Movatterモバイル変換

[0]ホーム
URL:

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Nature Reviews Molecular Cell Biology
  • Review Article
  • Published:

Mechanism and regulation of human non-homologous DNA end-joining

Nature Reviews Molecular Cell Biologyvolume 4, pages712–720 (2003)Cite this article

Key Points

  • In multicellular eukaryotes, non-homologous DNA end-joining (NHEJ) is the primary pathway for repairing double-stranded DNA breaks (DSBs). The other important pathway for the repair of such breaks is homologous recombination, which is restricted to late S and G2 phases in dividing cells.

  • Pathological DSBs result when there is replication across a nick, when ionizing radiation passes near the DNA, and when reactive-oxygen species contact DNA. Such breaks are repaired by NHEJ when they occur in G0, G1 or early S phases of the cell cycle, and often even during late S and G2 phases.

  • Physiological DSBs result duringV(D)J recombination and class-switch recombination. The rejoining phase of these two processes uses NHEJ.

  • NHEJ is typically imprecise in multicellular eukaryotes, making it the only main DNA-repair pathway that is error prone.

  • Because of its error-prone nature, NHEJ might contribute to cancer and ageing.

  • Defects in NHEJ result in sensitivity to ionizing radiation and in a lack of lymphocytes. The lack of lymphocytes results from the loss of the ability to completeV(D)J recombination. In humans, mutations in Artemis are responsible for about 15% of cases of severe combined immune deficiency syndrome. Artemis, in complex with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), is responsible for trimming the DNA ends in NHEJ.

Abstract

Non-homologous DNA end-joining (NHEJ) — the main pathway for repairing double-stranded DNA breaks — functions throughout the cell cycle to repair such lesions. Defects in NHEJ result in marked sensitivity to ionizing radiation and ablation of lymphocytes, which rely on NHEJ to complete the rearrangement of antigen-receptor genes. NHEJ is typically imprecise, a characteristic that is useful for immune diversification in lymphocytes, but which might also contribute to some of the genetic changes that underlie cancer and ageing.

This is a preview of subscription content,access via your institution

Access options

Access through your institution

Subscription info for Japanese customers

We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

￥ 4,980

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Physiological and pathological DNA breaks and their rejoining in vertebrates.
Figure 2: Non-homologous DNA end-joining and the proteins involved in vertebrates.
Figure 3: The Artemis–DNA-PKcs complex in NHEJ.

Similar content being viewed by others

References

  1. Haber, J. E.In vivo biochemistry: physical monitoring of recombination induced by site-specific endonucleases.BioEssays17, 609–620 (1995).

    CAS PubMed  Google Scholar 

  2. Roth, D. & Wilson, J. inGenetic Recombination (eds Kucherlapapti, R. & Smith, G. R.) 621–653 (American Society for Microbiology, Washington DC, 1988).

    Google Scholar 

  3. Critchlow, S. E. & Jackson, S. P. DNA end-joining: from yeast to man.Trends Biochem. Sci.23, 394–398 (1998).

    CAS PubMed  Google Scholar 

  4. 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 

  5. 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 

  6. Ma, Y., Pannicke, U., Schwarz, K. & Lieber, M. R. Hairpin opening and overhang processing by an Artemis:DNA-PKcs complex inV(D)J recombination and in nonhomologous end joining.Cell108, 781–794 (2002).Describes the nuclease activity of Artemis and of the Artemis–DNA-PKcs complex.

    CAS PubMed  Google Scholar 

  7. National Radiation Protection Board.Living with Radiation (Reading, England, 1986).

  8. Chance, B., Sies, H. & Boveris, A. Hydroperoxide metabolism in mammalian organs.Physiol. Rev.59, 527–603 (1979).

    CAS PubMed  Google Scholar 

  9. Raghavan, S. C., Kirsch, I. R. & Lieber, M. R. Analysis of theV(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints.J. Biol. Chem.276, 29126–29133 (2001).

    CAS PubMed  Google Scholar 

  10. 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 

  11. Lewis, S. M., Agard, E., Suh, S. & Czyzyk, L. Cryptic signals and the fidelity ofV(D)J joining.Mol. Cell. Biol.17, 3125–3136 (1997).

    CAS PubMed PubMed Central  Google Scholar 

  12. Kirsch, I. R. (ed.)The Causes and Consequences of Chromosomal Translocations 277–309 (CRC, Ann Arbor, 1993).

    Google Scholar 

  13. 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 

  14. 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 

  15. Gerstein, R. M. & Lieber, M. R. Coding end sequence can markedly affect the initiation ofV(D)J recombination.Genes Dev.7, 1459–1469 (1993).

    CAS PubMed  Google Scholar 

  16. Gerstein, R. M. & Lieber, M. R. Extent to which homology can constrain coding exon junctional diversity inV(D)J recombination.Nature363, 625–627 (1993).

    CAS PubMed  Google Scholar 

  17. Tsukamoto, Y., Kato, J. & Ikeda, H. Silencing factors participate in DNA repair and recombination inS. cerevisiae.Nature388, 900–903 (1997).

    CAS PubMed  Google Scholar 

  18. Wu, X., Wilson, T. E. & Lieber, M. R. A role for FEN-1 in nonhomologous DNA end joining.Proc. Natl Acad. Sci. USA96, 1303–1308 (1999).

    CAS PubMed PubMed Central  Google Scholar 

  19. 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 

  20. Lieber, M. R., Hesse, J. E., Mizuuchi, K. & Gellert, M. LymphoidV(D)J recombination: nucleotide insertion at signal joints as well as coding joints.Proc. Natl Acad. Sci. USA85, 8588–8592 (1988).

    CAS PubMed PubMed Central  Google Scholar 

  21. Agrawal, A. & Schatz, D. G. RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends inV(D)J recombination.Cell89, 43–53 (1997).

    CAS PubMed  Google Scholar 

  22. Hiom, K. & Gellert, M. Assembly of a 12/23 paired signal complex: a critical control point inV(D)J recombination.Mol. Cell1, 1011–1019 (1998).

    CAS PubMed  Google Scholar 

  23. Lieber, M. R. et al. The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments inV(D)J recombination.Cell55, 7–16 (1988).

    CAS PubMed  Google Scholar 

  24. Anderson, C. W. & Carter, T. H. inMolecular Analysis of DNA Rearrangements in the Immune System (eds Jessberger, R. & Lieber, M. R.) 91–112 (Springer, Heidelberg, 1996).

    Google Scholar 

  25. 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 

  26. Mimori, T. & Hardin, J. A. Mechanism of interaction between Ku protein and DNA.J. Biol. Chem.261, 10375–10379 (1986).

    CAS PubMed  Google Scholar 

  27. 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 

  28. 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 

  29. Walker, J. R., Corpina, R. A. & Goldberg, J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair.Nature412, 607–614 (2001).Describes the crystal structure of the doughnut-shaped Ku molecule.

    CAS PubMed  Google Scholar 

  30. 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 

  31. Hammarsten, O. & Chu, G. DNA-dependent protein kinase: DNA binding and activation in the absence of Ku.Proc. Natl Acad. Sci. USA95, 525–530 (1998).

    CAS PubMed PubMed Central  Google Scholar 

  32. 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 

  33. 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 

  34. 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 

  35. 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 

  36. Cary, R. B. et al. DNA looping by Ku and the DNA-dependent protein kinase.Proc. Natl Acad. Sci. USA94, 4267–4272 (1997).

    CAS PubMed PubMed Central  Google Scholar 

  37. 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 

  38. 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 

  39. 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 

  40. 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 

  41. 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 

  42. 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.Cell105, 177–186 (2001).Identification of Artemis as a defective component in human SCID.

    CAS PubMed  Google Scholar 

  43. Moshous, D. et al. A new gene involved in DNA double-strand break repair andV(D)J recombination is located on human chromosome 10p.Hum. Mol. Genet.9, 583–588 (2000).

    CAS PubMed  Google Scholar 

  44. Nicolas, N. et al. A human severe combined immunodeficiency condition with increased sensitivity to ionizing radiation and impairedV(D)J rearrangements defines a new DNA recombination/repair deficiency.J. Exp. Med.188, 627–634 (1998).

    CAS PubMed PubMed Central  Google Scholar 

  45. Rooney, S. et al. Leakyscid phenotype associated with defectiveV(D)J coding end processing in Artemis-deficient mice.Mol. Cell10, 65–74 (2002).TheArtemis-knockout mouse.

    Google Scholar 

  46. Paull, T. T. & Gellert, M. The 3′ to 5′ exonuclease activity of Mre11 facilitates repair of DNA double-strand breaks.Mol. Cell1, 969–979 (1998).

    CAS PubMed  Google Scholar 

  47. 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 

  48. Paull, T. T. & Gellert, M. A mechanistic basis for the Mre11-directed DNA joining at microhomologies.Proc. Natl Acad. Sci. USA97, 6409–6414 (2000).

    CAS PubMed PubMed Central  Google Scholar 

  49. 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 

  50. Harfst, E., Cooper, S., Neubauer, S., Distel, L. & Grawunder, U. NormalV(D)J recombination in cells from patients with Nijmegen breakage syndrome.Mol. Immunol.37, 915–929 (2000).

    CAS PubMed  Google Scholar 

  51. Yeo, T. C. et al.V(D)J rearrangement in Nijmegen breakage syndrome.Mol. Immunol.37, 1131–1139 (2000).

    CAS PubMed  Google Scholar 

  52. 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 

  53. Burgers, P. M. et al. Eukaryotic DNA polymerases: proposal for a revised nomenclature.J. Biol. Chem.276, 43487–43490 (2001).

    CAS PubMed  Google Scholar 

  54. Wilson, T. E., Grawunder, U. & Lieber, M. R. Yeast DNA ligase IV mediates non-homologous DNA end joining.Nature388, 495–498 (1997).

    CAS PubMed  Google Scholar 

  55. Schar, P., Herrmann, G., Daly, G. & Lindahl, T. A newly identified DNA ligase ofS. cerevisiae involved in RAD52-independent repair of DNA double-strand breaks.Genes Dev.11, 1912–1924 (1997).

    CAS PubMed PubMed Central  Google Scholar 

  56. Teo, S. H. & Jackson, S. P. Identification ofS. cerevisiae DNA ligase IV: involvement in DNA double-strand break repair.EMBO J.16, 4788–4795 (1997).

    CAS PubMed PubMed Central  Google Scholar 

  57. Grawunder, U. et al. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells.Nature388, 492–495 (1997).

    CAS PubMed  Google Scholar 

  58. 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 

  59. Taccioli, G. E. et al. Impairment ofV(D)J recombination in double-strand break repair mutants.Science260, 207–210 (1993).

    CAS PubMed  Google Scholar 

  60. 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 

  61. 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 

  62. 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 

  63. Grawunder, U., Zimmer, D., Fugmann, S., Schwarz, K. & Lieber, M. R. DNA ligase IV is essential forV(D)J recombination and DNA double-strand break repair in human precursor lymphocytes.Mol. Cell2, 477–484 (1998).

    CAS PubMed  Google Scholar 

  64. Gao, Y. et al. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis.Cell95, 891–902 (1998).

    CAS PubMed  Google Scholar 

  65. Frank, K. M. et al. Late embryonic lethality and impairedV(D)J recombination in mice lacking DNA ligase IV.Nature396, 173–177 (1998).

    CAS PubMed  Google Scholar 

  66. 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 

  67. Grawunder, U., Zimmer, D., Kulesza, P. & Lieber, M. R. Requirement for an interaction of XRCC4 with DNA ligase IV for wild-typeV(D)J recombination and DNA double-strand break repairin vivo.J. Biol. Chem.273, 24708–24714 (1998).

    CAS PubMed  Google Scholar 

  68. 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 

  69. Modesti, M., Hesse, J. E. & Gellert, M. DNA binding of XRCC4 is associated withV(D)J recombination but not with stimulation of DNA ligase IV activity.EMBO J.18, 2008–2018 (1999).

    CAS PubMed PubMed Central  Google Scholar 

  70. Robins, P. & Lindahl, T. DNA ligase IV from HeLa cell nuclei.J. Biol. Chem.271, 24257–24261 (1996).

    CAS PubMed  Google Scholar 

  71. 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 

  72. 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 

  73. 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 

  74. 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 Repair1, 1017–1026 (2002).

    CAS PubMed  Google Scholar 

  75. Gottlieb, T. & Jackson, S. P. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen.Cell72, 131–142 (1993).

    CAS PubMed  Google Scholar 

  76. Merkle, D. et al. The DNA-dependent protein kinase interacts with DNA to form a protein–DNA complex that is disrupted by phosphorylation.Biochemistry41, 12706–12714 (2002).

    PubMed  Google Scholar 

  77. 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 

  78. 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. USA90, 5613–5617 (1993).

    CAS PubMed PubMed Central  Google Scholar 

  79. 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 

  80. 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 

  81. 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. USA98, 12109–12113 (2001).

    CAS PubMed PubMed Central  Google Scholar 

  82. 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 

  83. Frank-Vaillant, M. & Marcand, S. Transient stability of DNA ends allows nonhomologous DNA end joining to precede homologous recombination.Mol. Cell10, 1189–1199 (2002).

    CAS PubMed  Google Scholar 

  84. 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 

  85. 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 

  86. Lieber, M. R. inThe Causes and Consequences of Chromosomal Translocations (ed. Kirsch, I.) 239–275 (CRC Press, Boca Raton, 1993).

    Google Scholar 

  87. Nussenzweig, A. et al. Requirement for Ku80 in growth and immunoglobulinV(D)J recombination.Nature382, 551–555 (1996).

    CAS PubMed  Google Scholar 

  88. Gu, Y. et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice.Immunity7, 653–665 (1997).

    CAS PubMed  Google Scholar 

  89. 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. USA96, 10770–10775 (1999).

    CAS PubMed PubMed Central  Google Scholar 

  90. 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 

  91. 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 

  92. Li, G. C. et al. Ku70: a candidate tumor suppressor gene for murine T cell lymphoma.Mol. Cell2, 1–8 (1998).

    CAS PubMed  Google Scholar 

  93. 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).

  94. Rouse, J. & Jackson, S. P. Interfaces between the detection, signaling and repair of DNA damage.Science297, 547–551 (2002).

    CAS PubMed  Google Scholar 

  95. 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 

  96. 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 

  97. Difilippantonio, M. J. et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation.Nature404, 510–514 (2000).

    CAS PubMed PubMed Central  Google Scholar 

  98. Gao, Y. et al. Interplay of p53 and DNA repair protein XRCC4 in tumorigenesis, genomic instability and development.Nature404, 897–900 (2000).

    CAS PubMed  Google Scholar 

  99. 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 

  100. 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 

Download references

Author information

Authors and Affiliations

  1. Departments of Pathology, Norris Comprehensive Cancer Center, Biochemistry and Molecular Biology, Microbiology, and Biology, University of Southern California School of Medicine, 1441 Eastlake Avenue, MS 9176, Los Angeles, 90089, California, USA

    Michael R. Lieber & Yunmei Ma

  2. Department of Transfusion Medicine, University of Ulm, Institute for Clinical Transfusion Medicine and Immunogenetics, Ulm, D-89081, Germany

    Ulrich Pannicke & Klaus Schwarz

Authors
  1. Michael R. Lieber
  2. Yunmei Ma
  3. Ulrich Pannicke
  4. Klaus Schwarz

Corresponding authors

Correspondence toMichael R. Lieber orKlaus Schwarz.

Glossary

ROBERTSONIAN TRANSLOCATION

A type of chromosomal translocation in which two acrocentric chromosomes become linked at their centromeres.

HAPLOINSUFFICIENCY

In a diploid organism, if both alleles are wild type or mutant, then the phenotype can be described as wild type or mutant. If one allele is mutant and the other is wild type, the organism typically appears wild type. However, for some genes, a phenotype arises even in these heterozygotes because half of the amount of the encoded protein is not sufficient. This is known as haploinsufficiency.

RAG COMPLEX

Immunoglobin heavy and light genes and T-cell-receptor genes are assembled from germline variable- and constant-region gene segments by a DNA recombination process in B and T cells, respectively. These gene rearrangements depend on the expression of recombination-activating genes (RAG)1 andRAG2.

V(D)J RECOMBINATION

A specialized form of recombination that assembles the genes that encode lymphocyte antigen receptors from variable (V), diversity (D) and joining (J) gene segments. Double-stranded DNA breaks are introduced between theV,D andJ segments and DNA-repair proteins then join the segments together.

TYPE II TOPOISOMERASE

Whereas type I topoisomerases nick one strand and thereby change supercoiling (actually the linking number) in steps of one, type II topoisomerases make a double-stranded DNA break, thereby changing the supercoiling in steps of two.

BREATHING

The hydrogen bonds within the Watson–Crick DNA helix are thought to transiently and focally 'melt'. Such breathing varies with the local sequence, particularly the A–T content. The length of DNA, duration and frequency of such sites of breathing has been studied for short test sequences, but is much less certain for longer stretches of DNA.

RAD50–MRE11–NBS1 COMPLEX

This complex is involved in homologous recombination, along with other proteins such as RAD51, RAD52, RAD54, RAD55, RAD57, XRCC2, XRCC3 and possibly BRCA1 and BRCA2. Patients who are mutant forNBS1 (known asXRS2 in yeast) have Nijmegen breakage syndrome, which includes microcephaly, increased malignancy and chromosomal instability. Mice with hypomorphic alleles ofRad50 have normalV(D)J recombination49,50,51, which indicates that this complex does not have a primary role in this pathway.

CLASS-SWITCH RECOMBINATION

This is the process by which the immunoglobulin heavy-chain isotype changes from IgM to IgG1, IgG2, IgG3, IgG4, IgA1, IgA2 or IgE in humans (and similar isotypes in mice and other vertebrates). It involves a double-stranded DNA break (DSB) at the switch regions (which are repetitive, G-rich and several kilobases in length) at the immunoglobulin heavy-chain locus. The DSBs are rejoined by some of the components of the non-homologous end-joining pathway.

TOROIDAL

Doughnut-shaped.

Rights and permissions

About this article

Cite this article

Lieber, M., Ma, Y., Pannicke, U.et al. Mechanism and regulation of human non-homologous DNA end-joining.Nat Rev Mol Cell Biol4, 712–720 (2003). https://doi.org/10.1038/nrm1202

Download citation

This article is cited by

Access through your institution
Buy or subscribe

Advertisement

Search

Advanced search

Quick links

Nature Briefing

Sign up for theNature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox.Sign up for Nature Briefing
[8]ページ先頭
©2009-2025 Movatter.jp