protein kinase. Genes Dev. 13, 916–934 (1999).
    CAS PubMed Google Scholar
  52. Baumann, P. & West, S. C. DNA end-joining cayalyzed by human cell free extracts. Proc. Natl Acad. Sci. USA 95, 14066–14070 (1998).
    CAS PubMed PubMed Central Google Scholar
  53. Labhart, P. Nonhomologous DNA end joining in cell-free systems. Eur. J. Biochem. 265, 849–861 (1999).
    CAS PubMed Google Scholar
  54. Ramsden, D. A. & Gellert, M. Ku protein stimulates DNA end joining by mammalian DNA ligases: a direct role for Ku in repair of DNA double-strand breaks. EMBO J. 17, 609–614 (1998).
    CAS PubMed PubMed Central Google Scholar
  55. McElhinny, S. A. N., Snowden, C. M., McCarville, J. & Ramsden, D. A. Ku recruits the XRCC4-ligase IV complex to DNA ends. Mol. Cell. Biol. 20, 2996–3003 (2000).
    Google Scholar
  56. Chen, L., Trujillo, K., Sung, P. & Tomkinson, A. E. Interactions of the DNA ligase IV–XRCC4 complex with DNA ends and the DNA-dependent protein kinase. J. Biol. Chem. 275, 26196–26205 (2000).
    CAS PubMed Google Scholar
  57. Feldmann, H. & Winnacker, E. L. A putative homologue of the human autoantigen Ku from Saccharomyces cerevisiae. J. Biol. Chem. 268, 12895–12900 (1993).
    CAS PubMed Google Scholar
  58. Siede, W., Friedl, A. A., Dianova, I., Eckardt-Schupp, F. & Friedberg, E. C. The Saccharomyces cerevisiae Ku autoantigen homologue affects radiosensitivity only in the absence of homologous recombination. Genetics 142, 91–102 (1996).
    CAS PubMed PubMed Central Google Scholar
  59. Boulton, S. J. & Jackson, S. P. Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J. 15, 5093–5103 (1996).
    CAS PubMed PubMed Central Google Scholar
  60. Tsukamoto, Y., Kato, J. & Ikeda, H. Hdf1, a yeast Ku protein homologue, is involved in illegitimate recombination, but not in homologous recombination. Nucl. Acids Res. 24, 2067–2072 (1996).
    CAS PubMed PubMed Central Google Scholar
  61. Milne, G. T., Jin, S., Shannon, K. B. & Weaver, D. T. Mutations in two Ku homologues define a DNA end-joining repair pathway in Saccharomyces cerevisiae. Mol. Cell. Biol. 16, 4189–4198 (1996). References 57–61 were instrumental in demonstrating Ku-dependent NHEJ in S. cerevisiae.
    CAS PubMed PubMed Central Google Scholar
  62. Barnes, G. & Rio, D. DNA double-strand break sensitivity, DNA replication, and cell cycle arrest phenotypes of Ku-deficient Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 94, 867–872 (1997).
    CAS PubMed PubMed Central Google Scholar
  63. Chen, L., Trujillo, K., Ramos, W., Sung, P. & Tomkinson, A. E. Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes. Mol. Cell 8, 1105–1115 (2001).
    CAS PubMed Google Scholar
  64. West, C. E. et al. Disruption of the Arabidopsis AtKu80 gene demonstrates an essential role for AtKu80 protein in efficient repair of DNA double-strand breaks in vivo. Plant J. 31, 517–528 (2002).
    CAS PubMed Google Scholar
  65. Gallego, M. E., Bleuyard, J. -Y., Daoudal-Cotterell, S., Jallut, N. & White, C. I. Ku80 plays a role in non-homologous recombination but is not required for T-DNA integration in Arabidopsis. Plant J. 35, 557–565 (2003).
    CAS PubMed Google Scholar
  66. Kooistra, R., Pastink, A., Zonneveld, J. B. M., Lohman, P. H. M. & Eeken, J. C. J. The Drosophila melanogaster DmRAD54 gene plays a crucial role in double-strand break repair after P-element excision and acts synergistically with Ku70 in the repair of X-ray damage. Mol. Cell. Biol. 19, 6269–6275 (1999).
    CAS PubMed PubMed Central Google Scholar
  67. Conway, C. et al. Ku is important for telomere maintenance, but not for differential expression of telomeric VSG genes, in African trypanosomes. J. Biol. Chem. 277, 21269–21277 (2002).
    CAS PubMed Google Scholar
  68. Weller, G. R. et al. Identification of a DNA nonhomologous end-joining complex in bacteria. Science 297, 1686–1689 (2002). Shows that the putative Ku homologues from prokaryotes are functional homologues and are likely to have a role in NHEJ in bacteria.
    CAS PubMed Google Scholar
  69. Lee, S. E. et al. Saccharomyces Ku70, Mre11/Rad50, and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 399–409 (1998).
  70. Liang, F. & Jasin, M. Ku80-deficient cells exhibit excess degradation of extrachromosomal DNA. J. Biol. Chem. 271, 14405–14411 (1996).
    CAS PubMed Google Scholar
  71. Hsu, H. -L., Yannone, S. M. & Chen, D. J. Defining interactions between DNA-PK and ligase IV/XRCC4. DNA Repair 1, 225–235 (2002).
    CAS PubMed Google Scholar
  72. Karmakar, P., Snowden, C. M., Ramsden, D. A. & Bohr, V. A. Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus. Nucl. Acids Res. 30, 3583–3591 (2002).
    CAS PubMed PubMed Central Google Scholar
  73. Cooper, M. P. et al. Ku complex interacts with and stimulates the Werner protein. Genes Dev. 14, 907–912 (2000).
    CAS PubMed PubMed Central Google Scholar
  74. Goedecke, W., Eijpe, M., Offenberg, H. H., van Aalderen, M. & Heyting, C. Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis. Nature Genet. 23, 194–198 (1999).
    CAS PubMed Google Scholar
  75. Galande, S. & Kohwi-Shigematsu, T. Poly(ADP-ribose) polymerase and Ku autoantigen form a complex and synergistically bind to matrix attachment sequences. J. Biol. Chem. 274, 20521–20528 (1999).
    CAS PubMed Google Scholar
  76. Van Dyck, E., Stasiak, A. Z., Stasiak, A. & West, S. C. Binding of double-strand breaks in DNA by human Rad52 protein. Nature 398, 728–731 (1999).
    CAS PubMed Google Scholar
  77. Pierce, A. J., Hu, P., Han, M., Ellis, N. & Jasin, M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 15, 3237–3242 (2001).
    CAS PubMed PubMed Central Google Scholar
  78. Allen, C., Kurimasa, A., Brenneman, M. A., Chen, D. J. & Nickoloff, J. A. DNA-dependent protein kinase suppresses double-strand break-induced and spontaneous homologous recombination. Proc. Natl Acad. Sci. USA 99, 3758–3763 (2002).
    CAS PubMed PubMed Central Google Scholar
  79. Ristic, D., Modesti, M., Kanaar, R. & Wyman, C. Rad52 and Ku bind to different DNA structures produced early in double-strand break repair. Nucl. Acids Res. 31, 5229–5237 (2003).
    CAS PubMed PubMed Central Google Scholar
  80. Rodgers, W., Jordan, S. J. & Capra, J. D. Transient association of Ku with nuclear substrates characterized using fluorescence photobleaching. J. Immunol. 168, 2348–2355 (2002).
    CAS PubMed Google Scholar
  81. Yavuzer, U., Smith, G. C. M., Bliss, T., Werner, D. & Jackson, S. P. DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D. Genes Dev. 12, 2188–2199 (1998).
    CAS PubMed PubMed Central Google Scholar
  82. Wang, X., Li, G. C., Iliakis, G. & Wang, Y. Ku affects the CHK1-dependent G2 checkpoint after ionizing radiation. Cancer Res. 62, 6031–6034 (2002).
    CAS PubMed Google Scholar
  83. Zhou, X. -Y. et al. Ku affects the ATM-dependent S phase checkpoint following ionizing radiation. Oncogene 21, 6377–6381 (2002).
    CAS PubMed Google Scholar
  84. Casellas, R. et al. Ku80 is required for immunoglobulin isotype switching. EMBO J. 17, 2404–2411 (1998).
    CAS PubMed PubMed Central Google Scholar
  85. Manis, J. P. et al. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J. Exp. Med. 187, 2081–2089 (1998).
    CAS PubMed PubMed Central Google Scholar
  86. Taccioli, G. E. et al. Ku80: Product of the XRCC5 gene and its role in DNA repair and V(D)J recombination. Science 265, 1442–1445 (1994).
    CAS PubMed Google Scholar
  87. Bassing, C. H., Swat, W. & Alt, F. W. The mechanism and regulation of chromosomal V(D)J recombination. Cell 109, S45–S55 (2002).
    CAS PubMed Google Scholar
  88. Zhu, C., Bogue, M. A., Lim, D., Hasty, P. & Roth, D. B. Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates. Cell 86, 379–389 (1996).
    CAS PubMed Google Scholar
  89. Kulesza, P. & Lieber, M. R. DNA-PK is essential only for coding joint formation in V(D)J recombination. Nucl. Acids Res. 26, 3944–3948 (1998).
    CAS PubMed PubMed Central Google Scholar
  90. Nussenzweig, A. et al. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 382, 551–555 (1996).
    CAS PubMed Google Scholar
  91. Barnes, D. E., Stamp, G., Rosewell, I., Denzel, A. & Lindahl, T. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr. Biol. 8, 1395–1398 (1998).
    CAS PubMed Google Scholar
  92. Han, J., Steen, S. B. & Roth, D. B. Ku86 is not required for protection of signal ends or for formation of nonstandard V(D)J recombination products. Mol. Cell. Biol. 17, 2226–2234 (1997).
    CAS PubMed PubMed Central Google Scholar
  93. Purugganan, M. M., Shah, S., Kearney, J. F. & Roth, D. B. Ku80 is required for addition of N nucleotides to V(D)J recombination junctions by terminal deoxynucleotidyl transferase. Nucl. Acids Res. 29, 1638–1646 (2001).
    CAS PubMed PubMed Central Google Scholar
  94. Mills, K. D., Ferguson, D. O. & Alt, F. W. The role of DNA breaks in genomic instability and tumorigenesis. Immunol. Rev. 194, 77–95 (2003).
    CAS PubMed Google Scholar
  95. Difilippantonio, M. J. et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404, 510–514 (2000). The first demonstration that Ku functions to prevent tumourigenesis in mammals.
    CAS PubMed PubMed Central Google Scholar
  96. Downs, J. A. & Jackson, S. P. Involvement of DNA end-binding protein Ku in Ty element retrotransposition. Mol. Cell. Biol. 19, 6260–6268 (1999).
    CAS PubMed PubMed Central Google Scholar
  97. Daniel, R., Katz, R. A. & Skalka, A. M. A role for DNA-PK in retroviral DNA integration. Science 284, 644–647 (1999).
    CAS PubMed Google Scholar
  98. Li, L. et al. Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection. EMBO J. 20, 3272–3281 (2001). References 96, 97 and 98 show the involvement of Ku in retroelement integration, in which there is no DNA DSB created in the host genome.
    CAS PubMed PubMed Central Google Scholar
  99. d'Adda di Fagagna, F., Weller, G. R., Doherty, A. J. & Jackson, S. P. The Gam protein of bacteriophage Mu is an orthologue of eukaryotic Ku. EMBO Rep. 4, 47–52 (2003).
    CAS PubMed Google Scholar
  100. Akroyd, J. & Symonds, N. Localization of the gam gene of bacteriophage Mu and characterisation of the gene product. Gene 49, 273–282 (1986).
    CAS PubMed Google Scholar
  101. Abraham, Z. H. L. & Symonds, N. Purification of overexpressed gam gene protein from bacteriophage Mu by denaturation-renaturation techniques and a study of its DNA-binding properties. Biochem. J. 269, 679–684 (1990).
    CAS PubMed PubMed Central Google Scholar
  102. Hediger, F., Neumann, F. R., Van Houwe, G., Dubrana, K. & Gasser, S. M. Live imaging of telomeres: yKu and Sir proteins define redundant telomere-anchoring pathways. Curr. Biol. 12, 2076–2089 (2002).
    CAS PubMed Google Scholar
  103. Nugent, C. I. et al. Telomere maintenance is dependent on activities required for end repair of double-strand breaks. Curr. Biol. 8, 657–660 (1998).
    CAS PubMed Google Scholar
  104. Boulton, S. J. & Jackson, S. P. Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. EMBO J. 17, 1819–1828 (1998).
    CAS PubMed PubMed Central Google Scholar
  105. Gravel, S., Larrivee, M., Labrecque, P. & Wellinger, R. J. Yeast Ku as a regulator of chromosomal DNA end structure. Science 280, 741–744 (1998).
    CAS PubMed Google Scholar
  106. Porter, S. E., Greenwell, P. W., Ritchie, K. B. & Petes, T. D. The DNA-binding protein Hdf1p (a putative Ku homologue) is required for maintaining normal telomere length in Saccharomyces cerevisiae. Nucl. Acids Res. 24, 582–585 (1996).
    CAS PubMed PubMed Central Google Scholar
  107. Gravel, S. & Wellinger, R. J. Maintenance of double-stranded telomeric repeats as the critical determinant for cell viability in yeast cells lacking Ku. Mol. Cell. Biol. 22, 2182–2193 (2002).
    CAS PubMed PubMed Central Google Scholar
  108. Cosgrove, A. J., Nieduszynski, C. A. & Donaldson, A. D. Ku complex controls the replication time of DNA in telomere regions. Genes Dev. 16, 2485–2490 (2002).
    CAS PubMed PubMed Central Google Scholar
  109. Bertuch, A. A. & Lundblad, V. The Ku heterodimer performs separable activities at double strand breaks and chromosome termini. Mol. Cell. Biol. 23, 8202–8215 (2003).
    CAS PubMed PubMed Central Google Scholar
  110. Stellwagen, A. E., Haimberger, Z. W., Veatch, J. R. & Gottschling, D. E. Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev. 17, 2384–2395 (2003).
    CAS PubMed PubMed Central Google Scholar
  111. Roy, R., Meier, B., McAinsh, A. D., Feldmann, H. M. & Jackson, S. P. Separation-of-function mutants of yeast Ku80 reveal a Yku80p–Sir4p interaction involved in telomeric silencing. J. Biol. Chem. 279, 86–94 (2004). References 109, 110 and 111 report the identification of separation-of-function mutations in Ku80, which show separate roles for Ku in NHEJ and at telomeres.
    CAS PubMed Google Scholar
  112. Baumann, P. & Cech, T. R. Protection of telomeres by the Ku protein in fission yeast. Mol. Biol. Cell 11, 3265–3275 (2000).
    CAS PubMed PubMed Central Google Scholar
  113. Riha, K., Watson, J. M., Parkey, J. & Shippen, D. E. Telomere length deregulation and enhanced sensitivity to genotoxic stress in Arabidopsis mutants deficient in Ku70. EMBO J. 21, 2819–2826 (2002).
    CAS PubMed PubMed Central Google Scholar
  114. Bundock, P., van Attikum, H. & Hooykaas, P. Increased telomere length and hypersensitivity to DNA damaging agents in an Arabidopsis KU70 mutant. Nucl. Acids Res. 30, 3395–3400 (2002).
    CAS PubMed PubMed Central Google Scholar
  115. Miyoshi, T., Sadaie, M., Kanoh, J. & Ishikawa, F. Telomeric DNA ends are essential for the localization of Ku at telomeres in fission yeast. J. Biol. Chem. 278, 1924–1931 (2003).
    CAS PubMed Google Scholar
  116. Hsu, H., Gilley, D., Blackburn, E. H. & Chen, D. J. Ku is associated with the telomere in mammals. Proc. Natl Acad. Sci. USA 96, 12454–12458 (1999).
    CAS PubMed PubMed Central Google Scholar
  117. d'Adda di Fagagna, F. et al. Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr. Biol. 11, 1192–1196 (2001).
    CAS PubMed Google Scholar
  118. Chai, W., Ford, L. P., Lenertz, L., Wright, W. E. & Shay, J. W. Human Ku70/80 associates physically with telomerase through interaction with hTERT. J. Biol. Chem. 277, 47242–47247 (2002).
    CAS PubMed Google Scholar
  119. Espejel, S. et al. Mammalian Ku86 mediates chromosome fusions and apoptosis caused by critically short telomeres. EMBO J. 21, 2207–2219 (2002).
    CAS PubMed PubMed Central Google Scholar
  120. Smogorzewska, A., Karlseder, J., Holtgreve-Grez, H., Jauch, A. & de Lange, T. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr. Biol. 12, 1635–1644 (2002).
    CAS PubMed Google Scholar
  121. Mo, X. & Dynan, W. S. Subnuclear localization of Ku protein: functional association with RNA polymerase II elongation sites. Mol. Cell. Biol. 22, 8088–8099 (2002).
    CAS PubMed PubMed Central Google Scholar
  122. Woodard, R. L., Lee, K., Huang, J. & Dynan, W. S. Distinct roles for Ku protein in transcriptional reinitiation and DNA repair. J. Biol. Chem. 276, 15423–15433 (2001).
    CAS PubMed Google Scholar
  123. Kuhn, A., Gottleib, T. M., Jackson, S. P. & Grummt, I. DNA-dependent protein kinase: a potent inhibitor of transcription by RNA polymerase I. Genes Dev. 9, 193–203 (1995).
    CAS PubMed Google Scholar
  124. Manis, J., Tian, M. & Alt, F. W. Mechanism and control of class-switch recombination. Trends Immunol. 23, 31–39 (2002).
    CAS PubMed Google Scholar
  125. Neuberger, M. S., Harris, R. S., Di Noia, J. & Petersen-Mahrt, S. K. Immunity through DNA deamination. Trends Biochem. Sci. 28, 305–312 (2003).
    CAS PubMed Google Scholar

Download references