Mechanism and regulation of human non-homologous DNA end-joining (original) (raw)

• Haber, J. E. In vivo biochemistry: physical monitoring of recombination induced by site-specific endonucleases. BioEssays 17, 609–620 (1995).
  CAS PubMed Google Scholar
• Roth, D. & Wilson, J. in Genetic Recombination (eds Kucherlapapti, R. & Smith, G. R.) 621–653 (American Society for Microbiology, Washington DC, 1988).
  Google Scholar
• Critchlow, S. E. & Jackson, S. P. DNA end-joining: from yeast to man. Trends Biochem. Sci. 23, 394–398 (1998).
  CAS PubMed Google Scholar
• Cheong, N., Wang, X., Wang, T. & Iliakis, G. Loss of S-phase-dependent radioresistance in irs-1 cells exposed to X-rays. Mut. Res. 314, 77–85 (1994).
  CAS Google Scholar
• Takata, M. et al. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 17, 5497–5508 (1998). Determines the division of labour for the repair of DSBs at different times during the cell cycle.
  CAS PubMed PubMed Central Google Scholar
• Ma, Y., Pannicke, U., Schwarz, K. & Lieber, M. R. Hairpin opening and overhang processing by an Artemis:DNA-PKcs complex in V(D)J recombination and in nonhomologous end joining. Cell 108, 781–794 (2002). Describes the nuclease activity of Artemis and of the Artemis–DNA-PKcs complex.
  CAS PubMed Google Scholar
• National Radiation Protection Board. Living with Radiation (Reading, England, 1986).
• Chance, B., Sies, H. & Boveris, A. Hydroperoxide metabolism in mammalian organs. Physiol. Rev. 59, 527–603 (1979).
  CAS PubMed Google Scholar
• Raghavan, S. C., Kirsch, I. R. & Lieber, M. R. Analysis of the V(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints. J. Biol. Chem. 276, 29126–29133 (2001).
  CAS PubMed Google Scholar
• Marculescu, R., Le, T., Simon, P., Jaeger, U. & Nadel, B. V(D)_J_-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites. J. Exp. Med. 195, 85–98 (2002).
  CAS PubMed PubMed Central Google Scholar
• Lewis, S. M., Agard, E., Suh, S. & Czyzyk, L. Cryptic signals and the fidelity of V(D)J joining. Mol. Cell. Biol. 17, 3125–3136 (1997).
  CAS PubMed PubMed Central Google Scholar
• Kirsch, I. R. (ed.) The Causes and Consequences of Chromosomal Translocations 277–309 (CRC, Ann Arbor, 1993).
  Google Scholar
• Roth, D. B. & Wilson, J. H. Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction. Mol. Cell. Biol. 6, 4295–4304 (1986).
  CAS PubMed PubMed Central Google Scholar
• Gu, H., Förster, I. & Rajewsky, K. Sequence homologies, N sequence insertion and JH gene utililization in VHDHJH joining: implications for the joining mechanism and the ontogenetic timing of Ly1 B cell and B-CLL progenitor generation. EMBO J. 9, 2133–2140 (1990).
  CAS PubMed PubMed Central Google Scholar
• Gerstein, R. M. & Lieber, M. R. Coding end sequence can markedly affect the initiation of V(D)J recombination. Genes Dev. 7, 1459–1469 (1993).
  CAS PubMed Google Scholar
• Gerstein, R. M. & Lieber, M. R. Extent to which homology can constrain coding exon junctional diversity in V(D)J recombination. Nature 363, 625–627 (1993).
  CAS PubMed Google Scholar
• Tsukamoto, Y., Kato, J. & Ikeda, H. Silencing factors participate in DNA repair and recombination in S. cerevisiae. Nature 388, 900–903 (1997).
  CAS PubMed Google Scholar
• Wu, X., Wilson, T. E. & Lieber, M. R. A role for FEN-1 in nonhomologous DNA end joining. Proc. Natl Acad. Sci. USA 96, 1303–1308 (1999).
  CAS PubMed PubMed Central Google Scholar
• Wilson, T. & Lieber, M. R. Efficient processing of DNA ends during yeast nonhomologous end joining: evidence for a DNA polymerase β (Pol4)-dependent pathway. J. Biol. Chem. 274, 23599–23609 (1999). Describes the genetic evidence for a specific polymerase in NHEJ.
  CAS PubMed Google Scholar
• Lieber, M. R., Hesse, J. E., Mizuuchi, K. & Gellert, M. Lymphoid V(D)J recombination: nucleotide insertion at signal joints as well as coding joints. Proc. Natl Acad. Sci. USA 85, 8588–8592 (1988).
  CAS PubMed PubMed Central Google Scholar
• Agrawal, A. & Schatz, D. G. RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination. Cell 89, 43–53 (1997).
  CAS PubMed Google Scholar
• Hiom, K. & Gellert, M. Assembly of a 12/23 paired signal complex: a critical control point in V(D)J recombination. Mol. Cell 1, 1011–1019 (1998).
  CAS PubMed Google Scholar
• Lieber, M. R. et al. The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination. Cell 55, 7–16 (1988).
  CAS PubMed Google Scholar
• Anderson, C. W. & Carter, T. H. in Molecular Analysis of DNA Rearrangements in the Immune System (eds Jessberger, R. & Lieber, M. R.) 91–112 (Springer, Heidelberg, 1996).
  Google Scholar
• Falzon, M., Fewell, J. & 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
• Mimori, T. & Hardin, J. A. Mechanism of interaction between Ku protein and DNA. J. Biol. Chem. 261, 10375–10379 (1986).
  CAS PubMed Google Scholar
• deVries, E., vanDriel, W., Bergsma, W. G., Arnberg, A. C. & vanderVliet, P. C. HeLa nuclear protein recognizing DNA termini and translocating on DNA forming a regular DNA-multimeric protein complex. J. Mol. Biol. 208, 65–78 (1989).
  CAS Google Scholar
• Yaneva, M., Kowalewski, T. & Lieber, M. R. Interaction of DNA-dependent protein kinase with DNA and with Ku: biochemical and atomic-force microscopy. EMBO J. 16, 5098–5112 (1997).
  CAS PubMed PubMed Central Google Scholar
• 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). Describes the crystal structure of the doughnut-shaped Ku molecule.
  CAS PubMed Google Scholar
• West, R. B., Yaneva, M. & Lieber, M. R. Productive and nonproductive complexes of Ku and DNA-PK at DNA termini. Mol. Cell. Biol. 18, 5908–5920 (1998).
  CAS PubMed PubMed Central Google Scholar
• 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
• Chiu, C. Y., Cary, R. B., Chen, D. J., Peterson, S. R. & Steward, P. L. Cryo-EM imaging of the catalytic subunit of the DNA-dependent protein kinase. J. Mol. Biol. 284, 1075–1081 (1998). The first physical image of DNA-PKcs.
  CAS PubMed Google Scholar
• Leuther, K. K., Hammarsten, O., Kornberg, R. D. & Chu, G. Structure of the DNA-dependent protein kinase: implications for its regulation by DNA. EMBO J. 18, 1114–1123 (1999). A low-resolution X-ray diffraction model of DNA-PKcs.
  CAS PubMed PubMed Central Google Scholar
• Hammarsten, O., DeFazio, L. G. & Chu, G. Activation of DNA-dependent protein kinase by single-stranded DNA ends. J. Biol. Chem. 275, 1541–1550 (2000). Defines the types of end that activate DNA-PKcs.
  CAS PubMed Google Scholar
• Pang, D., 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
• Cary, R. B. et al. DNA looping by Ku and the DNA-dependent protein kinase. Proc. Natl Acad. Sci. USA 94, 4267–4272 (1997).
  CAS PubMed PubMed Central Google Scholar
• 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
• Tuteja, N. et al. Human DNA helicase II: a novel DNA unwinding enzyme identified as the Ku autoantigen. EMBO J. 13, 4991–5001 (1994).
  CAS PubMed PubMed Central Google Scholar
• 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
• DeFazio, L. G., Stansel, R. M., Griffith, J. D. & Chu, G. Synapsis of DNA ends by DNA-dependent protein kinase. EMBO J. 21, 3192–3200 (2002).
  CAS PubMed PubMed Central Google Scholar
• Chappell, C., Hanakahi, L. A., Karimi-Busheri, F., Weinfeld, M. & West, S. C. Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining. EMBO J. 21, 2827–2832 (2003).
  Google Scholar
• Moshous, D. et al. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105, 177–186 (2001). Identification of Artemis as a defective component in human SCID.
  CAS PubMed Google Scholar
• Moshous, D. et al. A new gene involved in DNA double-strand break repair and V(D)J recombination is located on human chromosome 10p. Hum. Mol. Genet. 9, 583–588 (2000).
  CAS PubMed Google Scholar
• Nicolas, N. et al. A human severe combined immunodeficiency condition with increased sensitivity to ionizing radiation and impaired V(D)J rearrangements defines a new DNA recombination/repair deficiency. J. Exp. Med. 188, 627–634 (1998).
  CAS PubMed PubMed Central Google Scholar
• Rooney, S. et al. Leaky scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol. Cell 10, 65–74 (2002). The Artemis -knockout mouse.
  Google Scholar
• Paull, T. T. & Gellert, M. The 3′ to 5′ exonuclease activity of Mre11 facilitates repair of DNA double-strand breaks. Mol. Cell 1, 969–979 (1998).
  CAS PubMed Google Scholar
• Paull, T. T. & Gellert, M. Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex. Genes Dev. 13, 1276–1288 (1999).
  CAS PubMed PubMed Central Google Scholar
• Paull, T. T. & Gellert, M. A mechanistic basis for the Mre11-directed DNA joining at microhomologies. Proc. Natl Acad. Sci. USA 97, 6409–6414 (2000).
  CAS PubMed PubMed Central Google Scholar
• Bender, C. F. et al. Cancer predisposition and hematopoietic failure in Rad50(S/S) mice. Genes Dev. 16, 2237–2251 (2002).
  CAS PubMed PubMed Central Google Scholar
• Harfst, E., Cooper, S., Neubauer, S., Distel, L. & Grawunder, U. Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome. Mol. Immunol. 37, 915–929 (2000).
  CAS PubMed Google Scholar
• Yeo, T. C. et al. V(D)J rearrangement in Nijmegen breakage syndrome. Mol. Immunol. 37, 1131–1139 (2000).
  CAS PubMed Google Scholar
• Mahajan, K. N., Nick McElhinny, S. A., Mitchell, B. S. & Ramsden, D. A. Association of DNA polymerase μ (pol μ) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair. Mol. Cell. Biol. 22, 5194–5202 (2002).
  CAS PubMed PubMed Central Google Scholar
• Burgers, P. M. et al. Eukaryotic DNA polymerases: proposal for a revised nomenclature. J. Biol. Chem. 276, 43487–43490 (2001).
  CAS PubMed Google Scholar
• Wilson, T. E., Grawunder, U. & Lieber, M. R. Yeast DNA ligase IV mediates non-homologous DNA end joining. Nature 388, 495–498 (1997).
  CAS PubMed Google Scholar
• Schar, P., Herrmann, G., Daly, G. & Lindahl, T. A newly identified DNA ligase of S. cerevisiae involved in RAD52-independent repair of DNA double-strand breaks. Genes Dev. 11, 1912–1924 (1997).
  CAS PubMed PubMed Central Google Scholar
• Teo, S. H. & Jackson, S. P. Identification of S. cerevisiae DNA ligase IV: involvement in DNA double-strand break repair. EMBO J. 16, 4788–4795 (1997).
  CAS PubMed PubMed Central Google Scholar
• Grawunder, U. et al. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature 388, 492–495 (1997).
  CAS PubMed Google Scholar
• Critchlow, S., Bowater, R. & Jackson, S. P. Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Curr. Biol. 7, 588–598 (1997).
  CAS PubMed Google Scholar
• Taccioli, G. E. et al. Impairment of V(D)J recombination in double-strand break repair mutants. Science 260, 207–210 (1993).
  CAS PubMed Google Scholar
• Pergola, F., Zdzienicka, M. Z. & Lieber, M. V(D)J recombination in mammalian cell mutants defective in DNA double-strand break repair. Mol. Cell. Biol. 13, 3464–3471 (1993).
  CAS PubMed PubMed Central Google Scholar
• Giaccia, A. J., Richardson, E., Denko, N. & Stamato, T. D. Genetic analysis of the XR-1 mutation in hamster and human hybrids. Somat. Cell Mol. Genet. 15, 71–79 (1989).
  CAS PubMed Google Scholar
• Stamato, T. D., Weinstein, R., Giaccia, A. & Mackenzie, L. Isolation of cell-cycle dependent ã-ray sensitive Chinese hamster ovary cell. Somat. Cell Mol. Genet. 9, 165–173 (1983).
  CAS Google Scholar
• Grawunder, U., Zimmer, D., Fugmann, S., Schwarz, K. & Lieber, M. R. DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes. Mol. Cell 2, 477–484 (1998).
  CAS PubMed Google Scholar
• Gao, Y. et al. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95, 891–902 (1998).
  CAS PubMed Google Scholar
• Frank, K. M. et al. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396, 173–177 (1998).
  CAS PubMed Google Scholar
• Herrmann, G., Lindahl, T. & Schar, P. S. cerevisiae LIF1: a function involved in DNA double-strand break repair related to mammalian XRCC4. EMBO J. 17, 4188–4198 (1998).
  CAS PubMed PubMed Central Google Scholar
• Grawunder, U., Zimmer, D., Kulesza, P. & Lieber, M. R. Requirement for an interaction of XRCC4 with DNA ligase IV for wild-type V(D)J recombination and DNA double-strand break repair in vivo. J. Biol. Chem. 273, 24708–24714 (1998).
  CAS PubMed Google Scholar
• Mizuta, R., Cheng, H. L., Gao, Y. & Alt, F. W. Molecular genetic characterization of XRCC4 function. Int. Immunol. 9, 1607–1613 (1997).
  CAS PubMed Google Scholar
• Modesti, M., Hesse, J. E. & Gellert, M. DNA binding of XRCC4 is associated with V(D)J recombination but not with stimulation of DNA ligase IV activity. EMBO J. 18, 2008–2018 (1999).
  CAS PubMed PubMed Central Google Scholar
• Robins, P. & Lindahl, T. DNA ligase IV from HeLa cell nuclei. J. Biol. Chem. 271, 24257–24261 (1996).
  CAS PubMed Google Scholar
• Junop, M. S. et al. Crystal structure of the XRCC4 DNA repair protein and implications for end joining. EMBO J. 19, 5962–5970 (2000).
  CAS PubMed PubMed Central Google Scholar
• 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
• Nick McElhinny, S. A., 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).
  CAS PubMed PubMed Central Google Scholar
• Karanjawala, Z. E. et al. The embryonic lethality in DNA ligase IV-deficient mice is rescued by deletion of Ku: implications for unifying the heterogeneous phenotypes of NHEJ mutants. DNA Repair 1, 1017–1026 (2002).
  CAS PubMed Google Scholar
• Gottlieb, T. & 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
• Merkle, D. et al. The DNA-dependent protein kinase interacts with DNA to form a protein–DNA complex that is disrupted by phosphorylation. Biochemistry 41, 12706–12714 (2002).
  PubMed Google Scholar
• Chan, D. W. et al. Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Genes Dev. 16, 2333–2338 (2002).
  CAS PubMed PubMed Central Google Scholar
• Bennett, C. B., Lewis, A. L., Baldwin, K. K. & Resnick, M. A. Lethality induced by a single site-specific double-strand break in a dispensible yeast plasmid. Proc. Natl Acad. Sci. USA 90, 5613–5617 (1993).
  CAS PubMed PubMed Central Google Scholar
• 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
• Fukushima, T. et al. Genetic analysis of DNA-PK reveals an inhibitory role of Ku in late S–G2 phase of DNA double-strand break repair. J. Biol. Chem. 276, 44413–44418 (2001).
  CAS PubMed Google Scholar
• Adachi, N., Ishino, T., Ishii, Y., Takeda, S. & Koyama, H. DNA ligase IV-deficient cells are more resistant to ionizing radiation in the absence of Ku70: implications for DNA double-strand break repair. Proc. Natl Acad. Sci. USA 98, 12109–12113 (2001).
  CAS PubMed PubMed Central Google Scholar
• Delacote, F., Han, M., Stamato, T. D., Jasin, M. & Lopez, B. S. An XRCC4 defect or Wortmannin stimulates homologous recombination specifically induced by double-strand breaks in mammalian cells. Nucleic Acids Res. 30, 3454–3463 (2002).
  CAS PubMed PubMed Central Google Scholar
• Frank-Vaillant, M. & Marcand, S. Transient stability of DNA ends allows nonhomologous DNA end joining to precede homologous recombination. Mol. Cell 10, 1189–1199 (2002).
  CAS PubMed Google Scholar
• Prince, P. R., Emond, M. J. & Monnat, R. J. Loss of Werner syndrome protein function promotes aberrant mitotic recombination. Genes Dev. 15, 933–938 (2001).
  CAS PubMed PubMed Central Google Scholar
• Saintigny, Y., Makienko, K., Swanson, C., Emond, M. J. & Monnat, R. J. Homologous recombination resolution defect in Werner syndrome. Mol. Cell. Biol. 22, 6971–6978 (2002).
  CAS PubMed PubMed Central Google Scholar
• Lieber, M. R. in The Causes and Consequences of Chromosomal Translocations (ed. Kirsch, I.) 239–275 (CRC Press, Boca Raton, 1993).
  Google Scholar
• Nussenzweig, A. et al. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 382, 551–555 (1996).
  CAS PubMed Google Scholar
• Gu, Y. et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7, 653–665 (1997).
  CAS PubMed Google Scholar
• 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
• Li, B. & Comai, L. Functional interaction between Ku and the Werner syndrome protein in DNA end processing. J. Biol. Chem. 275, 28349–28352 (2000).
  CAS PubMed Google Scholar
• Yannone, S. M. et al. Werner syndrome protein is regulated and phosphorylated by DNA-dependent protein kinase. J. Biol. Chem. 276, 38242–38248 (2001).
  CAS PubMed Google Scholar
• 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
• Veuger, S. J., Curtin, N. J., Richardson, C. J., Smith, G. C. M. & Durkacz, B. W. Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res. (in the press).
• Rouse, J. & Jackson, S. P. Interfaces between the detection, signaling and repair of DNA damage. Science 297, 547–551 (2002).
  CAS PubMed Google Scholar
• Karanjawala, Z. E., Grawunder, U., Hsieh, C. -L. & Lieber, M. R. The nonhomologous DNA end joining pathway is important for chromosome stability in primary fibroblasts. Curr. Biol. 9, 1501–1504 (1999).
  CAS PubMed Google Scholar
• Karanjawala, Z., Murphy, N., Hinton, D. R., Hsieh, C. -L. & Lieber, M. R. Oxygen metabolism causes chromosome breaks and is associated with the neuronal apoptosis observed in double-strand break repair mutants. Curr. Biol. 12, 397–402 (2002).
  CAS PubMed Google Scholar
• Difilippantonio, M. J. et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404, 510–514 (2000).
  CAS PubMed PubMed Central Google Scholar
• Gao, Y. et al. Interplay of p53 and DNA repair protein XRCC4 in tumorigenesis, genomic instability and development. Nature 404, 897–900 (2000).
  CAS PubMed Google Scholar
• Martin, G. M., Smith, A. C., Ketterer, D. J., Ogburn, C. E. & Disteche, C. M. Increased chromosomal aberrations in first metaphases of cells isolated from the kidneys of aged mice. Israel J. Med. Sci. 21, 296–301 (1985).
  CAS PubMed Google Scholar
• Bertoncini, C. R. & Meneghini, R. DNA strand breaks produced by oxidative stress in mammalian cells exhibit 3′-phosphoglycolate termini. Nucl. Acids Res. 23, 2995–3002 (1995).
  CAS PubMed PubMed Central Google Scholar