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Recent Insights into the Formation of RAG-Induced Chromosomal Translocations

  • Vicky L. Brandt
  • David B. Roth
Part of the Advances in Experimental Medicine and Biology book series (volume 650)

Abstract

Chromosomal translocations are found in many types of tumors, where they may be either a cause or a result of malignant transformation. In lymphoid neoplasms, however, it is clear that pathogenesis is initiated by any of a number of recurrent DNA rearrangements. These particular translocations typically place an oncogene under the regulatory control of an Ig or TCR gene promoter, dysregulating cell growth, differentiation, or apoptosis. Given that physiological DNA rearrangements (V(D)J and class switch recombination) are integral to lymphocyte development, it is critical to understand how genomic stability is maintained during these processes. Recent advances in our understanding of DNA damage signaling and repair have provided clues to the kinds of mechanisms that lead to V(D)J-mediated translocations. In turn, investigations into the regulation of V(D)J joining have illuminated a formerly obscure pathway of DNA repair known as alternative NHEJ, which is error-prone and frequently involved in translocations. In this chapter we consider recent advances in our understanding of the functions of the RAG proteins, RAG interactions with DNA repair pathways, damage signaling and chromosome biology, all of which shed light on how mistakes at different stages of V(D)J recombination might lead to leukemias and lymphomas.

Keywords

Chromosomal Translocation Lymphoid Neoplasm NijmegenBreakage Syndrome Recombination Signal Sequence Antigen Receptor Gene 
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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References

  1. 1.
    Fisher SG, Fisher RI. The epidemiology of nonHodgkin’s lymphoma. Oncogene 2004; 23(38):6524–6534.PubMedCrossRefGoogle Scholar
  2. 2.
    Tycko B, Sklar J. Chromosomal translocations in lymphoid neoplasia: a reappraisal of the recombinase model. Cancer Cells 1990; 2:1–8.PubMedGoogle Scholar
  3. 3.
    Vanasse GJ, Concannon P, Willerford DM. Regulated genomic instability and neoplasia in the lymphoid lineage. Blood 1999; 94(12):3997–4010.PubMedGoogle Scholar
  4. 4.
    Kirsch IR, Morton CC, Nakahara K et al. Human immunoglobulin heavy chain genes map to a region of translocations in malignant B lymphocytes. Science 1982; 216(4543):301–303.PubMedCrossRefGoogle Scholar
  5. 5.
    Dalla-Favera R, Bregni M, Erikson J et al. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA 1982; 79(24):7824–7827.PubMedCrossRefGoogle Scholar
  6. 6.
    Look AT. Oncogenic transcription factors in the human acute leukemias. Science 1997; 278(5340):1059–1064.PubMedCrossRefGoogle Scholar
  7. 7.
    Lewis SM. The mechanism of V(D)J joining: Lessons from molecular, immunological and comparative analyses. Adv Immunol 1994; 56:27–150.PubMedCrossRefGoogle Scholar
  8. 8.
    Kuppers R, Dalla-Favera R. Mechanisms of chromosomal translocations in B-cell lymphomas. Oncogene 2001; 20(40):5580–5594.PubMedCrossRefGoogle Scholar
  9. 9.
    Saada R, Weinberger M, Shahaf G et al. Models for antigen receptor gene rearrangement: CDR3 length. Immunol Cell Biol 2007; 85(4):323–332.PubMedCrossRefGoogle Scholar
  10. 10.
    Krangel MS. Gene segment selection in V(D)J recombination: accessibility and beyond. Nat Immunol 2003; 4(7):624–630.PubMedCrossRefGoogle Scholar
  11. 11.
    Schlissel MS. Regulating antigen-receptor gene assembly. Nat Rev Immunol 2003; 3(11):890–899.PubMedCrossRefGoogle Scholar
  12. 12.
    Jung D, Giallourakis C, Mostoslavsky R et al. Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol 2006; 24:541–570.PubMedCrossRefGoogle Scholar
  13. 13.
    Gellert M. V(D)J recombination: RAG proteins, repair factors and regulation. Annu Rev Biochem 2002; 71:101–132.PubMedCrossRefGoogle Scholar
  14. 14.
    Fugmann SD, Lee AI, Shockett PE et al. The RAG proteins and V(D)J recombination: complexes, ends and transposition. Annu Rev Immunol 2000; 18:495–527.PubMedCrossRefGoogle Scholar
  15. 15.
    Steen SB, Gomelsky L, Roth DB. The 12/23 rule is enforced at the cleavage step of V(D)J recombination in vivo. Genes to Cells 1996; 1(6):543–553.PubMedCrossRefGoogle Scholar
  16. 16.
    Eastman QM, Leu TMJ, Schatz DG. Initiation of V(D)J recombination in vitro obeying the 12/23 rule. Nature 1996; 380:85–88.PubMedCrossRefGoogle Scholar
  17. 17.
    van Gent DC, Ramsden DA, Gellert M. The RAG1 and RAG2 proteins establish the 12/23 rule in V(D)J recombination. Cell 1996; 85:107–113.PubMedCrossRefGoogle Scholar
  18. 18.
    Hesse JE, Lieber MR, Mizuuchi K et al. V(D)J recombination: a functional definition of the joining signals. Genes Dev 1989; 3:1053–1061.PubMedCrossRefGoogle Scholar
  19. 19.
    Nadel B, Tang A, Escuro G et al. Sequence of the spacer in the recombination signal sequence affects V(D)J rearrangement frequency and correlates with nonrandom Vkappa usage in vivo. J Exp Med 1998; 187(9):1495–1503.PubMedCrossRefGoogle Scholar
  20. 20.
    Bassing CH, Alt FW, Hughes MM et al. Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule. Nature 2000; 405(6786):583–586.PubMedCrossRefGoogle Scholar
  21. 21.
    Feeney AJ, Goebel P, Espinoza CR. Many levels of control of V gene rearrangement frequency. Immunol Rev 2004; 200:44–56.PubMedCrossRefGoogle Scholar
  22. 22.
    Swanson PC. The bounty of RAGs: recombination signal complexes and reaction outcomes. Immunol Rev 2004; 200:90–114.PubMedCrossRefGoogle Scholar
  23. 23.
    Oettinger MA, Schatz DG, Gorka C et al. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 1990; 248:1517–1523.PubMedCrossRefGoogle Scholar
  24. 24.
    van Gent DC, Hiom K, Paull TT et al. Stimulation of V(D)J cleavage by high mobility group proteins. EMBO J 1997; 16(10):2665–2670.PubMedCrossRefGoogle Scholar
  25. 25.
    Dai Y, Wong B, Yen YM et al. Determinants of HMGB proteins required to promote RAG1/2-recombination signal sequence complex assembly and catalysis during V(D)J recombination. Mol Cell Biol 2005; 25(11):4413–4425.PubMedCrossRefGoogle Scholar
  26. 26.
    Roth DB, Nakajima PB, Menetski JP et al. V(D)J recombination in mouse thymocytes: Double-strand breaks near T-cell receptor delta rearrangement signals. Cell 1992; 69:41–53.PubMedCrossRefGoogle Scholar
  27. 27.
    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; 70:983–991.PubMedCrossRefGoogle Scholar
  28. 28.
    Roth DB, Zhu C, Gellert M. Characterization of broken DNA molecules associated with V(D)J recombination. Proc Natl Acad Sci USA 1993; 90:10788–10792.PubMedCrossRefGoogle Scholar
  29. 29.
    Schlissel M, Constantinescu A, Morrow T et al. Double-strand signal sequence breaks in V(D)J recombination are blunt, 5′-phosphorylated, RAG-dependent and cell cycle regulated. Genes Dev 1993; 7:2520–2532.PubMedCrossRefGoogle Scholar
  30. 30.
    McBlane JF, van Gent DC, Ramsden DA et al. Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. Cell 1995; 83:387–395.PubMedCrossRefGoogle Scholar
  31. 31.
    Tycko B, Palmer JD, Sklar J. T-cell receptor gene trans-rearrangements: chimeric gamma delta genes in normal lymphoid tissues. Science 1989; 245:1242–1246.PubMedCrossRefGoogle Scholar
  32. 32.
    Kobayashi Y, Tycko B, Soreng AL et al. Transrearrangements between antigen receptor genes in normal human lymphoid tissues and in ataxia telangiectasia. J Immunol 1991; 147:3201–3209.PubMedGoogle Scholar
  33. 33.
    Davodeau F, Peyrat MA, Gaschet J et al. Surface expression of functional T-cell receptor chains formed by interlocus recombination on human T-lymphocytes. J Exp Med 1994; 180(5):1685–1691.PubMedCrossRefGoogle Scholar
  34. 34.
    Bailey SN, Rosenberg N. Assessing the pathogenic potential of the V(D)J recombinase by interlocus immunoglobulin light-chain gene rearrangement. Mol Cell Biol 1997; 17(2):887–894.PubMedGoogle Scholar
  35. 35.
    Marculescu R, Le T, Simon P et al. V(D)J-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites. J Exp Med 2002; 195(1):85–98.PubMedCrossRefGoogle Scholar
  36. 36.
    Garcia IS, Kaneko Y, Gonzalez-Sarmiento R et al. A study of chromosome 11p13 translocations involving TCR beta and TCR delta in human T-cell leukaemia. Oncogene 1991; 6(4):577–582.PubMedGoogle Scholar
  37. 37.
    Han J-O, Steen SB, Roth DB. Intermolecular V(D)J recombination is prohibited specifically at the joining step. Mol Cell 1999; 3:331–338.PubMedCrossRefGoogle Scholar
  38. 38.
    Tevelev A, Schatz DG. Intermolecular V(D)J recombination. J Biol Chem 2000; 275(12):8341–8348.PubMedCrossRefGoogle Scholar
  39. 39.
    Agard EA, Lewis SM. Postcleavage sequence specificity in V(D)J recombination. Mol Cell Biol 2000; 20(14):5032–5040.PubMedCrossRefGoogle Scholar
  40. 40.
    Lipkowitz S, Stern MH, Kirsch IR. Hybrid T-cell receptor genes formed by interlocus recombination in normal and ataxia-telangiectasia lymphocytes. J Exp Med 1990; 172(2):409–418.PubMedCrossRefGoogle Scholar
  41. 41.
    Kirsch IR, Lipkowitz S. A measure of genomic instability and its relevance to lymphomagenesis. Cancer Res 1992; 52:5545s–5546s.PubMedGoogle Scholar
  42. 42.
    Theunissen JW, Kaplan MI, Hunt PA et al. Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice. Mol Cell 2003; 12(6):1511–1523.PubMedCrossRefGoogle Scholar
  43. 43.
    Lewis SM, Agard E, Suh S et al. Cryptic signals and the fidelity of V(D)J joining. Mol Cell Biol 1997; 17(6):3125–3136.PubMedGoogle Scholar
  44. 44.
    Zhang M, Swanson PC. V(D)J recombinase binding and cleavage of cryptic recombination signal sequences identified from lymphoid malignancies. J Biol Chem 2008:283(11):6717–27.PubMedCrossRefGoogle Scholar
  45. 45.
    Tycko B, Reynolds TC, Smith SD et al. Consistent breakage between consensus recombinase heptamers of chromosome 9 DNA in a recurrent chromosomal translocation of human T-cell leukemia. J Exp Med 1989; 169(2):369–377.PubMedCrossRefGoogle Scholar
  46. 46.
    Cowell LG, Davila M, Yang K et al. Prospective estimation of recombination signal efficiency and identification of functional cryptic signals in the genome by statistical modeling. J Exp Med 2003; 197(2):207–220.PubMedCrossRefGoogle Scholar
  47. 47.
    Yancopoulos GD, Alt FW. Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell 1985; 40(2):271–281.PubMedCrossRefGoogle Scholar
  48. 48.
    Stanhope-Baker P, Hudson KM, Shaffer AL et al. Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro. Cell 1996; 85(6):887–897.PubMedCrossRefGoogle Scholar
  49. 49.
    Baumann M, Mamais A, McBlane F et al. Regulation of V(D)J recombination by nucleosome positioning at recombination signal sequences. EMBO J 2003; 22(19):5197–5207.PubMedCrossRefGoogle Scholar
  50. 50.
    Muegge K, West M, Durum SK. Recombination sequence-binding protein in thymocytes undergoing T-cell receptor gene rearrangement. Proc Nat Acad Sci USA 1993; 90:4151–4155.PubMedCrossRefGoogle Scholar
  51. 51.
    Kwon J, Imbalzano AN, Matthews A et al. Accessibility of nucleosomal DNA to V(D)J cleavage is modulated by RSS positioning and HMG1. Mol Cell 1998; 2(6):829–839.PubMedCrossRefGoogle Scholar
  52. 52.
    Oettinger MA. How to keep V(D)J recombination under control. Immunol Rev 2004; 200:165–181.PubMedCrossRefGoogle Scholar
  53. 53.
    Saha A, Wittmeyer J, Cairns BR. Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 2006; 7(6):437–447.PubMedCrossRefGoogle Scholar
  54. 54.
    Ruthenburg AJ, Li H, Patel DJ et al. Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 2007; 8(12):983–994.PubMedCrossRefGoogle Scholar
  55. 55.
    Li H, Ilin S, Wang W et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 2006; 442(7098):91–95.PubMedGoogle Scholar
  56. 56.
    Pena PV, Davrazou F, Shi X et al. Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 2006; 442(7098):100–103.PubMedGoogle Scholar
  57. 57.
    Shi X, Hong T, Walter KL et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 2006; 442(7098):96–99.PubMedGoogle Scholar
  58. 58.
    Wysocka J, Swigut T, Xiao H et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 2006; 442(7098):86–90.PubMedGoogle Scholar
  59. 59.
    Liu Y, Subrahmanyam R, Chakraborty T et al. A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity 2007; 27(4):561–571.PubMedCrossRefGoogle Scholar
  60. 60.
    Ramon-Maiques S, Kuo AJ, Carney D et al. The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2. Proc Natl Acad Sci USA 2007; 104(48):18993–18998.PubMedCrossRefGoogle Scholar
  61. 61.
    Matthews AG, Kuo AJ, Ramon-Maiques S et al. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 2007; 450(7172):1106–1110.PubMedCrossRefGoogle Scholar
  62. 62.
    Krangel MS. T-cell development: better living through chromatin. Nat Immunol 2007; 8(7):687–694.PubMedCrossRefGoogle Scholar
  63. 63.
    Hu H, Wang B, Borde M et al. Foxp1 is an essential transcriptional regulator of B-cell development. Nat Immunol 2006; 7(8):819–826.PubMedCrossRefGoogle Scholar
  64. 64.
    Fuxa M, Skok J, Souabni A et al. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev 2004; 18(4):411–422.PubMedCrossRefGoogle Scholar
  65. 65.
    Roldan E, Fuxa M, Chong W et al. Locus ‘decontraction’ and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nat Immunol 2005; 6(1):31–41.PubMedCrossRefGoogle Scholar
  66. 66.
    Skok JA, Gisler R, Novatchkova M et al. Reversible contraction by looping of the Tcra and Tcrb loci in rearranging thymocytes. Nat Immunol 2007; 8(4):378–387.PubMedCrossRefGoogle Scholar
  67. 67.
    Liang HE, Hsu LY, Cado D et al. The “dispensable” portion of RAG2 is necessary for efficient V-to-DJ rearrangement during B-and T-cell development. Immunity 2002; 17(5):639–651.PubMedCrossRefGoogle Scholar
  68. 68.
    Akamatsu Y, Monroe R, Dudley DD et al. Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice. Proc Natl Acad Sci USA 2003; 100(3):1209–1214.PubMedCrossRefGoogle Scholar
  69. 69.
    Steen SB, Gomelsky L, Speidel SL et al. Initiation of V(D)J recombination in vivo: role of recombination signal sequences in formation of single and paired double-strand breaks. EMBO Journal 1997; 16(10):2656–2664.PubMedCrossRefGoogle Scholar
  70. 70.
    Bakhshi A, Wright JJ, Graninger W et al. Mechanism of the t(14; 18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners. Proc Natl Acad Sci USA 1987; 84:2396–2400.PubMedCrossRefGoogle Scholar
  71. 71.
    Posey JE, Brandt VL, Roth DB. Paradigm switching in the germinal center. Nat Immunol 2004; 5(5):476–477.PubMedCrossRefGoogle Scholar
  72. 72.
    Weterings E, Chen DJ. The endless tale of nonhomologous end-joining. Cell Res 2008; 18(1):114–124.PubMedCrossRefGoogle Scholar
  73. 73.
    Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell Res 2008; 18(1):134–147.PubMedCrossRefGoogle Scholar
  74. 74.
    Gottlieb TM, Jackson SP. The DNA-dependent protein kinase: Requirement for DNA ends and association with ku antigen. Cell 1993;72:131–142.PubMedCrossRefGoogle Scholar
  75. 75.
    Walker JR, Corpina RA, Goldberg J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 2001; 412(6847):607–614.PubMedCrossRefGoogle Scholar
  76. 76.
    Roberts SA, Ramsden DA. Loading of the nonhomologous end joining factor, ku, on protein-occluded DNA ends. J Biol Chem 2007; 282(14):10605–10613.PubMedCrossRefGoogle Scholar
  77. 77.
    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):781–794.PubMedCrossRefGoogle Scholar
  78. 78.
    Leber R, Wise TW, Mizuta R et al. The XRCC4 gene product is a target for and interacts with the DNA-dependent protein kinase. J Biol Chem 1998;273(3):1794–1801.PubMedCrossRefGoogle Scholar
  79. 79.
    Mahajan KN, Gangi-Peterson L, Sorscher DH et al. Association of terminal deoxynucleotidyl transferase with ku. Proc Natl Acad Sci USA 1999; 96(24):13926–13931.PubMedCrossRefGoogle Scholar
  80. 80.
    Purugganan MM, Shah S, Kearney JF et al. Ku80 is required for addition of N nucleotides to V(D)J recombination junctions by terminal deoxynucleotidyl transferase. Nucleic Acids Res 2001; 29(7):1638–1646.PubMedCrossRefGoogle Scholar
  81. 81.
    Critchlow SE, Bowater RP, Jackson SP. Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Current Biology 1997; 7:588–598.PubMedCrossRefGoogle Scholar
  82. 82.
    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; 388:492–495.PubMedCrossRefGoogle Scholar
  83. 83.
    Modesti M, Hesse JE, Gellert M. DNA binding of Xrcc4 protein is associated with V(D)J recombination but not with stimulation of DNA ligase IV activity. EMBO J 1999; 18(7):2008–2018.PubMedCrossRefGoogle Scholar
  84. 84.
    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):2462–2467.PubMedCrossRefGoogle Scholar
  85. 85.
    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):287–299.PubMedCrossRefGoogle Scholar
  86. 86.
    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):301–313.PubMedCrossRefGoogle Scholar
  87. 87.
    Callebaut I, Malivert L, Fischer A et al. Cernunnos interacts with the XRCC4 × DNA-ligase IV complex and is homologous to the yeast nonhomologous end-joining factor Nej1. J Biol Chem 2006; 281(20):13857–13860.PubMedCrossRefGoogle Scholar
  88. 88.
    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):7851–7856.PubMedCrossRefGoogle Scholar
  89. 89.
    Lieber MR, Lu H, Gu J et al. Flexibility in the order of action and in the enzymology of the nuclease, polymerases and ligase of vertebrate nonhomologous DNA end joining: relevance to cancer, aging and the immune system. Cell Res 2008; 18(1):125–133.PubMedCrossRefGoogle Scholar
  90. 90.
    Jhappan C, Morse HC, Fleischmann RD et al. DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Nat Genet 1997; 17:483–486.PubMedCrossRefGoogle Scholar
  91. 91.
    Custer RP, Bosma GC, Bosma MJ. Severe combined immunodeficiency in the mouse: pathology, reconstitution, neoplasms. Am J Pathol 1985; 120:464–477.PubMedGoogle Scholar
  92. 92.
    Gu Y, Seidl KJ, Rathbun GA et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 1997; 7:653–665.PubMedCrossRefGoogle Scholar
  93. 93.
    Li GC, Ouyang H, Li X et al. Ku70: a candidate tumor suppressor gene for murine T-cell lymphoma. Mol Cell 1998; 2(1):1–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Difilippantonio MJ, JZ, JT C et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 2000; 404:510–514.PubMedCrossRefGoogle Scholar
  95. 95.
    Gao Y, Ferguson DO, WX et al. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 2000; 404:897–900.PubMedCrossRefGoogle Scholar
  96. 96.
    Zhu C, Mills KD, Ferguson DO et al. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 2002; 109(7):811–821.PubMedCrossRefGoogle Scholar
  97. 97.
    Moshous D, Pannetier C, de Chasseval R et al. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J Clin Invest 2003; 111:381–387.PubMedGoogle Scholar
  98. 98.
    Ferguson DO, Alt FW. DNA double strand break repair and chromosomal translocation: lessons from animal models. Oncogene 2001; 20(40):5572–5579.PubMedCrossRefGoogle Scholar
  99. 99.
    Ferguson DO, Sekiguchi JM, Chang S et al. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc Natl Acad Sci USA 2000; 97(12):6630–6633.PubMedCrossRefGoogle Scholar
  100. 100.
    Sharpless NE, Ferguson DO, O’Hagan RC et al. Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications and deletions. Mol Cell 2001; 8(6):1187–1196.PubMedCrossRefGoogle Scholar
  101. 101.
    Gladdy RA, Taylor MD, Williams CJ et al. The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice. Cancer Cell 2003; 3(1):37–50.PubMedCrossRefGoogle Scholar
  102. 102.
    Riballo E, Critchlow SE, Teo S-H et al. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr Biol 1999; 9:699–702.PubMedCrossRefGoogle Scholar
  103. 103.
    Toita N, Hatano N, Ono S et al. Epstein-Barr virus-associated B-cell lymphoma in a patient with DNA ligase IV (LIG4) syndrome. Am J Med Genet A. 2007; 143(7):742–745.PubMedGoogle Scholar
  104. 104.
    Wilson JH, Berget PB, Pipas JM. Somatic cells efficiently join unrelated DNA segments end-to-end. Mol Cell Biol 1982; 2(10):1258–1269.PubMedGoogle Scholar
  105. 105.
    Roth DB, Porter TN, Wilson JH. Mechanisms of nonhomologous recombination in mammalian cells. Mol Cell Biol 1985; 5:2599–2607.PubMedGoogle Scholar
  106. 106.
    Roth DB, Wilson JH. Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction. Mol Cell Biol 1986; 6:4295–4304.PubMedGoogle Scholar
  107. 107.
    Alt FW, Baltimore D. Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH fusions. Proc Natl Acad Sci USA 1982; 79:4118–4122.PubMedCrossRefGoogle Scholar
  108. 108.
    Pergola F, Zdzienicka MZ, Lieber MR. V(D)J recombination in mammalian mutants defective in DNA double-strand break repair. Mol Cell Biol 1993; 13:3464–3471.PubMedGoogle Scholar
  109. 109.
    Taccioli GE, Rathbun G, Oltz E et al. Impairment of V(D)J recombination in double-strand break repair mutants. Science 1993; 260:207–210.PubMedCrossRefGoogle Scholar
  110. 110.
    Getts RC, Stamato TD. Absence of a Ku-like DNA end binding activity in the xrs double-strand DNA repair-deficient mutant. J Biol Chem 1994; 269:15981–15984.PubMedGoogle Scholar
  111. 111.
    Taccioli GE, Cheng H-L, Varghese AJ et al. A DNA repair defect in chinese hamster ovary cells affects V(D)J recombination similarly to the murine scid mutation. J Biol Chem 1994; 269:7439–7442.PubMedGoogle Scholar
  112. 112.
    Taccioli GE, Gottlieb TM, Blunt T et al. Ku80: Product of the XRCC5 gene and its role in DNA repair and V(D)J recombination. Science 1994; 265:1442–1445.PubMedCrossRefGoogle Scholar
  113. 113.
    Kabotyanski EB, Gomelsky L, Han J-O et al. Double-strand break repair in Ku86-and XRCC4-deficient cells. Nucleic Acids Res 1998; 26(23):5333–5342.PubMedCrossRefGoogle Scholar
  114. 114.
    Baumann P, West SC. DNA End-joining catalyzed by human cell-free extracts. Proc Natl Acad Sci USA 1998; 95:14066–14070.PubMedCrossRefGoogle Scholar
  115. 115.
    Verkaik NS, Esveldt-van Lange RE, van Heemst D et al. Different types of V(D)J recombination and end-joining defects in DNA double-strand break repair mutant mammalian cells. Eur J Immunol 2002; 32(3):701–709.PubMedCrossRefGoogle Scholar
  116. 116.
    Lewis S, Gellert M. The mechanism of antigen receptor gene assembly. Cell 1989; 59:585–588.PubMedCrossRefGoogle Scholar
  117. 117.
    Zhu C, Bogue MA, Lim D-S et al. Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates. Cell 1996; 86:379–389.PubMedCrossRefGoogle Scholar
  118. 118.
    Huye LE, Purugganan MM, Jiang MM et al. Mutational analysis of all conserved basic amino acids in RAG-1 reveals catalytic, step arrest and joining-deficient mutants in the V(D)J recombinase. Mol Cell Biol 2002; 22(10):3460–3473.PubMedCrossRefGoogle Scholar
  119. 119.
    Yarnall Schultz H, Landree MA, Qiu JX et al. Joining-deficient RAG1 mutants block V(D)J recombination in vivo and hairpin opening in vitro. Mol Cell 2001; 7(1):65–75.CrossRefGoogle Scholar
  120. 120.
    Qiu JX, Kale SB, Yarnell Schultz H et al. Separation-of-function mutants reveal critical roles for RAG2 in both the cleavage and joining steps of V(D)J recombination. Mol Cell 2001; 7(1):77–87.PubMedCrossRefGoogle Scholar
  121. 121.
    Tsai CL, Drejer AH, Schatz DG. Evidence of a critical architectural function for the RAG proteins in end processing, protection and joining in V(D)J recombination. Genes Dev 2002; 16(15):1934–1949.PubMedCrossRefGoogle Scholar
  122. 122.
    Richardson C, Jasin M. Coupled homologous and nonhomologous repair of a double-strand break preserves genomic integrity in mammalian cells. Mol Cell Biol 2000; 20(23):9068–9075.PubMedCrossRefGoogle Scholar
  123. 123.
    Lee GS, Neiditch MB, Salus SS et al. RAG proteins shepherd double-strand breaks to a specific pathway, suppressing error-prone repair, but RAG nicking initiates homologous recombination. Cell 2004; 117(2):171–184.PubMedCrossRefGoogle Scholar
  124. 124.
    Corneo B, Wendland RL, Deriano L et al. Rag mutations reveal robust alternative end joining. Nature 2007; 449(7161):483–486.PubMedCrossRefGoogle Scholar
  125. 125.
    Yan CT, Boboila C, Souza EK et al. IgH class switching and translocations use a robust nonclassical end-joining pathway. Nature 2007; 449(7161):478–482.PubMedCrossRefGoogle Scholar
  126. 126.
    Soulas-Sprauel P, Le Guyader G, Rivera-Munoz P et al. Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination. J Exp Med 2007; 204(7):1717–1727.PubMedCrossRefGoogle Scholar
  127. 127.
    DiBiase SJ, Zeng ZC, Chen R et al. DNA-dependent protein kinase stimulates an independently active, nonhomologous, end-joining apparatus. Cancer Res 2000; 60(5):1245–1253.PubMedGoogle Scholar
  128. 128.
    Meaburn KJ, Misteli T, Soutoglou E. Spatial genome organization in the formation of chromosomal translocations. Semin Cancer Biol 2007; 17(1):80–90.PubMedCrossRefGoogle Scholar
  129. 129.
    Soutoglou E, Dorn JF, Sengupta K et al. Positional stability of single double-strand breaks in mammalian cells. Nat Cell Biol 2007; 9(6):675–682.PubMedCrossRefGoogle Scholar
  130. 130.
    Lisby M, Mortensen UH, Rothstein R. Colocalization of multiple DNA double-strand breaks at a single Rad52 repair centre. Nat Cell Biol 2003; 5(6):572–577.PubMedCrossRefGoogle Scholar
  131. 131.
    Lukasova E, Kozubek S, Kozubek M et al. Localisation and distance between ABL and BCR genes in interphase nuclei of bone marrow cells of control donors and patients with chronic myeloid leukaemia. Hum Genet 1997; 100(5–6):525–535.PubMedGoogle Scholar
  132. 132.
    Kozubek S, Lukasova E, Ryznar L et al. Distribution of ABL and BCR genes in cell nuclei of normal and irradiated lymphocytes. Blood 1997; 89(12):4537–4545.PubMedGoogle Scholar
  133. 133.
    Branco MR, Pombo A. Intermingling of chromosome territories in interphase suggests role in translocations and transcription-dependent associations. PLoS Biol 2006; 4(5):e138.PubMedCrossRefGoogle Scholar
  134. 134.
    Chen HT, Bhandoola A, Difilippantonio MJ et al. Response to RAG-mediated VDJ cleavage by NBS1 and gamma-H2AX. Science 2000; 290(5498):1962–1965.PubMedCrossRefGoogle Scholar
  135. 135.
    Perkins EJ, Nair A, Cowley DO et al. Sensing of intermediates in V(D)J recombination by ATM. Genes Dev 2002; 16(2):159–164.PubMedCrossRefGoogle Scholar
  136. 136.
    Bender CF, Sikes ML, Sullivan R et al. Cancer predisposition and hematopoietic failure in Rad50(S/S) mice. Genes Dev 2002; 16(17):2237–2251.PubMedCrossRefGoogle Scholar
  137. 137.
    Celeste A, Petersen S, Romanienko PJ et al. Genomic instability in mice lacking histone H2AX. Science 2002; 296(5569):922–927.PubMedCrossRefGoogle Scholar
  138. 138.
    Liyanage M, Weaver Z, Barlow C et al. Abnormal rearrangement within the alpha/delta T-cell receptor locus in lymphomas from Atm-deficient mice. Blood 2000; 96(5):1940–1946.PubMedGoogle Scholar
  139. 139.
    Kang J, Bronson RT, Xu Y. Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair. EMBO J 2002; 21(6):1447–1455.PubMedCrossRefGoogle Scholar
  140. 140.
    Difilippantonio S, Celeste A, Fernandez-Capetillo O et al. Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nat Cell Biol 2005; (7):675–685.PubMedCrossRefGoogle Scholar
  141. 141.
    Ward IM, Difilippantonio S, Minn K et al. 53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice. Mol Cell Biol 2005; 25(22):10079–10086.PubMedCrossRefGoogle Scholar
  142. 142.
    Liao MJ, Van Dyke T, Critical role for atm in suppressing V(D)J recombination-driven thymic lymphoma. Genes Dev 1999; 13(10):1246–1250.PubMedCrossRefGoogle Scholar
  143. 143.
    Petiniot LK, Weaver Z, Vacchio M et al. RAG-mediated V(D)J recombination is not essential for tumorigenesis in atm-deficient mice. Mol Cell Biol 2002; 22(9):3174–3177.PubMedCrossRefGoogle Scholar
  144. 144.
    Bredemeyer AL, Sharma GG, Huang CY et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 2006; 442(7101):466–470.PubMedCrossRefGoogle Scholar
  145. 145.
    Callen E, Jankovic M, Difilippantonio S et al. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell 2007; 130(1):63–75.PubMedCrossRefGoogle Scholar
  146. 146.
    Rosenwald A. DNA microarrays in lymphoid malignancies. Oncology (Williston Park). ec 2003; 17(12):1743–1748; discussion 1750, 1755, 1758–1749 passim.Google Scholar
  147. 147.
    Matsuoka S, Ballif BA, Smogorzewska A et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 2007; 316(5828):1160–1166.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Department of Pathology and Program in Molecular Pathogenesis The Helen L. and Martin S. Kimmel Center for Biology and Medicine Skirball Institute for Biomolecular MedicineNew York University School of MedicineNew YorkUSA

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