RAG and RAG defects

Current Opinion in Immunology

Volumn 11, Issue 4, 1999, Pages 435-442

  Notarangelo, Luigi D ^a   Villa, Anna ^b   Schwarz, Klaus ^c  

^a UNIVERSITY OF BRESCIA   (Italy)

^b CNR   (Italy)

^c UNIVERSITY OF ULM   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID SEQUENCE; B LYMPHOCYTE; CELL MATURATION; GENE MUTATION; GENETIC RECOMBINATION; HOMEOSTASIS; LYMPHOID CELL; PROTEIN DOMAIN; REVIEW; T LYMPHOCYTE;

EID: 0033179119     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(99)80073-9     Document Type: Article

References (78)

1. Bogue M, Roth DB: Mechanism of V(D)J recombination. Curr Opin Immunol 1996, 8:175-180.
2. Gellert M: Recent advances in understanding V(D)J recombination. Adv Immunol 1997, 64:39-64.
3. VanGent 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.
4. Besmer E, Mansilla-Soto J, Cassard S, Sawchuck DJ, Brown G, Sadofsky M, Lewis SM, Nussenzweig MC, Cortes P: Hairpin coding end opening is mediated by Rag1 and Rag2 proteins. Mol Cell 1998, 2:817-828. This elegant study shows that rag1 and rag2 are involved in hairpin opening. Mutations in either rag1 or rag2 can interfere with this process, suggesting that rags have a single active site that catalyzes several distinct DNA cleavage reactions.
5. Paull TT, Gellert M: The 3′ to 5′ exonuclease activity of Mre11 facilites repair of Dna double-strand breaks. Mol Cell 1998, 1:969-979. This paper provides evidence that the Mre11 protein also participates in opening of the hairpin during V(D)J recombination.
6. Schatz DG, Oettinger MA, Baltimore D: The V(D)J recombination activating gene Rag1. Cell 1989, 59:1035-1048.
7. Oettinger MA, Schatz DG, Gorka C, Baltimore D: Rag1 and Rag2, adjacent genes that synergistically activate V(D)J recombination. Science 1990, 248:1517-1523.
8. Bernstein RM, Schluter SF, Bernstein H, Marchalonis JJ: Primordial emergence of the recombination activating gene 1 (Rag1): Sequence of the complete shark gene indicates homology to microbial integrases. Proc Natl Acad Sci USA 1996, 93:9454-9459.
9. Oettinger MA, Stanger B, Schatz DG, Glaser T, Call K, Housman D, Baltimore D: The recombination activating genes, Rag1 and Rag2, are on chromosome 11p in humans and chromosome 2p in mice. Immunogenetics 1992, 35:97-101.
10. Zarrin AA, Fong I, Malkin L, Marsden P, Berinstein NL: Cloning and characterization of the human recombination activating gene 1 (Rag1) and Rag2 promoter regions. J Immunol 1997, 159:4382-4394.
11. Agrawal A, Eastman Q, Schatz D: Transposition mediated by Rag1 and Rag2 and its implications for the evolution of the immune system. Nature 1998, 394:744-751. This report (together with [12••]) shows that rag proteins can drive the insertion of cleaved recombination into new DNA sites in a transpositional reaction.
12. 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. See annotation [11••].
13. Van Gent DC, McBlane JF, Ramsden DA, Sadofsky MJ, Hesse JE, Gellert M: Initiation of VDJ recombination in a cell-free system. Cell 1995, 81:925-934.
14. McMahan CJ, Sadofsky MJ, Schatz DG: Definition of a large region of Rag1 that is important for coimmunoprecipitation of Rag2. J Immunol 1997, 158:2202-2210.
15. Rodgers KK, Bu Z, Fleming KG, Schatz DG, Engelman DM, Coleman JE: A zinc binding domain involved in the dimerization of Rag1. J Mol Biol 1996, 260:70-84.
16. Cortes P, Ye ZS, Baltimore D: Rag1 interacts with the repeated amino acid motif of the human homologue of the yeast protein SRP1. Proc Natl Acad Sci USA 1994, 91:7633-7637.
17. Cuomo CA, Oettinger MA: Analysis of regions of Rag2 important for VDJ recombination. Nucleic Acids Res 1994, 22:1810-1814.
18. Spanopoulou E, Cortes P, Huang E, Shih C, Silver D, Svec P, Baltimore D: Localization, interaction and RNA-binding properties of the V(D)J recombination activating proteins Rag1 and Rag2. Immunity 1995, 3:715-726.
19. Bellon SF, Rodgers K, Schatz DG, Coleman JE, Steitz TA: Crystal structure of the Rag1 dimerization domain reveals multiple zinc-binding motifs including a novel binuclear cluster. Nat Struct Biol 1997, 7:586-591.
20. Spanopoulou E, Zaitseva F, Wang F-H, Santagata S, Baltimore D, Panayotou G: The homeodomain region of Rag1 reveals the parallel mechanisms of bacterial and V(D)J recombination. Cell 1996, 87:263-276.
21. Difilippantonio M, McMahan CJ, Eastman QM, Spanopoulou E, Schatz DG: Rag-1 mediates signal sequence recognition and recruitment of Rag-2 in V(D)J recombination. Cell 1996, 87:253-262.
22. Bernstein R, Schluter SF, Bernstein H, Marchalonis JJ: Primordial emergence of the recombination activating gene 1 (RAG1): Sequence of the complete shark gene indicates homology to microbial integrases. Proc Natl Scad Sci USA 1996, 93:9454-9459.
23. Sadofsky MJ, Hesse JE, Gellert M: Definition of a core region of Rag2 that is functional in VDJ recombination. Nucleic Acids Res 1994, 22:1805-1809.
24. Callebaut I, Mornon JP: The VDJ recombination activating protein rag2 consists of a six-bladed propeller and PHD fingerlike domain, as revealed by sequence analysis. Cell Mol Life Sci 1998, 54:880-891. Using sensitive methods of protein domain structure analysis, the authors show that the active core of rag2 is composed of a six-fold repeat related to kelch/mipp motifs and that the last quarter can potentially interact with chromatin components.
25. H rearrangement, which represents a primary point of regulation in immunoglobulin gene assembly.
26. Kurioka H, Kishi H, Isshiki H, Tagoh H, Mori K, Kitawaga T, Nagota T, Dohi K, Muraguchi A: Isolation and characterization of a TATA-less promoter for the human RAG-1 gene. Mol Immunol 1996, 33:1059-1066.
27. Brown ST, Miranda GA, Galic Z, Hartmann JZ, Lyon CJ, Aguilera RJ: Regulation of the RAG-1 promoter by the NF-Y transcription factor. J Immunol 1997, 158:5071-5074.
28. Fuller K, Storb U: Identification and characterization of the murine Rag1 promoter. Mol Immunol 1998, 34:939-954.
29. Menetski JP, Gellert M: V(D)J recombination activity in lymphoid cell lines is increased by agents that elevate cAMP. Proc Natl Acad Sci USA 1990, 87:9324-9328.
30. Reya T, Grosschedl R: Transcriptional regulation of B-cell differentiation. Curr Opin Immunol 1998, 10:158-165.
31. Clevers H, Ferrier P: Transcriptional control during T-cell development. Curr Opin Immunol 1998, 10:166-175.
32. -/- mice. These early progenitor cells are not pluripotent but are committed solely to B cell development. Thus B cell commitment precedes, and is independent of, V(D)J recombination.
33. Tagoh H, Kishi H, Okumura A, Kitayawa T, Nagata T, Mori K, Mureguchi A: Induction of recombination activating gene expression in a human lymphoid progenitor cell line: Requirement of two separate signals from stromal cells and cytokines. Blood 1996, 88:4463-4473.
34. - marrow progenitors. Blood 1998, 91:1662-1670.
35. Han S, Zheng B, Schatz DG, Spanopoulou E, Kelsoe G: Neoteny in lymphocytes: RAG1 and RAG2 expression in germinal centers. Science 1996, 274:2094-2097.
36. Hikida M, Mori M, Takai T, Tomochika K-J, Hamatami K, Ohmori H: Reexpression of RAG1 and RAG2 genes in activated mature mouse B cells. Science 1996, 274:2092-2094.
37. Papavasiliou F, Casellas R, Suh H, Qin X-F, Besmer E, Pellanda R, Nemazee D, Rajewski K, Nussenzweig MC: V(D)J recombination in mature B cells: A mechanism for altering antibody responses. Science 1997, 278:298-301.
38. Hikida M, Ohmori H: Rearrangement of λ light chain genes in mature B cells in vitro and in vivo: Function of reexpressed recombination-activating gene products. J Exp Med 1998, 187:795-799.
39. + T cells with low affinity TCRs may be rescued from apoptosis.
40. Qin X-F, Schwers S, Yu W, Papavasiliou F, Suh H, Nussenzweig A, Rajewski K, Nussenzweig MC: Secondary V(D)J recombination in B-1 cells. Nature 1999, 397:355-359. This paper demonstrates that murine peritoneal B-1 cells (a population of B lymphocytes that are predisposed to autoantibody production) can express the rag1 and rag2 genes and undergo secondary V(D)J recombination. The authors propose that secondary immunoglobulin-gene rearrangements outside organized lymphoid organs may contribute to the development of autoimmunity.
41. Mombaerts P, Lacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE: Rag1-deficient mice have no mature B and T lymphocytes. Cell 1992, 68:869-877.
42. Shinkai Y, Rathbun G, Lam K-P, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM, Alt F: Rag2-deficient mice lack mature lymphocytes owing to inability to initiate V(D) rearrangement Cell 1992, 68:855-867.
43. Abe T, Tsuge I, Kamachi Y, Torii S, Utsumi K, Akahori Y, Ichihara Y, Kurosawa Y, Matsuoka H: Evidence for defects in V(D)J rearrangements in patients with severe combined immunodeficiency. J Immunol 1994, 152:5504-5513.
44. H locus. J Exp Med 1991, 174:1039-1048.
45. 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 1996, 274:97-99.
46. De Saint-Basile G, Le Deist F, De Villartay JP, Cerf-Bensussan N, Journet O, Brousse N, Griscelli C, Fischer A: Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). J Clin Invest 1991, 87:1352-1359.
47. Schandene L, Ferster A, Mascart-Lemone F, Crusiaux A, Gerard C, Marchant A, Lybin M, Velu T, Sariban E, Goldman M: T helper 2-like cells and therapeutic effects of interferon gamma in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). Eur J Immunol 1993, 23:56-60.
48. Chilosi M, Facchetti F, Notarangelo LD, Romagnoni S, Del Prete G, Almerigogna F, De Carli M, Pizzolo G: CD30 cell expression and abnormal soluble CD30 serum accumulation in Omenn's syndrome: Evidence for a T helper-2 mediated condition. Eur J Immunol 1996, 26:329-334.
49. Brugnoni D, Airò P, Facchetti F, Blanzuoli L, Ugazio AG, Cattaneo R, Notarangelo LD: In vitro cell death of activated lymphocytes in Omenn's syndrome. Eur J Immunol 1997, 27:2765-2773.
50. Harville TO, Adams DM, Howard TA, Ware RE: Oligoclonal expansion of CD45RO+ T lymphocytes in Omenn syndrome. J Clin Immunol 1997, 17:322-332.
51. Rieux-Laucat F, Bahadoran P, Brousse N, Selz F, Fischer A, Le Deist F, De Villartay JP: Highly restricted human T cell repertoire in peripheral blood and tissue-infiltrating lymphocytes in Omenn's syndrome. J Clin Invest 1998, 102:312-321. This paper demonstrates that patients with OS exhibit a highly restricted T cell repertoire, with different predominant specificities in different tissues - implying a potential (auto)antigen driven peripheral expansion of T cell clones as a major determinant of the autoimmune features of the disease.
52. Brooks EG, Filipovich AH, Padgett JW, Mamlock R, Goldblum RM: T cell receptor analysis in Omenn's syndrome: Evidence for defects in gene rearrangement and assembly. Blood 1999, 93:242-250. In addition to confirming that the T cell repertoire is restricted in patients with OS, the authors provide evidence for aberrant V(D)J recombination and also show that the clinical and immunological features of OS may arise from different conditions associated with severely disturbed thymic architecture - including DiGeorge syndrome.
53. Gomez L, LeDeist F, Blanche S, Cavazzana-Calvo M, Griscelli C, Fischer A: Treatment of Omenn syndrome by bone marrow transplantation. J Pediatr 1995, 127:76-81.
54. Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, Benerini Gatta L, Ochs HD, Schwarz K, Notarangelo L et al.: Partial V(D)J recombination activity leads to Omenn syndrome. Cell 1998, 93:885-896. This paper demonstrates that hypomorphic RAG1 and RAG2 alleles cause OS in humans. Careful biochemical analysis of the mutants indicates that OS is due to mutations that impair formation of a stable complex between target DNA, RAG1 and RAG2 in the initial stages of the V(D)J recombination process.
55. Grawunder U, West RB, Lieber MR: Antigen receptor gene rearrangement. Curr Opin Immunol 1998, 10:172-180. This report (together with [56•,57•]) summarizes the lymphocyte-specific as well as the dsb-repair components of the V(D)J recombination machinery. In addition, models for a mechanistic understanding of the V(D)J biochemistry are discussed.
56. Jeggo PA: DNA breakage and repair. Adv Genet 1998, 38:185-218. See annotation [55•].
57. Jeggo PA: Identification of genes involved in repair of DNA double-strand breaks in mammalian cells. Radiat Res 1998, 150(suppl 5):80-91. See annotation [55•].
58. Nicolas N, Moshous D, Cavazzana-Calvo M, Papadopoulo D, De Chasserat R, Le Deist F, Fischer A, De Villartay JP: A human severe combined immunodeficiency (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. This study emphasizes the existence of a human T-cell-negative and B-cell-negative SCID with radiation sensitivity and V(D)J recombination deficiency but without defects in DNA-PK components, XRCC4 or ligase IV. Based on these observations, the authors suggest that additional factors may be involved in V(D)J recombination or DNA repair.
59. CS, XRCC4 and ligase IV for the DNA nonhomologous end-joining (NHEJ) process. Fractionation studies of the extracts reveal the necessity for as yet unknown factors in the NHEJ pathway.
60. Ouyang H, Nussenzweig A, Kurimasa A, Soares V, Li X, Cordon-Cardo C, Li W, Cheong N, Nussenzweig M, Iliakis G et al.: Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo. J Exp Med 1997, 186:921-929.
61. Gu Y, Seidl KJ, Rathbun GA, Zhu C, Manis JP, van der Steop N, Davidson L, Cheng HL, Sekiguchi JM, Frank K: Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 1997, 7:653-665.
62. Manis JP, Gu Y, Lansford R, Sonoda E, Ferrini R, Davidson L, Rajewski K, Alt FW: Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J Exp Med 1998, 187:2081-2089. The authors prove that the KU70 antigen is involved in the site-specific recombination process of immunoglobulin heavy-chain class switching.
63. Zhu C, Bogue MA, Lin 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.
64. 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. Nature 1996, 382:551-555.
65. Nussenzweig A, Sokol K, Burgmann P, Li L, Li GC: Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: The effects of ionizing radiation on growth survival and development. Proc Natl Acad Sci USA 1997, 94:13588-13593.
66. Casellas R, Nussenzweig A, Wuerffel R, Pelanda R, Reichlin A, Heikyung S, Qin X-F, Besmer E, Kenter A, Rajewski K, Nussenzweig MC: Ku80 is required for immunoglobulin isotype switching. EMBO J 1998, 17:2404-2411. The study describes the requirement of KU80 for isotype class switching - suggesting a significant overlap between the molecular V(D)J recombination machinery, dsb repair and isotype switching.
67. Liang F, Romanienko PJ, Weaver DT, Jeggo PA, Jasin M: Chromosomal double-strand break repair in Ku80-deficient cells. Proc Natl Acad Sci USA 1996, 93:8929-8933.
68. Relink A, Melchers F, Andersson J: The SCID but not the RAG-2 gene product is required for Smu-sepsilon heavy chain class switching. Immunity 1996, 5:319-330.
69. CS-independent nonhomologous end-joining pathway.
70. CS-null mutants.
71. CS: T-cell tumor suppressor encoded at the mouse scid locus. Nat Genet 1997, 17:483-486.
72. CS-independent nonhomologous end-joining pathway for 'privileged' recombination sites.
73. 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 1995, 92:11485-11489.
74. 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 1995, 83:1079-1089.
75. Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ, Sekiguchi JM, Rathbun GA, Swat W, Wang J et al.: A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 1998, 95:891-902. The authors demonstrate that XRCC4 is required for nonhomologous end-joining. This study reveals in addition the necessity of XRCC4 and ligase IV during neuronal development and pushes forward the interesting question about the cause and physiologic relevance of DNA-dsbs during neurogenesis.
76. Grawunder U, Zimmer D, Fugmann S, Schwarz K, Lieber MR: DNA ligase IV is essential for V(D)J recombination and DNA double-stand break repair in human precursor lymphocytes. Mol Cell 1998, 2:477-484. The authors inactivated both ligase IV alleles in a human pre-B cell. Because neither DNA ligase I nor III but only ligase IV can functionally complement the defective cellular phenotype, the authors establish that ligase IV is the only DNA ligase necessary for V(D)J recombination and dsb repair.
77. Frank KM, Sekiguchi JM, Seidl KJ, Swat W, Rathbun GA, Cheng H-L, Davidson L, Kangaloo L, Alt FW: Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 1998, 396:173-177. This paper, along with [78••], defines in vivo, through homologous inactivation in mice, the importance of DNA ligase IV for nonhomologous end-joining - in particular for V(D)J recombination. Animals deficient in ligase IV show a late embryonic lethality, which - in contrast to DNA-PK components - puts ligase IV in an essential biochemical pathway in early mammalian development.
78. Barnes DE, Stamp G, Roswell I, Denzel A, Lindahl T: Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr Biol 1998, 8:1395-1398. See annotation [77••].