V(D)J Recombination Deficiencies

  • Jean-Pierre de Villartay
Part of the Advances in Experimental Medicine and Biology book series (volume 650)


V(D)J recombination not only comprises the molecular mechanism that insures diversity of the immune system but also constitutes a critical checkpoint in the developmental program of B- and T-lymphocytes. The analysis of human patients with Severe Combined Immune Deficiency (SCID) has contributed to the understanding of the biochemistry of the V(D)J recombination reaction. The molecular study V(D)J recombination settings in humans, mice and in cellular mutants has allowed to unravel the process of Non Homologous End Joining (NHEJ), one of the key pathway that insure proper repair of DNA double strand breaks (dsb), whether they occur during V(D)J recombination or secondary to other DNA injuries. Two NHEJ factors, Artemis and Cernunnos, were indeed discovered through the study of human V(D)J recombination defective human SCID patients.


iNKT Cell Primary Immunodeficiency Disease Nijmegen Breakage Syndrome Severe Combine Immune Deficiency Omenn Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Tonegawa S. Somatic generation of antibody diversity. Nature 1983; 302(5909):575–81.PubMedCrossRefGoogle Scholar
  2. 2.
    Schatz DG, Oettinger MA, Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell 1989; 59(6):1035–48.PubMedCrossRefGoogle Scholar
  3. 3.
    Oettinger MA, Schatz DG, Gorka C et al. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 1990; 248(4962):1517–23.PubMedCrossRefGoogle Scholar
  4. 4.
    Dudley DD, Chaudhuri J, Bassing CH et al. Mechanism and Control of V(D)J Recombination versus Class Switch Recombination: Similarities and Differences. Adv Immunol 2005; 8643–112.Google Scholar
  5. 5.
    Fischer, A. Human primary immunodeficiency diseases: a perspective. Nat Immunol 2004; 5(1):23–30.PubMedCrossRefGoogle Scholar
  6. 6.
    Villa A, Sobacchi C, Notarangelo LD et al. V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 2001; 97(1):81–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Shinkai Y, Rathbun G, Lam KP et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 1992; 68(5):855–67.PubMedCrossRefGoogle Scholar
  8. 8.
    Mombaerts P, Iacomini J, Johnson RS et al. RAG-1-deficient mice have no mature B-and T-lymphocytes. Cell 1992; 68(5):869–77.PubMedCrossRefGoogle Scholar
  9. 9.
    Schwarz K, Hansen-Hagge TE, Knobloch C et al. Severe combined immunodeficiency (SCID) in man: B-cell-negative (B-) SCID patients exhibit an irregular recombination pattern at the JH locus. J Exp Med 1991; 174(5):1039–48.PubMedCrossRefGoogle Scholar
  10. 10.
    Abe T, Tsuge I, Kamachi Y et al. Evidence for defects in V(D)J rearrangements in patients with severe combined immunodeficiency. J Immunol 1994; 152(11):5504–13.PubMedGoogle Scholar
  11. 11.
    Schwarz K, Gauss GH, Ludwig L et al. RAG mutations in human B-cell-negative SCID. Science 1996; 274(5284):97–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Sobacchi C, Marrella V, Rucci F et al. RAG-dependent primary immunodeficiencies. Hum Mutat 2006; 27(12):1174–84.PubMedCrossRefGoogle Scholar
  13. 13.
    Omenn GS. Familial Reticuloendotheliosis with Eosinophilia. N Engl J Med 1965; 273:427–32.PubMedCrossRefGoogle Scholar
  14. 14.
    de Saint-Basile G, Le Deist F, de Villartay JP et al. Restricted heterogeneity of T-lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn’s syndrome). J Clin Invest 1991; 87(4):1352–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Villa A, Santagata S, Bozzi F et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell 1998; 93(5):885–96.PubMedCrossRefGoogle Scholar
  16. 16.
    Corneo B, Moshous D, Gungor T et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood 2001; 97(9):2772–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Ege M, Ma Y, Manfras B et al. Omenn syndrome due to ARTEMIS mutations. Blood 2005; 105(11):4179–86.PubMedCrossRefGoogle Scholar
  18. 18.
    Giliani S, Bonfim C, de Saint Basile G et al. Omenn syndrome in an infant with IL7RA gene mutation. J Pediatr 2006; 148(2):272–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Roifman CM, Gu Y, Cohen A. Mutations in the RNA component of RNase mitochondrial RNA processing might cause Omenn syndrome. J Allergy Clin Immunol 2006; 117(4):897–903.PubMedCrossRefGoogle Scholar
  20. 20.
    Markert ML, Alexieff MJ, Li J et al. Complete DiGeorge syndrome: development of rash, lymphadenopathy and oligoclonal T-cells in 5 cases. J Allergy Clin Immunol 2004; 113(4):734–41.PubMedCrossRefGoogle Scholar
  21. 21.
    Ehl S, Schwarz K, Enders A et al. A variant of SCID with specific immune responses and predominance of gamma delta T-cells. J Clin Invest 2005; 115(11):3140–8.PubMedCrossRefGoogle Scholar
  22. 22.
    de Villartay JP, Lim A, Al-Mousa H et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest 2005; 115(11):3291–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Schandene L, Ferster A, Mascart-Lemone F et al. T-helper type 2-like cells and therapeutic effects of interferon-gamma in combined immunodeficiency with hypereosinophilia (Omenn’s syndrome). Eur J Immunol 1993; 23(1):56–60.PubMedCrossRefGoogle Scholar
  24. 24.
    Cavadini P, Vermi W, Facchetti F et al. AIRE deficiency in thymus of 2 patients with Omenn syndrome. J Clin Invest 2005; 115(3):728–32.PubMedGoogle Scholar
  25. 25.
    Anderson MS, Venanzi ES, Klein L et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002; 298(5597):1395–401.PubMedCrossRefGoogle Scholar
  26. 26.
    Marrella V, Poliani PL, Casati A et al. A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. J Clin Invest 2007; 117(5):1260–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Matangkasombut P, Pichavant M, Saez DE et al. Lack of iNKT cells in patients with combined immune deficiency due to hypomorphic RAG mutations. Blood 2007 [epub ahead of print.]Google Scholar
  28. 28.
    Khiong K, Murakami M, Kitabayashi C et al. Homeostatically proliferating CD4 T-cells are involved in the pathogenesis of an Omenn syndrome murine model. J Clin Invest 2007; 117(5):1270–81.PubMedCrossRefGoogle Scholar
  29. 29.
    Milner JD, Ward JM, Keane-Myers A et al. Lymphopenic mice reconstituted with limited repertoire T-cells develop severe, multiorgan, Th2-associated inflammatory disease. Proc Natl Acad Sci USA 2007; 104(2):576–81.PubMedCrossRefGoogle Scholar
  30. 30.
    Milner J, Ward J, Keane-Myers A et al. Repertoire-dependent immunopathology. J Autoimmun 2007; 29 (4):257–61.PubMedCrossRefGoogle Scholar
  31. 31.
    Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature 1983; 301(5900):527–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Fulop GM, Phillips RA. The scid mutation in mice causes a general defect in DNA repair. Nature 1990; 347479–482.Google Scholar
  33. 33.
    Biedermann KA, Sum JR, Giaccia AJ et al. Scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair. Proc Natl Acad Sci USA 1991; 88:1394–1397.PubMedCrossRefGoogle Scholar
  34. 34.
    Hendrickson EA, Qin XQ, Bump EA et al. A link between double-strand break related repair and V(D)J recombination: the scid mutation. Proc Natl Acad Sci USA 1991; 88:4061–4065.PubMedCrossRefGoogle Scholar
  35. 35.
    Lieber MR, Hesse JE, Lewis S et al. The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination. Cell 1988; 55(1):7–16.PubMedCrossRefGoogle Scholar
  36. 36.
    Roth DB, Menetski JP, Nakajima PB et al. V(D)J recombination: broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes. Cell 1992; 70(6):983–91.PubMedCrossRefGoogle Scholar
  37. 37.
    Taccioli GE, Rathbun G, Oltz E et al. Impairment of V(D)J recombination in double-strand break repair mutants. Science 1993; 260(5105):207–10.PubMedCrossRefGoogle Scholar
  38. 38.
    Pergola F, Zdzienicka MZ, Lieber MR. V(D)J recombination in mammalian cell mutants defective in DNA double-strand break repair. Mol Cell Biol 1993; 13(6):3464–71.PubMedGoogle Scholar
  39. 39.
    Weterings E, van Gent DC. The mechanism of nonhomologous end-joining: a synopsis of synapsis. DNA Repair (Amst) 2004; 3(11):1425–35.CrossRefGoogle Scholar
  40. 40.
    Cavazzana-Calvo M, Le Deist F, de Saint Basile G et al. Increased radiosensitivity of granulocyte macrophage colony-forming units and skin fibroblasts in human autosomal recessive Severe Combined Immunodeficiency. J Clin Invest 1993; 91:1214–1218.PubMedCrossRefGoogle Scholar
  41. 41.
    Moshous D, Li L, de Chasseval R 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 2000; 9(4):583–588.PubMedCrossRefGoogle Scholar
  42. 42.
    Nicolas N, Moshous D, Papadopoulo D et al. A human SCID condition with increased sensitivity to ionizing radiations and impaired V(D)J rearrangements defines a new DNA Recombination/Repair deficiency. J Exp Med 1998; 188:627–634.PubMedCrossRefGoogle Scholar
  43. 43.
    Nicolas N, Finnie NJ, Cavazzana-Calvo M et al. Lack of detectable defect in DNA double-strand break repair and DNA-dependant protein kinase activity in radiosesitive human severe combined immunodeficiency fibroblasts. Eur J Immunol 1996; 26:1118–1122.PubMedCrossRefGoogle Scholar
  44. 44.
    Li L, Drayna D, Hu D et al. The gene for severe combined immunodeficiency disease in Athabascanspeaking Native Americans is located on chromosome 10p. Am J Hum Genet 1998; 62(1):136–44.PubMedCrossRefGoogle Scholar
  45. 45.
    Moshous D, Callebaut I, de Chasseval R et al. ARTEMIS, a Novel DNA Double-Strand Break Repair/ V(D)J Recombination Protein, is Mutated in Human Severe Combined Immune Deficiency. Cell 2001; 105:177–186.PubMedCrossRefGoogle Scholar
  46. 46.
    Rooney S, Sekiguchi J, Zhu C et al. Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol Cell 2002; 10(6):1379–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Li L, Salido E, Zhou Y et al. Targeted disruption of the Artemis murine counterpart results in SCID and defective V(D)J recombination that is partially corrected with bone marrow transplantation. J Immunol 2005; 174(4):2420–8.PubMedGoogle Scholar
  48. 48.
    Gennery AR, Hodges E, Williams AP et al. Omenn’s syndrome occurring in patients without mutations in recombination activating genes. Clin Immunol 2005; 116(3):246–56.PubMedCrossRefGoogle Scholar
  49. 49.
    Evans PM, Woodbine L, Riballo E et al. Radiation-induced delayed cell death in a hypomorphic Artemis cell line. Hum Mol Genet 2006; 15(8):1303–11.PubMedCrossRefGoogle Scholar
  50. 50.
    Aravind L. An evolutionary classification of the metallo-beta-lactamase fold proteins. In Silico Biol 1999; 1(2):69–91.PubMedGoogle Scholar
  51. 51.
    Ma Y, Pannicke U, Schwarz K et al. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 2002; 108(6):781–94.PubMedCrossRefGoogle Scholar
  52. 52.
    Lenain C, Bauwens S, Amiard S et al. The Apollo 5′ exonuclease functions together with TRF2 to protect telomeres from DNA repair. Curr Biol 2006; 16(13):1303–10.PubMedCrossRefGoogle Scholar
  53. 53.
    van Overbeek M, de Lange T. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr Biol 2006; 16(13):1295–302.PubMedCrossRefGoogle Scholar
  54. 54.
    Inagaki K, Ma C, Storm TA et al. A Role of DNA-PKcs and Artemis in Opening Viral DNA Hairpin Termini in Various Tissues in Mice. J Virol 2007; 81(20):11304–21PubMedCrossRefGoogle Scholar
  55. 55.
    Callebaut I, Moshous D, Mornon JP et al. Metallo-β-lactamase fold within nucleic acids processing enzymes: the β-CASP family. Nucl Acid Res 2002; 30:3592–3601.CrossRefGoogle Scholar
  56. 56.
    Poinsignon C, Moshous D, Callebaut I et al. The Metallo-β-Lactamase/β-CASP Domain of Artemis Constitutes the Catalytic Core Required for V(D)J Recombination. J Exp Med 2004; 199:315–321.PubMedCrossRefGoogle Scholar
  57. 57.
    Pannicke U, Ma Y, Hopfner KP et al. Functional and biochemical dissection of the structure-specific nuclease ARTEMIS. EMBO J 2004; 23(9):1987–97.PubMedCrossRefGoogle Scholar
  58. 58.
    Niewolik D, Pannicke U, Lu H et al. DNA-PKcs dependence of Artemis endonucleolytic activity, differences between hairpins and 5′ and 3′ overhangs. J Biol Chem 2006; 281(45):33900–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Ishikawa H, Nakagawa N, Kuramitsu S et al. Crystal structure of TTHA0252 from Thermus thermophilus HB8, a RNA degradation protein of the metallo-beta-lactamase superfamily. J Biochem (Tokyo) 2006; 140(4):535–42.Google Scholar
  60. 60.
    Mandel CR, Kaneko S, Zhang H et al. Polyadenylation factor CPSF-73 is the pre-mRNA 3′-end-processing endonuclease. Nature 2006; 444(7121):953–6.PubMedCrossRefGoogle Scholar
  61. 61.
    Poinsignon C, de Chasseval R, Soubeyrand S et al. Phosphorylation of Artemis following irradiation-induced DNA damage. Eur J Immunol 2004; 34(11):3146–55.PubMedCrossRefGoogle Scholar
  62. 62.
    Riballo E, Kuhne M, Rief N et al. A pathway of double-strand break rejoining dependent upon ATM, Artemis and proteins locating to gamma-H2AX foci. Mol Cell 2004; 16(5):715–24.PubMedCrossRefGoogle Scholar
  63. 63.
    Zhang X, Succi J, Feng Z et al. Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response. Mol Cell Biol 2004; 24(20):9207–20.PubMedCrossRefGoogle Scholar
  64. 64.
    Chen L, Morio T, Minegishi Y et al. Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage. Cancer Sci 2005; 96(2):134–41.PubMedCrossRefGoogle Scholar
  65. 65.
    Ma Y, Pannicke U, Lu H et al. The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis. J Biol Chem 2005; 280(40):33839–46.PubMedCrossRefGoogle Scholar
  66. 66.
    Wang J, Pluth JM, Cooper PK et al. Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. DNA Repair (Amst) 2005; 4(5):556–70.CrossRefGoogle Scholar
  67. 67.
    Soubeyrand S, Pope L, De Chasseval R et al. Artemis phosphorylated by DNA-dependent protein kinase associates preferentially with discrete regions of chromatin. J Mol Biol 2006; 358(5):1200–11.PubMedCrossRefGoogle Scholar
  68. 68.
    Goodarzi AA, Yu Y, Riballo E et al. DNA-PK autophosphorylation facilitates Artemis endonuclease activity. EMBO J 2006; 25(16):3880–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Drouet J, Frit P, Delteil C et al. Interplay between Ku, Artemis and the DNA-dependent protein kinase catalytic subunit at DNA ends. J Biol Chem 2006; 281(38):27784–93.PubMedCrossRefGoogle Scholar
  70. 70.
    Rogakou EP, Pilch DR, Orr AH et al. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 1998; 273(10):5858–68.PubMedCrossRefGoogle Scholar
  71. 71.
    Darroudi F, Wiegant W, Meijers M et al. Role of Artemis in DSB repair and guarding chromosomal stability following exposure to ionizing radiation at different stages of cell cycle. Mutat Res 2007; 615(1–2):111–24.PubMedGoogle Scholar
  72. 72.
    Povirk LF, Zhou T, Zhou R et al. Processing of 3′-phosphoglycolate-terminated DNA double strand breaks by Artemis nuclease. J Biol Chem 2007; 282(6):3547–58.PubMedCrossRefGoogle Scholar
  73. 73.
    Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K et al. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 2004; 7339–85.Google Scholar
  74. 74.
    Geng L, Zhang X, Zheng S et al. Artemis links ATM to G2/M checkpoint recovery via regulation of Cdk1-cyclin B. Mol Cell Biol 2007; 27(7):2625–35.PubMedCrossRefGoogle Scholar
  75. 75.
    Krempler A, Deckbar D, Jeggo PA et al. An imperfect G2M checkpoint contributes to chromosome instability following irradiation of S and G2 phase cells. Cell Cycle 2007; 6(14):1682–6.PubMedGoogle Scholar
  76. 76.
    Deckbar D, Birraux J, Krempler A et al. Chromosome breakage after G2 checkpoint release. J Cell Biol 2007; 176(6):749–55.PubMedCrossRefGoogle Scholar
  77. 77.
    O’Driscoll M, Cerosaletti KM, Girard PM et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 2001; 8(6):1175–85.PubMedCrossRefGoogle Scholar
  78. 78.
    Ben-Omran TI, Cerosaletti K, Concannon P et al. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A 2005; 137(3):283–7.Google Scholar
  79. 79.
    Buck D, Moshous D, de Chasseval R et al. Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. Eur J Immunol 2006; 36(1):224–35.PubMedCrossRefGoogle Scholar
  80. 80.
    Enders A, Fisch P, Schwarz K et al. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J Immunol 2006; 176(8):5060–8.PubMedGoogle Scholar
  81. 81.
    van der Burg M, van Veelen LR, Verkaik NS et al. A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J Clin Invest 2006; 116(1):137–45.PubMedCrossRefGoogle Scholar
  82. 82.
    Buck D, Malivert L, de Chasseval R et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 2006; 124(2):287–99.PubMedCrossRefGoogle Scholar
  83. 83.
    Revy P, Buck D, le Deist F et al. The repair of DNA damages/modifications during the maturation of the immune system: lessons from human primary immunodeficiency disorders and animal models. Adv Immunol 2005; 87237–95.Google Scholar
  84. 84.
    Ahnesorg P, Smith P, Jackson SP. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 2006; 124(2):301–13.PubMedCrossRefGoogle Scholar
  85. 85.
    Zha S, Alt FW, Cheng HL et al. Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells. Proc Natl Acad Sci USA 2007; 104(11):4518–23.PubMedCrossRefGoogle Scholar
  86. 86.
    Dai Y, Kysela B, Hanakahi LA et al. Nonhomologous end joining and V(D)J recombination require an additional factor. Proc Natl Acad Sci USA 2003; 100(5):2462–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Hentges P, Ahnesorg P, Pitcher RS et al. Evolutionary and functional conservation of the DNA nonhomologous end-joining protein, XLF/Cernunnos. J Biol Chem 2006; 281(49):37517–26.PubMedCrossRefGoogle Scholar
  88. 88.
    Sibanda BL, Critchlow SE, Begun J et al. Crystal structure of an Xrcc4-DNA ligase IV complex. Nat Struct Biol 2001; 8(12):1015–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Junop MS, Modesti M, Guarne A et al. Crystal structure of the Xrcc4 DNA repair protein and implications for end joining. EMBO J 2000; 19(22):5962–70.PubMedCrossRefGoogle Scholar
  90. 90.
    Callebaut I, Malivert L, Fischer A et al. Cernunnos interacts with the XRCC4 x DNA-ligase IV complex and is homologous to the yeast nonhomologous end-joining factor Nej1. J Biol Chem 2006; 281(20):13857–60.PubMedCrossRefGoogle Scholar
  91. 91.
    Lu H, Pannicke U, Schwarz K et al. Length-dependent binding of human XLF to DNA and stimulation of XRCC4.DNA ligase IV activity. J Biol Chem 2007; 282(15):11155–62.PubMedCrossRefGoogle Scholar
  92. 92.
    Deshpande RA, Wilson TE. Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4. DNA Repair (Amst) 2007; 6(10):1507–16.CrossRefGoogle Scholar
  93. 93.
    Frank-Vaillant M, Marcand S. NHEJ regulation by mating type is exercised through a novel protein, Lif2p, essential to the ligase IV pathway. Genes Dev 2001; 15(22):3005–12.PubMedCrossRefGoogle Scholar
  94. 94.
    Kegel A, Sjostrand JO, Astrom SU. Nej1p, a cell type-specific regulator of nonhomologous end joining in yeast. Curr Biol 2001; 11(20):1611–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Valencia M, Bentele M, Vaze MB et al. NEJ1 controls nonhomologous end joining in Saccharomyces cerevisiae. Nature 2001; 414(6864):666–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Cavero S, Chahwan C, Russell P. Xlf1 is required for DNA repair by nonhomologous end joining in Schizosaccharomyces pombe. Genetics 2007; 175(2):963–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Wu PY, Frit P, Malivert L et al. Interplay between Cernunnos/XLF and nonhomologous end-joining proteins at DNA ends in the cell. J Biol Chem 2007; 282(44):31937–43.PubMedCrossRefGoogle Scholar
  98. 98.
    Ahnesorg P, Jackson SP. The nonhomologous end-joining protein Nej1p is a target of the DNA damage checkpoint. DNA Repair (Amst) 2007; 6(2):190–201.CrossRefGoogle Scholar
  99. 99.
    Grawunder U, Zimmer D, Leiber MR. DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains. Curr Biol 1998; 8(15):873–6.PubMedCrossRefGoogle Scholar
  100. 100.
    Teo SH, Jackson SP. Lif1p targets the DNA ligase Lig4p to sites of DNA double-strand breaks. Curr Biol 2000; 10(3):165–8.PubMedCrossRefGoogle Scholar
  101. 101.
    Grawunder U, Wilm M, Wu X et al. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature 1997; 388(6641):492–5.PubMedCrossRefGoogle Scholar
  102. 102.
    Tsai CJ, Kim SA, Chu G. Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends. Proc Natl Acad Sci USA 2007; 104(19):7851–6.PubMedCrossRefGoogle Scholar
  103. 103.
    Gu J, Lu H, Tsai AG et al. Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence. Nucleic Acids Res 2007; 35(17):5755–62.PubMedCrossRefGoogle Scholar
  104. 104.
    Gao Y, Sun Y, Frank KM et al. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 1998; 95(7):891–902.PubMedCrossRefGoogle Scholar
  105. 105.
    Frank KM, Sekiguchi JM, Seidl KJ et al. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 1998; 396(6707):173–7.PubMedCrossRefGoogle Scholar
  106. 106.
    Franco S, Alt FW, Manis JP. Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations. DNA Repair (Amst) 2006; 5(9–10):1030–41.CrossRefGoogle Scholar
  107. 107.
    Moshous D, Pannetier C, Chasseval Rd R et al. Partial T-and B-lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J Clin Invest 2003; 111(3):381–7.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Jean-Pierre de Villartay
    • 1
    • 2
    • 3
    • 4
  1. 1.U768, Unité Développement Normal et Pathologique du Système ImmunitaireINSERMParisFrance
  2. 2.Faculté de Médecine René DescartesUniversité Paris-DescartesParisFrance
  3. 3.Service d’Immunologie et d’Hématologie PédiatriqueAP-HP, Hôpital Necker Enfants MaladesParisFrance
  4. 4.INSERM U768Hôpital Necker Enfants MaladesParisFrance

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