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Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system

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Abstract

The RAG1 and RAG2 proteins together initiate V(D)J recombination by performing cleavage of chromosomal DNA adjacent to antigen receptor gene segments. Like the adaptive immune system itself,RAG1 andRAG2 are found only in jawed vertebrates. The hypothesis thatRAG1 andRAG2 arose in evolution as components of a transposable element has received dramatic support from our recent finding that the RAG proteins are a fully functional transposase in vitro. This result strongly suggests that antigen receptor genes acquired their unusual structure as a consequence of the insertion of a transposable element into an ancestral receptor gene by RAG1 and RAG2 approx 450 million years ago.

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References

  1. Rast JP, Anderson MK, Strong SJ, Luer C, Litman RT, Litman GW: α, Β, γ, and δ T cell antigen receptor genes arose early in vertebrate phylogeny. Immunity 1997;6:1–11.

    Article  PubMed  CAS  Google Scholar 

  2. Lewis SM: The mechanism of V(D)J joining: lessons from molecular, immunological, and comparative analyses. Adv Immunol 1994;56: 27–150.

    Article  PubMed  CAS  Google Scholar 

  3. Berg DE, Howe MM: Mobile DNA Washington, DC, American Society for Microbiology, 1989.

  4. Hozumi N, Tonegawa S: Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions. Proc Natl Acad Sci USA 1976;73: 3628–3632.

    Article  PubMed  CAS  Google Scholar 

  5. Sakano H, Hüppi K, Heinrich G, Tonegawa S: Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature 1979;280:288–294.

    Article  PubMed  CAS  Google Scholar 

  6. Davis MM, Bjorkman PJ: T-cell antigen receptor genes and T-cell recognition. Nature 1988;334: 395–402.

    Article  PubMed  CAS  Google Scholar 

  7. Schatz DG, Oettinger MA, Balti-more D: The V(D)J recombination activating gene (RAG-1). Cell 1989;59:1035–1048.

    Article  PubMed  CAS  Google Scholar 

  8. Oettinger MA, Schatz DG, Gorka C, Baltimore D: RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 1990;248: 1517–1523.

    Article  PubMed  CAS  Google Scholar 

  9. Schatz DG, Baltimore D: Stable expression of immunoglobulin gene V(D)J recombinase activity by gene transfer into 3T3 fibroblasts. Cell 1988;53:107–115.

    Article  PubMed  CAS  Google Scholar 

  10. van Gent DC, McBlane JF, Rams-den DA, Sadofsky MJ, Hesse JE, Geliert M: Initiation of V(D)J recombination in a cell-free system. Cell 1995;81:925–934.

    Article  PubMed  Google Scholar 

  11. McBlane JF, van Gent DC, Rams-den DA, Romeo C, Cuomo CA, Geliert M, 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.

    Article  PubMed  CAS  Google Scholar 

  12. Kennedy A, Guhathakurta A, Kleck-ner N, Haniford D: Tn10 transposition via a DNA hairpin intermediate. Cell 1998;95:125–134.

    Article  PubMed  CAS  Google Scholar 

  13. Thompson CB: New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity 1995;3:531–539.

    Article  PubMed  CAS  Google Scholar 

  14. van Gent DC, Mizuuchi K, Geliert M: Similarities between initiation of V(D)J recombination and retroviral integration. Science 1996; 271:1592–1594.

    Article  PubMed  Google Scholar 

  15. MelekM, Gellert M, van Gent DC: Rejoining of DNA by the RAG1 and RAG2 proteins. Science 1998; 280:301–303.

    Article  PubMed  CAS  Google Scholar 

  16. Tonegawa S: Somatic generation of antibody diversity. Nature 1983;302:575–581.

    Article  PubMed  CAS  Google Scholar 

  17. Hiom K, Gellert M: A stable RAG1RAG2-DNA complex that is active in V(D)J cleavage. Cell 1997;88: 65–72.

    Article  PubMed  CAS  Google Scholar 

  18. Sawchuk DJ, Weis-Garcia F, Malik S, Besmer E, Bustin M, Nussen-zweig MC, et al.: V(D)J recombination: Modulation of RAG1 and RAG2 cleavage activity on 12/23 substrates by whole cell extract and DNA bending proteins. J Exp Med 1997; 185:2025–2032.

    Article  PubMed  CAS  Google Scholar 

  19. van Gent DC, Hiom K, Pauli TT, Geliert M: Stimulation of V(D)J cleavage by high mobility group proteins. EMBO J 1997;16: 2665–2670.

    Article  PubMed  Google Scholar 

  20. Hiom K, Gellert M: Assembly of a 12/23 paired signal complex: A critical control point in V(D)J recombination. Mol Cell 1998; 1:1011–1019.

    Article  PubMed  CAS  Google Scholar 

  21. Sheehan KM, Lieber MR: V(D)J recombination: signal and coding joint resolution are uncoupled and depend on parallel synapsis of the sites. Mol Cell Biol 1993; 13: 1363–1370.

    PubMed  CAS  Google Scholar 

  22. Lewis SM, Hesse JE: Cutting and closing without recombination in V(D)J joining. EMBO J 1991 ; 10: 3631–3639.

    PubMed  CAS  Google Scholar 

  23. Eastman QM, Leu TMJ, Schatz DG: Initiation of V(D)J recombination in vitro obeying the 12/23 rule. Nature 1996;380:85–88.

    Article  PubMed  CAS  Google Scholar 

  24. Eastman QM, Schatz DG: Nicking is asynchronous and stimulated by synapsis in 12/23 ruleregulated V(D)J cleavage. Nucleic Acids Res 1997;25:4370–4378.

    Article  PubMed  CAS  Google Scholar 

  25. Difilippantonio MJ, McMahan CJ, Eastman QM, Spanopoulou E, Schatz DG: RAG1 mediates signal sequence recognition and recruitment of RAG2 in V(D)J recombination. Cell 1996;87: 253–262.

    Article  PubMed  CAS  Google Scholar 

  26. Spanopoulou E, Zaitseva F, Wang F-H, Santagata S, Baltimore D, Panayotou G: The homeodomain of RAG-1 reveals the parallel mechanisms of bacterial and V(D)J recombination. Cell 1996;87:263–276.

    Article  PubMed  CAS  Google Scholar 

  27. Swanson PC, Desiderio S: V(D)J recombination signal recognition distinct, overlapping DNA-protein contacts in complexes containing RAG1 with and without RAG2. Immunity 1998;9:115–125.

    Article  PubMed  CAS  Google Scholar 

  28. Eastman QM, Schatz DG: Detection of RAG protein-V(D)J recombination signal interactions near the site of DNA cleavage by UV crosslinking. Mol Cell Biol 1999;19:3788–3797.

    PubMed  CAS  Google Scholar 

  29. Smider V, Chu G: The end-joining reaction in V(D)J recombination. Semin Immunol 1997;9: 189–197.

    Article  PubMed  CAS  Google Scholar 

  30. Li ZY, Otevrel T, Gao YJ, Cheng HL, Seed B, Stamato TD, et al.: The XRCC4 gene encodes a novel protein involved in DNA doublestrand break repair and V(D)J recombination. Cell 1995;83: 1079–1089.

    Article  PubMed  CAS  Google Scholar 

  31. Grawunder U, Zimmer D, Fug-mann S, Schwarz K, Lieber MR: DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes. Mol Cell 1998;2:477–484.

    Article  PubMed  CAS  Google Scholar 

  32. Frank KM, Sekiguchi JM, Seidl KJ, Swat W, Rathbun GA, Cheng HL, et al.: Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV Nature 1998;396:173–177.

    Article  PubMed  CAS  Google Scholar 

  33. Agrawal A, Schatz DG: RAG1 and RAG2 form a stable post-cleavage synaptic complex with DNA containing signal ends in V(D)J recombination. Cell 1997;89:43–53.

    Article  PubMed  CAS  Google Scholar 

  34. Roth DB, Nakajima PB, Menetski JP, Bosma MJ, Gellert M: V(D)J recombination in mouse thymocytes: double-stranded breaks near T-cell receptor delta rearrangement signals. Cell 1992;69: 41–53.

    Article  PubMed  CAS  Google Scholar 

  35. Ramsden DA, Gellert M: Formation and resolution of doublestrand break intermediates in V(D)J rearrangement. Genes Dev 1995;9:2409–2420.

    Article  PubMed  CAS  Google Scholar 

  36. Livàk F, Schatz DG: T-cell receptor alpha locus V(D)J recombination by-products are abundant in thymocytes and mature T cells. Mol Cell Biol 1996;16:609–618.

    PubMed  Google Scholar 

  37. Livàk F, Schatz DG: Identification of V(D)J recombination coding end intermediates in normal thymocytes. J Mol Biol 1997;267:1–9.

    Article  PubMed  Google Scholar 

  38. Schlissel MS: Structure of nonhairpin coding-end DNA breaks in cells undergoing V(D)J recombination. Mol Cell Biol 1998;18: 2029–2037.

    PubMed  CAS  Google Scholar 

  39. Zhu CM, Bogue MA, Lim DS, Hasty P, Roth DB: Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates. Cell 1996;86: 379–389.

    Article  PubMed  CAS  Google Scholar 

  40. Guidos CJ, Williams CJ, Ildiko G, Knowles G, Huang MTF, Danska JS: V(D)J recombination activates a p53-dependent DNA damage checkpoint inscid lymphocyte precursors. Genes Dev 1996; 10: 2038–2054.

    Article  PubMed  CAS  Google Scholar 

  41. Leu TMJ, Eastman QM, Schatz DG: Coding joint formation in a cell free V(D)J recombination system. Immunity 1997;7:303–314.

    Article  PubMed  CAS  Google Scholar 

  42. Ramsden DA, Pauli TT, Gellert M: Cell-free V(D)J recombination. Nature 1997;388:488–491.

    Article  PubMed  CAS  Google Scholar 

  43. Levchenko I, Luo L, Baker TA: Disassembly of the Mu transposase tetramer by the C1pX chaperone. Genes Dev 1995;9: 2399–2408.

    Article  PubMed  CAS  Google Scholar 

  44. Kruklitis R, Welty DJ, Nakai H: ClpX protein ofEscherichia coli activates bacteriophage Mu transposase in the strand transfer complex for initiation of Mu DNA synthesis. EMBO J 1996;15: 935–944.

    PubMed  CAS  Google Scholar 

  45. Besmer E, Mansilla-Soto J, Cas-sard S, Sawchuk DJ, Brown G, Sadofsky M, et al.: Hairpin coding end opening is mediated by RAG1 and RAG2 proteins. Mol Cell 1998; 2:817–828.

    Article  PubMed  CAS  Google Scholar 

  46. Agrawal A, Eastman QM, Schatz DG: Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 1998;394: 744–751.

    Article  PubMed  CAS  Google Scholar 

  47. West RB, Lieber MR: The RAGHMG1 complex enforces the 12/ 23 rule of V(D)J recombination specifically at the double-hairpin formation step. Mol Cell Biol 1998;18:6408–6415.

    PubMed  CAS  Google Scholar 

  48. Hiom K, Melek M, Geliert M: DNA transposition by the RAG1 and RAG2 proteins: A possible source of oncogenic translocations. Cell 1998;94:463–470.

    Article  PubMed  CAS  Google Scholar 

  49. Kleckner N, Chalmers RM, Kwon D, Sakai J, Bolland S: Tn10 and IS10 transposition and chromosome rearrangements: mechanism and regulation in vivo and in vitro. Curr Top Microbiol Immunol 1996;204:49–82.

    PubMed  CAS  Google Scholar 

  50. Chalmers R, Guhathakurta A, Ben-jamin H, Kleckner N: IHF modulation ofTn10 transposition: sensory transduction of supercoiling status via a proposed protein/DNA molecular spring. Cell 1998;93: 897–908.

    Article  PubMed  CAS  Google Scholar 

  51. Weinert TA, Derbyshire KM, Hughson FM, Grindley NDF: Replicative and conservative transpositional recombination of insertion sequences. Cold Spring Harbor Symp Quant Biol 1984; 49:251–260.

    PubMed  CAS  Google Scholar 

  52. Mizuuchi K: Transpositional recombination: Mechanistic insights from studies of Mu and other elements. Annu Rev Biochem 1992;61:1011–1051.

    Article  PubMed  CAS  Google Scholar 

  53. Litman GW, Rast JP, Shamblott MJ, Haire RN, Hulst M, Roess W, et al.:Phylogenetic diversification of immunoglobulin genes and the antibody repertoire. Mol Biol Evol 1993;10:60–72.

    PubMed  CAS  Google Scholar 

  54. Graninger WB, Goldman PL, Morton CC, O’Brien SJ, Kors-meyer SJ: The K-deleting ele-ment. J Exp Med 1988;167: 488–501.

    Article  PubMed  CAS  Google Scholar 

  55. Janeway CA: The evolution of self:non-self discrimination systems. The Immunologist 1993; 1:36–39.

    Google Scholar 

  56. McCormack WT, Tjoelker LW, Thompson CB: Avian B cell development: Generation of an immunoglobulin repertoire by gene conversion. Annu Rev Immunol 1991;9:219–241.

    Article  PubMed  CAS  Google Scholar 

  57. Becker RS, Knight KL: Somatic diversification of immunoglobulin heavy chain VDJ genes: evidence for somatic gene conversion in rabbits. Cell 1990;63:987–997.

    Article  PubMed  CAS  Google Scholar 

  58. Reynaud C-A, Mackay CR, Muller RG, Weill J-C: Somatic generation of diversity in a mammalian primary lymphoid organ: the sheep ileal Peyer’s patches. Cell 1991; 64:995–1005.

    Article  PubMed  CAS  Google Scholar 

  59. Roth DB, Craig NL:V(D)Jrecombination-a transposase goes to work. Cell 1998;94:411–414.

    Article  PubMed  CAS  Google Scholar 

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  1. Yale University School of Medicine, 310 Cedar Street, 06520-8011, New Haven, CT

    David G. Schatz

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Schatz, D.G. Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system. Immunol Res 19, 169–182 (1999). https://doi.org/10.1007/BF02786485

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