Specificity in V(D)J recombination: New lessons from biochemistry and genetics

Current Opinion in Immunology

Volumn 9, Issue 1, 1997, Pages 114-120

  Ramsden, Dale A ^a   Van Gent, Dik C ^b   Gellert, Martin ^a  

^a NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

^b ERASMUS MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

DOUBLE STRANDED DNA; IMMUNOGLOBULIN J CHAIN; LYMPHOCYTE ANTIGEN RECEPTOR;

ANTIGEN PRESENTATION; ARTICLE; DNA REPAIR; IMMUNOGLOBULIN VARIABLE REGION; INTEGRATION;

EID: 0031045205     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(97)80167-7     Document Type: Article

References (42)

1. Gellert M. Molecular analysis of V(D)J recombination. Annu Rev Genet. 22:1992;425-446.
2. Lewis SM. The mechanism of V(D)J joining: lessons from molecular, immunological, and comparative analyses. Adv Immunol. 56:1994;27-150.
3. Schatz DG, Oettinger MA, Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 59:1989;1035-1048.
4. Oettinger MA, Schatz DG, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 248:1990;1517-1523.
5. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Friedrich W, Seger RA, Hansen-Hagge TE, Desiderio S, et al. RAG mutations in human B cell-negative SCID. Science. 274:1996;97-99.
6. Roth DB, Nakajima PB, Menetski JP, Bosma MJ, Gellert M. V(D)J recombination in mouse thymocytes: double-strand breaks near T cell receptor δ rearrangement signals. Cell. 69:1992;41-53.
7. Schlissel M, Constantinescu A, Morrow T, Baxter M, Peng A. Double-strand signal sequence breaks in V(D)J recombination are blunt, 5'-phosphorylated, RAG-dependent, and cell-cycle-regulated. Genes Dev. 7:1993;2520-2532.
8. Ramsden DA, Gellert M. Formation and resolution of double strand break intermediates in V(D)J rearrangement. of outstanding interest Genes Dev. 9:1995;2409-2420 Broken signal ends can be chased into signal joints, showing that DNA molecules broken at RSSs are real intermediates in V(D)J recombination. Hairpin coding ends are also detected in actively rearranging cells, supporting the notion that they are precursors to coding joints.
9. Steen SB, Gomelsky L, Roth DB. The 12/23 rule is enforced at the cleavage step of V(D)J recombination in vivo. of special interest Genes to Cells. 1:1996;543-553 In cells, formation of DSBs correlates well with the ability to finish V(D)J recombination. If one RSS cannot be cut because of a mutation, the other one is also not cut efficiently, suggesting that the ability to perform V(D)J recombination is regulated at the cleavage step.
10. Roth DB, Zhu C, Gellert M. Characterization of broken DNA molecules associated with V(D)J recombination. Proc Natl Acad Sci USA. 90:1993;10788-10792.
11. Roth DB, Menetski JP, Nakajima PB, Bosma MJ, Gellert M. V(D)J recombination: broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes. Cell. 70:1992;983-991.
12. Zhu C, Roth DB. Characterization of coding ends in thymocytes of scid mice: implications for the mechanism of V(D)J recombination. Immunity. 2:1995;101-112.
13. Van Gent DC, McBlane JF, Ramsden DA, Sadofsky MJ, Hesse JE, Gellert M. Initiation of V(D)J recombination in a cell-free system. of special interest Cell. 81:1995;925-934 The first description of a cell-free system to study initiation of V(D)J recombination. The RAG1 and RAG2 proteins are shown to be directly involved in the formation of DSBs at RSSs.
14. McBlane JF, Van Gent DC, Ramsden DA, Romeo C, Cuomo CA, Gellert M, Oettinger MA. Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. of outstanding interest Cell. 83:1995;387-395 Purified RAG1 and RAG2 proteins are shown to cleave a V(D)J signal, generating a hairpin coding end and a blunt signal end, just as found in vivo.
15. Van Gent DC, Mizuuchi K, Gellert M. Similarities between initiation of V(D)J recombination and retroviral integration. of outstanding interest Science. 271:1996;1592-1594 This paper describes the detailed mechanism of V(D)J cleavage. Hairpins are formed by direct trans-esterification, in a reaction very similar to transpositional recombination.
16. Mizuuchi K, Adzuma K. Inversion of the phosphate chirality at the target site of Mu DNA strand transfer: evidence for a one-step transesterification mechanism. Cell. 66:1991;129-140.
17. Engelman A, Mizuuchi K, Craigie R. HIV-1 DNA integration: mechanism of viral DNA cleavage and DNA strand transfer. Cell. 67:1991;1211-1221.
18. Vink C, Yeheskiely E, Van der Marel GA, Van Boom JH, Plasterk RHA. Site-specific hydrolysis and alcoholysis of human immunodeficiency virus DNA termini mediated by the viral integrase protein. Nucleic Acids Res. 19:1991;6691-6698.
19. Thompson CB. New insights into V(D)J recombination and its role in the evolution of the immune system. Immunity. 3:1995;531-539.
20. Dreyfus DH. Evidence suggesting an evolutionary relationship between transposable elements and immune system recombination sequences. Mol Immunol. 29:1992;807-810.
21. Hesse JE, Lieber MR, Mizuuchi K, Gellert M. V(D)J recombination: a functional definition of the joining signals. Genes Dev. 3:1989;1053-1061.
22. Cuomo CA, Mundy CL, Oettinger MA. DNA sequence and structure requirements for cleavage of V(D)J recombination signal sequences. of outstanding interest Mol Cell Biol. 16:1996;5683-5690 See annotation [23].
23. Ramsden DA, McBlane JF, Van Gent DC, Gellert M. Distinct DNA sequence and structure requirements for the two steps of V(D)J recombination signal cleavage. of outstanding interest EMBO J. 15:1996;3197-3206 This paper, together with [22], shows that the ability of mutated RSSs to be cleaved to hairpins generally correlates with their recombination in cells. Unpairing of the DNA at the signal border is found to be an important feature of V(D)J cleavage.
24. 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. 87:1996;253-262.
25. Spanopoulou E, Zaitseva F, Wang F, Santagata S, Baltimore D, Panayotou G. The homeodomain region of Rag-1 reveals the parallel mechanisms of bacterial and V(D)J recombination. Cell. 87:1996;263-276.
26. Hiom K, Gellert M. A stable RAG1-RAG2-DNA complex that is active in V(D)J cleavage. Cell. 1997;. in press.
27. Van Gent DC, Ramsden DA, Gellert M. The RAG1 and RAG2 proteins establish the 12/23 rule in V(D)J recombination. of outstanding interest Cell. 85:1996;107-113 The RAG1 and RAG2 proteins by themselves are shown to be sufficient to establish the 12/23 rule in V(D)J recombination. See also annotation [29].
28. 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. 13:1993;1363-1370.
29. Eastman QM, Leu TM, Schatz DG. Initiation of V(D)J recombination in vitro obeying the 12/23 rule. of outstanding interest Nature. 380:1996;85-88 Cleavage in cell extracts is shown to follow the 12/23 rule. Both signals have to be functional for efficient cleavage.
30. Sadofsky M, Hesse JE, Van Gent DC, Gellert M. RAG-1 mutations that affect the target specificity of V(D)J recombination: a possible direct role of RAG-1 in site recognition. Genes Dev. 9:1995;2193-2199.
31. Roman CAJ, Baltimore D. Genetic evidence that the RAG1 protein directly participates in V(D)J recombination through substrate recognition. Proc Natl Acad Sci USA. 93:1996;2333-2338.
32. Bogue M, Roth DB. Mechanism of V(D)J recombination. Curr Opin Immunol. 8:1996;175-180.
33. CS complements the mouse scid mutation.
34. Kirchgessner CU, Patil CK, Evans JW, Cuomo CA, Fried LM, Carter T, Oettinger MA, Brown JM. DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. of special interest Science. 267:1995;1178-1183 See annotation [33].
35. Peterson SR, Kurimasa A, Oshimura M, Dynan WS, Bradbury EM, Chen DJ. Loss of the catalytic subunit of the DNA-dependent protein kinase in DNA double-strand-break-repair mutant mammalian cells. of special interest Proc Natl Acad Sci USA. 92:1995;3171-3174 See annotation [33].
36. Blunt T, Gell D, Fox M, Taccioli GE, Lehmann AR, Jackson SP, Jeggo PA. Identification of a nonsense mutation in the carboxyterminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse. Proc Natl Acad Sci USA. 93:1996;10285-10290.
37. Danska JS, Holland DP, Mariathasan S, Williams KM, Guidos CJ. Biochemical and genetic defects in the DNA-dependent protein kinase in murine scid lymphocytes. Mol Cell Biol. 16:1996;5507-5517.
38. Wiler R, Leber R, Moore BB, Van Dyk LF, Perryman LE, Meek K. Equine severe combined immunodeficiency: a defect in V(D)J recombination and DNA-dependent protein kinase activity. Proc Natl Acad Sci USA. 92:1995;11485-11489.
39. Nussenzweig A, Chen C, Da Costa Soares V, Sanchez M, Sokol K, Nussenzweig MC, Li GC. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. of outstanding interest Nature. 382:1996;551-555 See annotation [40].
40. Zhu C, Bogue MA, Lim DS, Hasty P, Roth DB. Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates. of outstanding interest Cell. 86:1996;379-389 Together with [39], this paper shows that the gene encoding the large subunit of the Ku heterodimer is required for efficient V(D)J recombination in mice. Surprisingly, mice lacking Ku86 retained intact signal ends, showing that these DNA termini are protected even in the absence of the DNA-end-binding Ku heterodimer.
41. Li Z, Otevrel T, Gao Y, Cheng H-L, Seed B, Stamato TD, Taccioli GE, Alt FW. The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination. of special interest Cell. 83:1995;1079-1089 This paper describes the cloning of the XRCC4 gene, whose function is required for efficient V(D)J recombination and DSB repair.
42. Stanhope-Baker P, Hudson KM, Shaffer AL, Constantinescu A, Schlissel MS. Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro. of outstanding interest Cell. 85:1996;887-897 An assay to study V(D)J signal accessibility in isolated nuclei is described. In general, the pattern of cleavage (by RAG1, RAG2, and a cell extract) faithfully reproduced patterns of V(D)J recombination observed in development (e.g. certain immunoglobulin loci are cleaved only in nuclei derived from the B-cell lineage).