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Gene Review

RAG2  -  recombination activating gene 2

Homo sapiens

Synonyms: RAG-2, V(D)J recombination-activating protein 2
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Disease relevance of RAG2


High impact information on RAG2

  • Here we review the prevalence of autoantibodies in the initial antibody repertoire, their regulation by receptor editing, and the role of the recombinase proteins (RAG1 and RAG2) in this process [6].
  • The products of three of the genes--IL-2RG, Jak3, and IL-7R alpha--are components of cytokine receptors, and the products of three more-RAG1, RAG2, and Artemis-are essential for effecting antigen receptor gene rearrangement [7].
  • When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease [8].
  • We describe an in vitro system in which human bone marrow CD34+ cells proliferate, acquire the expression of the lymphoid-specific RAG-2 gene and a broad repertoire of rearranged T-cell receptor genes, develop the ability to produce T cell-specific interleukin-2 and achieve a range of T-cell immunophenotypes [9].
  • Six of 14 B- SCID patients tested were found to carry a mutation of the recombinase activating gene 1 (RAG-1), RAG-2, or both [10].

Chemical compound and disease context of RAG2

  • Importantly, in vivo administration of IL-7 mice accelerated the expansion of IL-7R(high) memory CD4(+) LPLs and thereby exacerbated chronic colitis in RAG-2(-/-) mice transferred with CD4(+) LPLs from colitic TCR-alpha(-/-) mice [11].
  • STUDY DESIGN/MATERIALS AND METHODS: In a model of RAG-2-mice bearing a human oral squamous cell carcinoma xenograft (XF 354), the in vivo efficiency assessed as growth retardation or remission caused by Photofrin II and free mTHPC was compared with mTHPC coupled in two different ways to polyethylene glycol (PEG) [12].
  • STUDY DESIGN: To facilitate the study of the transplantation of endometriosis into immunodeficient RAG-2/gamma(c)KO mice, endometriosis biopsy specimens were collected from 19 women by laparoscopic surgery and grafted subcutaneously into the mice, which were treated subsequently with estradiol and progesterone to create 28-day artificial cycles [13].

Biological context of RAG2

  • Expression of human recombination activating genes (RAG1 and RAG2) in neoplastic lymphoid cells: correlation with cell differentiation and antigen receptor expression [14].
  • Promoter regions of human RAG1 and RAG2 are active in both lymphoid and nonlymphoid cell lines, suggesting that an outside regulatory element is probably involved in the tissue-specific transcriptional regulation of the RAG genes [15].
  • In contrast, transcription of RAG2 initiates at two distinct regions of the genome [15].
  • We have characterized the genomic organization of the human RAG locus, mapped the transcriptional initiation sites, and partially sequenced and performed functional reporter assays on the 5' flanking regions of human RAG1 and RAG2 [15].
  • Effect of CpG methylation on RAG1/RAG2 reactivity: implications of direct and indirect mechanisms for controlling V(D)J cleavage [16].

Anatomical context of RAG2

  • We demonstrate that these peripheral blood neutrophils express variable and individual-specific TCRalphabeta repertoires and the RAG1/RAG2 recombinase complex [17].
  • The protein products of the recombination activating genes (RAG1 and RAG2) initiate the formation of immunoglobulin (Ig) and T-cell receptors, which are essential for B- and T-cell development, respectively [18].
  • RAG2 mRNA was only found in tonsil naive B cells, centrocytes, and to a lesser extent in centroblasts [19].
  • RAG1 and RAG2 mRNA was detected in all bone marrow preparations but was absent in all peripheral blood samples [20].
  • RAG1 and RAG2 expression was localized in the epithelial layer and absent in the lamina propria [20].

Associations of RAG2 with chemical compounds

  • To address this, we individually mutated 36 evolutionarily conserved basic and hydroxy group containing residues within RAG2 [21].
  • Here we report that RAG-mediated transposition is suppressed by physiological concentrations of the guanine nucleotide GTP, and by the full-length RAG2 protein [22].
  • We also observe that another intracellular signaling molecule, Ca(2+), stimulates RAG-mediated transposition and is capable of activating transposition even in reactions containing full-length RAG2 and GTP [22].
  • Although the plasma cells used express both RAG-1 and RAG-2, the expression level of these proteins was not affected by caffeine or okadaic acid [23].
  • After depletion of this labile repressor by cycloheximide treatment, steady-state RAG-1 and RAG-2 RNA levels, and their transcription rates, were elevated four- to six-fold; but were still susceptible to elimination by TPA treatment [24].

Regulatory relationships of RAG2

  • RAG-2 promotes heptamer occupancy by RAG-1 in the assembly of a V(D)J initiation complex [25].

Other interactions of RAG2

  • During V(D)J recombination, the RAG1 and RAG2 proteins form a complex and initiate the process of rearrangement by cleaving between the coding and signal segments and generating hairpins at the coding ends [26].
  • Moreover, one of the largest genes associated with a member of the 6.7 family, the 3.8-1 gene found proximal to HLA-B, was found to demonstrate limited, composite similarity to RAG2 and complement C4a gene sequences [27].
  • Sequences of six purified cDNA clones specifically detecting RAG co-expressing transcripts included matches to portions of the human RAG2 and BSAP regions and to four novel partial cDNAs (three with homologies to human ESTs) [28].
  • Mutations in either RAG1 or RAG2 that interfere with RSS cleavage also interfere with hairpin opening, suggesting that RAGs have a single active site that catalyzes several distinct DNA cleavage reactions [29].
  • Mutation analyses of polymerase chain reaction products of RAG1/RAG2 genes were performed in 14 cases (T-B- SCID = 6 and OS = 8) [30].

Analytical, diagnostic and therapeutic context of RAG2


  1. Human RAG2, like RAG1, is on chromosome 11 band p13 and therefore not linked to ataxia telangiectasia complementation groups. Sherrington, P.D., Forster, A., Seawright, A., van Heyningen, V., Rabbitts, T.H. Genes Chromosomes Cancer (1992) [Pubmed]
  2. Novel RAG1 mutation in a case of severe combined immunodeficiency. Zhang, J., Quintal, L., Atkinson, A., Williams, B., Grunebaum, E., Roifman, C.M. Pediatrics (2005) [Pubmed]
  3. Epstein-Barr virus induction of recombinase-activating genes RAG1 and RAG2. Srinivas, S.K., Sixbey, J.W. J. Virol. (1995) [Pubmed]
  4. Expression of the recombination activating genes (RAG1 and RAG2) is not detectable in Epstein-Barr virus-associated human lymphomas. Meru, N., Jung, A., Lisner, R., Niedobitek, G. Int. J. Cancer (2001) [Pubmed]
  5. Clinically relevant oral cancer model for serum proteomic eavesdropping on the tumour microenvironment. Balys, R., Alaoui-Jamali, M., Hier, M., Black, M., Domanowski, G., Rochon, L., Jie, S. The Journal of otolaryngology. (2006) [Pubmed]
  6. RAGs and regulation of autoantibodies. Jankovic, M., Casellas, R., Yannoutsos, N., Wardemann, H., Nussenzweig, M.C. Annu. Rev. Immunol. (2004) [Pubmed]
  7. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Buckley, R.H. Annu. Rev. Immunol. (2004) [Pubmed]
  8. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Madsen, L.S., Andersson, E.C., Jansson, L., krogsgaard, M., Andersen, C.B., Engberg, J., Strominger, J.L., Svejgaard, A., Hjorth, J.P., Holmdahl, R., Wucherpfennig, K.W., Fugger, L. Nat. Genet. (1999) [Pubmed]
  9. Generation of human T lymphocytes from bone marrow CD34+ cells in vitro. Freedman, A.R., Zhu, H., Levine, J.D., Kalams, S., Scadden, D.T. Nat. Med. (1996) [Pubmed]
  10. RAG mutations in human B cell-negative SCID. Schwarz, K., Gauss, G.H., Ludwig, L., Pannicke, U., Li, Z., Lindner, D., Friedrich, W., Seger, R.A., Hansen-Hagge, T.E., Desiderio, S., Lieber, M.R., Bartram, C.R. Science (1996) [Pubmed]
  11. IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4+ mucosal T cells in mice. Okada, E., Yamazaki, M., Tanabe, M., Takeuchi, T., Nanno, M., Oshima, S., Okamoto, R., Tsuchiya, K., Nakamura, T., Kanai, T., Hibi, T., Watanabe, M. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  12. Comparison of the in vivo efficiency of photofrin II-, mTHPC-, mTHPC-PEG- and mTHPCnPEG-mediated PDT in a human xenografted head and neck carcinoma. Reuther, T., Kübler, A.C., Zillmann, U., Flechtenmacher, C., Sinn, H. Lasers in surgery and medicine. (2001) [Pubmed]
  13. Human endometriotic xenografts in immunodeficient RAG-2/gamma(c)KO mice. Greenberg, L.H., Slayden, O.D. Am. J. Obstet. Gynecol. (2004) [Pubmed]
  14. Expression of human recombination activating genes (RAG1 and RAG2) in neoplastic lymphoid cells: correlation with cell differentiation and antigen receptor expression. Bories, J.C., Cayuela, J.M., Loiseau, P., Sigaux, F. Blood (1991) [Pubmed]
  15. Cloning and characterization of the human recombination activating gene 1 (RAG1) and RAG2 promoter regions. Zarrin, A.A., Fong, I., Malkin, L., Marsden, P.A., Berinstein, N.L. J. Immunol. (1997) [Pubmed]
  16. Effect of CpG methylation on RAG1/RAG2 reactivity: implications of direct and indirect mechanisms for controlling V(D)J cleavage. Nakase, H., Takahama, Y., Akamatsu, Y. EMBO Rep. (2003) [Pubmed]
  17. From the Cover: A variable immunoreceptor in a subpopulation of human neutrophils. Puellmann, K., Kaminski, W.E., Vogel, M., Nebe, C.T., Schroeder, J., Wolf, H., Beham, A.W. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  18. The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins. Noordzij, J.G., de Bruin-Versteeg, S., Verkaik, N.S., Vossen, J.M., de Groot, R., Bernatowska, E., Langerak, A.W., van Gent, D.C., van Dongen, J.J. Blood (2002) [Pubmed]
  19. RAG1 and RAG2 expression by B cell subsets from human tonsil and peripheral blood. Girschick, H.J., Grammer, A.C., Nanki, T., Mayo, M., Lipsky, P.E. J. Immunol. (2001) [Pubmed]
  20. RAG1 and RAG2 expression in human intestinal epithelium: evidence of extrathymic T cell differentiation. Lynch, S., Kelleher, D., McManus, R., O'Farrelly, C. Eur. J. Immunol. (1995) [Pubmed]
  21. Identification of basic residues in RAG2 critical for DNA binding by the RAG1-RAG2 complex. Fugmann, S.D., Schatz, D.G. Mol. Cell (2001) [Pubmed]
  22. Regulation of RAG1/RAG2-mediated transposition by GTP and the C-terminal region of RAG2. Tsai, C.L., Schatz, D.G. EMBO J. (2003) [Pubmed]
  23. Induction of light chain replacement in human plasma cells by caffeine is independent from both the upregulation of RAG protein expression and germ line transcription. Tachibana, H., Haruta, H., Ueda, K., Chiwata, T., Yamada, K. J. Biol. Chem. (2000) [Pubmed]
  24. Expression of the V(D)J recombinase gene RAG-1 is tightly regulated and involves both transcriptional and post-transcriptional controls. Neale, G.A., Fitzgerald, T.J., Goorha, R.M. Mol. Immunol. (1992) [Pubmed]
  25. RAG-2 promotes heptamer occupancy by RAG-1 in the assembly of a V(D)J initiation complex. Swanson, P.C., Desiderio, S. Mol. Cell. Biol. (1999) [Pubmed]
  26. Functional and biochemical dissection of the structure-specific nuclease ARTEMIS. Pannicke, U., Ma, Y., Hopfner, K.P., Niewolik, D., Lieber, M.R., Schwarz, K. EMBO J. (2004) [Pubmed]
  27. Studies of the 6.7 family of dispersed genomic fragments within the MHC class I Region. Pichon, L., Venditti, C., Harris, J., Ten Elshof, A., Pinelli, M., Chorney, M. Exp. Clin. Immunogenet. (1997) [Pubmed]
  28. Isolation of genes negatively or positively co-expressed with human recombination activating gene 1 (RAG1) by differential display PCR (DD RT-PCR). Verkoczy, L.K., Berinstein, N.L. Nucleic Acids Res. (1998) [Pubmed]
  29. Hairpin coding end opening is mediated by RAG1 and RAG2 proteins. Besmer, E., Mansilla-Soto, J., Cassard, S., Sawchuk, D.J., Brown, G., Sadofsky, M., Lewis, S.M., Nussenzweig, M.C., Cortes, P. Mol. Cell (1998) [Pubmed]
  30. Detection of RAG mutations and prenatal diagnosis in families presenting with either T-B- severe combined immunodeficiency or Omenn's syndrome. Tabori, U., Mark, Z., Amariglio, N., Etzioni, A., Golan, H., Biloray, B., Toren, A., Rechavi, G., Dalal, I. Clin. Genet. (2004) [Pubmed]
  31. The V(D)J recombination activating protein RAG2 consists of a six-bladed propeller and a PHD fingerlike domain, as revealed by sequence analysis. Callebaut, I., Mornon, J.P. Cell. Mol. Life Sci. (1998) [Pubmed]
  32. The recombination activating gene 2 (RAG2) of the rainbow trout Oncorhynchus mykiss. Hansen, J.D., Kaattari, S.L. Immunogenetics (1996) [Pubmed]
  33. Definition of minimal domains of interaction within the recombination-activating genes 1 and 2 recombinase complex. Aidinis, V., Dias, D.C., Gomez, C.A., Bhattacharyya, D., Spanopoulou, E., Santagata, S. J. Immunol. (2000) [Pubmed]
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