Antigen receptor gene rearrangement

Current Opinion in Immunology

Volumn 10, Issue 2, 1998, Pages 172-180

  Grawunder, Ulf ^a   West, Robert B ^a   Lieber, Michael R ^a  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DOUBLE STRANDED DNA; LYMPHOCYTE ANTIGEN RECEPTOR;

B LYMPHOCYTE; BIOCHEMISTRY; CELL MATURATION; DNA REPAIR; DNA STRAND BREAKAGE; GENE REARRANGEMENT; GENE SEQUENCE; GENETIC RECOMBINATION; NONHUMAN; RECEPTOR GENE; REVIEW; T LYMPHOCYTE;

EID: 0031978710     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(98)80246-X     Document Type: Article

References (69)

1. Tonegawa S. Somatic generation of antibody diversity. Nature. 302:1983;575-581.
2. Schatz DG, Oettinger MA, Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 59:1989;1035-1048.
3. Oettinger MA, Schatz D, Gorka C, Baltimore D. Rag-1 and Rag-2, adjacent genes that synergistically activate V(D)J recombination. Science. 248:1990;1517-1523.
4. Van Gent DC, McBlane JF, Ramsden DA, Sadofsky MJ, Hesse JE, Gellert M. Initiation of V(D)J recombination in a cell-free system. Cell. 81:1995;925-934.
5. 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. Cell. 83:1995;387-395.
6. of outstanding interest Van Gent DC, Mizuuchi K, Gellert M. Similarities between of V(D)J recombination and retroviral integration. Science. 271:1996;1592-1594 This reports that the chemistry of the V(D)J gene nicking step in V(D)J recombination is like the nicking sep in transposable element nicking or retrovirus 3′ end nicking. The chemistry of the hairpinning step of V(D)J recombination is the same as the strand transfer step of prokaryotic transposition or the integration step of retroviruses. All of this is consistent with the original hypothesis of Sakano and Tonegawa that V(D)J recombination derived from transposable elements.
7. Craig NL. V(D)J recombination and transposition: closer than expected. Science. 271:1996;1512-1513.
8. of special interest Hoim K, Gellert M. A stable RAG1-RAG2-DNA complex that is active in V(D)J cleavage. Cell. 88:1997;65-72 Binding contacts between the recombination-activating genes (RAGs) and the heptamer and nonamer of a single recombination signal require both RAG-1 and RAG-2.
9. Grawunder U, Lieber MR. A complex of RAG-1 and RAG-2 persists on the DNA after single-strand cleavage at V(D)J recombination signal sequences. Nucleic Acids Res. 25:1997;1375-1382.
10. 2+, which promotes cleavage events at isolated recombination signals. However, the efficiency and accuracy of cleavage events according to the 12/23 base-pair paradigm is relatively low. References [12,13] below provide a possible explanation for this.
11. 2+ as a divalent cation is mandatory in order to enforce the 12/23 base-pair rule.
12. of special interest Sawchuk D, Weis-Garcia F, Malik S, Besmer E, Bustin M, Nussenzweig M, Cortes P. 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. 185:1997;2025-2032 This study analyzes cleavage at 12/23 base-pair recombination signals by purified core recombination-activating gene (RAG)-1 and -2 proteins. The authors find that the efficiency of concerted cutting is greatly enhanced in the presence of either total cell extracts or a mix of DNA bending high-mobility group (HMG)-1 and -2 proteins.
13. of outstanding interest Van Gent D, Hoim K, Paull T, Gellert M. Stimulation of V(D)J cleavage by high mobility group proteins. EMBO J. 16:1997;2665-2670 The paper shows that HMG-1 protein stimulates recombination-activating gene cleavage at isolated signals with a 23 base-pair spacer, as well as concerted cutting at synapsed 12/23 base-pair recombination signals.
14. of outstanding interest Difilippantonio M, McMahan C, Eastman O, Spanopoulou E, Schatz DG. RAG1 mediates signal sequence recognition and recruitment of RAG2 in V(D)J recombination. Cell. 87:1996;253-262 This study uses a clever method of fusing core recombination-activating gene (RAG)-1 and RAG-2 proteins to a transcriptional activator. Binding of the RAG protein moieties to DNA is assayed by luciferase expression from a reporter construct containing the luciferase gene driven by tandem arrays of various recombination signal sequences and a minimal cytomegalovirus promoter. It was found that RAG-1 fusion proteins mediate binding to signals mainly through the nonamer. RAG-2 protein does not display significant signal-binding activity and appears to be recruited to the cleavage site by RAG-1.
15. of outstanding interest Spanopoulou E, Zaitseva F, Wang FH, 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 Signal sequence binding of recombinant full-length and core recombination-activating gene (RAG) proteins, as well as mutants thereof, was measured using surface plasmon resonance. In agreement with [14], binding to signals was only detectable by RAG-1, but not by RAG-2, protein. The authors further determined that DNA binding is mainly mediated by a region in RAG-1 that displays homology to bacterial Hin recombinase. As in [14] binding appears to mediated mainly by the nonamer of the recombination signal.
16. Hsieh C, McCloskey RP, Lieber MR. V(D)J recombination on minichromosomes is not affected by transcription. J Biol Chem. 267:1992;5613-5619.
17. Schlissel M, Voronova A, Baltimore D. Helix-loop-helix transcription factor E47 activates germ-line immunoglobulin heavy-chain gene transcription and rearrangement in a pre-T-cell line. Genes Dev. 5:1991;1367-1376.
18. Alvarez JD, Anderson SJ, Loh DY. V(D)J recombination and allelic exclusion of a TCR beta chain minilocus occurs in the absence of a functional promoter. J Immunol. 155:1995;1191-1202.
19. Engler P, Roth P, Kim JY, Storb U. Factors affecting the rearrangement efficiency of an Ig test gene. J Immunol. 146:1991;2826-2835.
20. Ferrier P, Krippl B, Blackwell TK, Furley AJW, Suh H, Winoto A, Cook WD, Hood L, Constantini F, Alt FW. Separate elements control DJ and VDJ rearrangement in a transgenic recombination substrate. EMBO J. 9:1990;117-125.
21. Capone M, Watrin F, Fernex C, Horvat B, Krippl B, Wu L, Scollay R, Ferrier P. TCRβ and TCRα gene enhancers confer tissue- and stage-specificity to V(D)J recombination events. EMBO J. 12:1993;4335-4346.
22. Fernex C, Caillol D, Capone M, Krippl B, Ferrier P. Sequences affecting the V(D)J recombinational activity of the IgH intronic enhancer in a transgenic substrate. Nucleic Acids Res. 22:1994;792-798.
23. Lichtenstein M, Keini G, Cedar H, Bergman Y. B cell-specific demethylation: a novel role for the intronic κ chain enhancer sequence. Cell. 76:1994;913-923.
24. Engler P, Weng A, Storb U. Influence of CpG methylation and target spacing on V(D)J recombination in a transgenic substrate. Mol Cell Biol. 13:1993;571-577.
25. Hsieh C, Lieber MR. CpG methylated minichromosomes become inaccessible for V(D)J recombination after undergoing replication. EMBO J. 11:1992;315-325.
26. Constantinescu A, Schlissel MS. Changes in locus-specific V(D)J recombinase activity induced by immunoglobulin gene products during B cell development. J Exp Med. 185:1996;609-620.
27. of special interest Stanhope 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. Cell. 85:1996;887-897 This study analyzes cleavage events at recombination signals in isolated nuclei (i.e. in intact chromatin) catalyzed by recombinant core recombination-activating gene (RAG) proteins using ligation-mediated polymerase chain reaction. The authors find that the developmental stage of the cells from which the nuclei were derived determines the accessibility for in vitro cleavage by RAG proteins.
28. of outstanding interest Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Friedrich W, Seger RA, Hansen HT, Desiderio S, et al. RAG mutations in human B cell-negative SCID. Science. 274:1996;97-99 This study is the first demonstration that genetic mutations in recombination enzymes can result in human disease; specifically, 14% of human severe combined immunodeficiency (SCID) patients have mutations in the recombination-activating genes (RAGs)-1 and -2. This study uses human V(D)J recombination functional assays to show that these mutations result in 100- to 1000-fold decreases in the efficiency of recombination.
29. Roth DB, Menetski JP, Nakajima P, 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.
30. Danska JS, Holland DP, Mariathasan S, Williams KM, Guidos CJ. Biochemical and genetic defects in DNA-dependent protein kinase in murine scid lymphocytes. Mol Cell Biol. 16:1996;5507-5517.
31. of special interest Blunt T, Gell D, Fox M, Taccioli G, Lehman A, Jackson S, Jeggo PA. Identification of a nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse. Proc Natl Acad Sci USA. 93:1996;10285-10290 The sequence alteration responsible for murine severe combined immunod-eficiency (SCID) is described.
32. of special interest Ramsden D, Paull T, Gellert M. Cell-free V(D)J recombination. Nature. 388:1997;488-491 The authors describe the formation of signal and coding joints in an in vitro assay using proteins encoded by recombinant core recombination-activating genes and plasmid recombination substrates as detected by polymerase chain reaction. The authors show that signal and coding joint formation requires coupling of the cleavage and joining phase of V(D)J gene recombination and claim that DNA ligase I is the only one of the three known mammalian DNA ligases that stimulates V(D)J recombination in that system.
33. of special interest Leu TM, Eastman QM, Schatz DG. Coding joint formation in a cell-free V(D)J recombination system. Immunity. 7:1997;303-314 This study describes an in vitro system that allows formation of coding (but not signal) joints using extracts from cells overexpressing recombination-activating gene (RAG)-1 and -2 proteins, detected by a recombinase activating gene polymerase chain reaction assay. In agreement with [32], signal joint formation requires coupling of RAG-cleavage and DNA end-joining, suggesting a structural or mechanistic function of RAGs beyond the initial cleavage step.
34. Gottlieb T, Jackson SP. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell. 72:1993;131-142.
35. of outstanding interest 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. Cell. 86:1996;379-389 The authors demonstrate that a targeted deletion of the Ku86 gene in mice abolishes B- and T-cell development due to the inability of precursor lymphocytes to join coding and signal ends. In addition the mutation causes dwarfism in mice, suggesting other functions of Ku86. Unlike mice with SCID, Ku86 knockout mice to do not appear to be leaky for the development of mature lymphocytes with increasing age.
36. of outstanding interest Nussenzweig A, Chen C, de Costa Soares V, Sanchez M, Sokol K, Nussenzweig MC, Li GC. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature. 382:1996;551-555 The authors demonstrate that a targeted deletion of the Ku86 gene in mice abolishes B- and T-cell development due to the inability of precursor lymphocytes to join coding and signal ends. In addition the mutation causes dwarfism in mice, suggesting other functions of Ku86. Unlike mice with severe combined immunodeficiency, Ku86 knockout mice do not appear to be leaky for the development of mature lymphocytes with increasing age.
37. +, the precursor B-cell stage in bone marrow.
38. of special interest Gu Y, Jin S, Gao Y, Weaver DT, Alt FW. Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination. Proc Natl Acad Sci USA. 94:1997;8076-8081 Using embryonic stem cells carrying deletions in either allele of Ku70, the authors show that a deletion of Ku70 results in increased sensitivity to ionizing radiation and the inability to mediate V(D)J gene recombination events on extrachromosomal substrates.
39. DeVries E, Driel WW, Bergsma WG, Arnberg AC, van der Vliet PC. HeLa nuclear protein recognizing DNA termini and translocating on DNA forming a regular DNA-multimeric protein complex. J Mol Biol. 208:1989;65-78.
40. Brush G, Anderson CW, Kelly TJ. The DNA-activated protein kinase is required for the phosphorylation of replication protein A during SV40 DNA replication. Proc Natl Acad Sci USA. 91:1994;12520-12524.
41. of special interest Yaneva M, Kowaleski T, Lieber MR. Interaction of DNA-dependent protein kinase with DNA and with Ku: biochemical and atomic-force microscopy. EMBO J. 16:1997;5098-5112 DNA-dependent protein kinase (DNA-PK) can bind to DNA termini and be activated for kinase activity in the absence of Ku antigen. This may reconcile different phenotypes of the Ku70, Ku86 and DNA-PK mutations, whereas complete kinase dependence on Ku (see [34]) is more difficult to reconcile with these phenotypes.
42. Pan Z, Amin AA, Gibbs E, Niu H, Hurwitz J. Phosphorylation of the p34 subunit of human single-stranded-DNA-binding protein in cyclin A-activated G1 extracts is catalyzed by cdk-cyclin A complex and DNA-dependent protein kinase. Proc Natl Acad Sci USA. 91:1994;8343-8347.
43. Dvir A, Peterson SR, Knuth MW, Lu H, Dynan WS. Ku autoantigen is the regulatory component of a template-associated protein kinase that phosphorylates RNA polymerase II. Proc Natl Acad Sci USA. 89:1992;11920-11924.
44. Dvir A, Stein LY, Calore BL, Dynan WS. Purification and characterization of a template-associated protein kinase that phosphorylates RNA polymerase II. J Biol Chem. 268:1993;10440-10447.
45. Lieber MR, Hesse JE, Lewis S, Bosma GC, Rosenberg N, Mizuuchi K, Bosma MJ, Gellert M. The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination. Cell. 55:1988;7-16.
46. Levchenko I, Luo L, Baker TA. Disassembly of the Mu transposase tetramer by the ClpX chaperone. Genes Dev. 9:1995;2399-2408.
47. Lieber MR, Hesse JE, Mizuuchi K, Gellert M. Lymphoid V(D)J recombination: nucleotide insertion at signal joints as well as coding joints. Proc Natl Acad Sci USA. 85:1988;8588-8592.
48. Lewis SM. The mechanism of V(D)J joining: lessons from molecular, immunological and comparative analyses. Adv Immunol. 56:1994;27-150.
49. of outstanding interest Agrawal A, Schatz DG. RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination. Cell. 89:1997;43-53 This study demonstrates that the DNA ends generated after recombination-activating gene (RAG)-catalyzed concerted cleavage are held in a postsynaptic complex that protects the DNA ends from, for example, exonucleolytic degradation in vitro. Coding-end complexes bind Ku70/86 heterodimers, DNA-dependent protein kinase and high-mobility group proteins, whereas signal ends in addition to these factors also retain RAG proteins.
50. Lewis S, Hesse JE, Mizuuchi K, Gellert M. Novel strand exchanges in V(D)J recombination. Cell. 55:1988;1099-1107.
51. Harrington JJ, Lieber MR. Functional domains within FEN-1 and RAD2 define a family of structure-specific endonucleases: implications for nucleotide excision repair. Genes Dev. 8:1994;1344-1355.
52. Lieber MR, Grawunder U, Wu X, Yaneva M. Tying loose ends: roles of Ku and DNA-dependent protein kinase in the repair of double-strand breaks. Curr Opin Genet Dev. 7:1997;99-104.
53. 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. Cell. 83:1995;1079-1089.
54. of outstanding interest Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, Lieber MR. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature. 388:1997;492-495 This paper describes the association of the X-ray cross complementation group (XRCC)4 protein with DNA ligase IV by co-immunoprecipitation and using the yeast two-hybrid system. Complex formation results in stimulation of DNA ligase IV activity in vitro. Based on the relevance of XRCC4 for DNA end-joining in general DNA double-strand break-repair and V(D)J gene recombination this study suggests that DNA ligase IV is the factor responsible for catalyzing the final DNA ligation steps in both processes.
55. of special interest Critchlow S, Bowater R, Jackson SP. Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Curr Biol. 7:1997;588-598 The authors show association of native X-ray cross complementation group (XRCC)4 with DNA ligase IV by co-immunoprecipitation and after several chromatography purification steps. They find that XRCC4 is a substrate for DNA-dependent protein kinase in vitro.
56. Hsieh CL, Arlett CF, Lieber MR. V(D)J recombination in ataxia-telangiectasia, Bloom's syndrome, and a DNA ligase I-associated immunodeficiency disorder. J Biol Chem. 268:1993;20105-20109.
57. Petrini J, Donovan JW, Dimare C, Weaver DT. Normal V(D)J coding junction formation in DNA ligase I deficiency syndromes. J Immunol. 152:1994;176-183.
58. of outstanding interest Wilson TE, Grawunder U, Lieber MR. Yeast DNA ligase IV mediates non-homologous DNA end joining. Nature. 388:1997;495-498 This study demonstrates that Saccharomyces cerevisiea has a second, as yet unidentified, DNA ligase activity recognized as being due to a homologue to DNA ligase IV. Targeted disruption of the yeast DNA ligase IV gene (DNL4) reduces nonhomologous DNA end-joining by 98% percent, suggesting that DNA ligase IV is the dominant DNA ligase for rejoining DNA ends in eukaryotes.
59. of outstanding interest Teo SH, Jackson SP. Identification of S. cerevisiae DNA ligase IV: involvement in DNA double-strand break repair. EMBO J. 16:1997;4788-4795 The authors demonstrate that Saccharomyces cerevisiae has a second as yet unidentified DNA ligase activity identified as a homolog to DNA ligase IV. Targeted disruption of the yeast DNA ligase IV gene reduces non-homologous DNA end joining, suggesting that DNA liase IV is the dominant DNA ligase for rejoining DNA ends in eukaryotes.
60. of outstanding interest Schar P, Herrmann G, Daly G, Lindahl T. A newly identified DNA ligase of S. cerevisiae involved in RAD52-independent repair of DNA double-strand breaks. Genes Dev. 11:1997;1912-1924 The authors demonstrate that Saccharomyces cerevisiae has a second as yet unidentified DNA ligase activity identfied as a homolog to DNA ligase IV. Targeted disruption of the yeast DNA ligase IV gene reduces non-homologous DNA end joining, suggesting that DNA ligase IV is the dominant DNA ligase for rejoining DNA ends in eukaryotes.
61. of special interest Cortes P, Weis-Garcia F, Misulovin Z, Nussenzweig A, Lai J, Li G, Nussenzweig M, Baltimore D. In vitro V(D)J recombination: signal joint formation. Proc Natl Acad Sci USA. 93:1996;14008-14013 This describes a system that was developed to allow the formation of signal joints using purified core recombination-activating gene proteins and nuclear extracts on plasmid substrates as assayed by polymerase chain reaction. The reaction can be inhibited by the addition of anti-Ku antibodies.
62. of special interest Weis-Garcia F, Besmer E, Sawchuk DJ, Yu W, Hu Y, Cassard S, Nussenzweig M, Cortes P. V(D)J recombination: in vitro coding joint formation. Mol Cell Biol. 17:1997;6379-6385 This paper describes a system that allows the formation of coding joints using purified core recombination-activating gene proteins and nuclear extracts on plasmid substrates as assayed by polymerase chain reaction. The reaction can be inhibited by the addition of antibodies against DNA-dependent protein kinase.
63. of outstanding interest Robins P, Lindahl T. DNA ligase IV from HeLa cell nuclei. J Biol Chem. 271:1996;24257-24261 In this study, DNA ligase IV was isolated from HeLa cells and assayed for its in vitro activity. It was found that DNA ligase IV was difficult to adenylate, suggesting a high degree of preadenylation in cells. Under standard ligation conditions, DNA ligase IV was only able to perform nick ligations and unable to catalyze duplex ligations.
64. of outstanding interest Rolink A, Melchers F, Andersson J. The SCID but not the RAG-2 gene product is required for Sm-Se heavy chain switching. Immunity. 5:1996;319-330 This paper exploits the ability of precursor B cells to differentiate into surface IgM positive B cells in vitro. These cells are then responsive to stimulation by anti-CD40 plus IL-4, which induce isotype switching. Using B-cell precursors derived from recombination-activating gene (RAG)-2 deficient mice as well as mice with severe combined immunodeficiency (SCID), the authors show that V(D)J gene recombination (or RAG-2 gene function) is not required for class-switch recombination, whereas the scid gene product (DNA-dependent protein kinase) is. This implicates that end-joining in class-switch recombination might occur by the same pathway also employed for V(D)J recombination and general DNA double-strand break-repair.
65. Daniels GA, Lieber MR. RNA:DNA complex formation upon transcription of immunoglobulin switch regions: implications for the mechanism and regulation of class switch recombination. Nucleic Acids Res. 23:1995;5006-5011.
66. Daniels GA, Lieber MR. Strand-specificity in the transcriptional targeting of recombination at immunoglobulin class switch sequences. Proc Natl Acad Sci USA. 92:1995;5625-5629.
67. Stavnezer J. Immunoglobulin class switching. Curr Opin Immunol. 8:1996;199-205.
68. Lorenz M, Jung S, Radbruch A. Switch transcripts in immunoglobulin class switching. Science. 267:1995;1825-1828.
69. Sheehan K, 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.