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Gene Review

Rag1  -  recombination activating gene 1

Mus musculus

Synonyms: RAG-1, Rag-1, V(D)J recombination-activating protein 1
 
 
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Disease relevance of Rag1

  • The resolution of bacteremia coincided with an expansion and persistence of B1b lymphocytes, and purified B1b lymphocytes from convalescent wild-type or TCR-betaxdelta-/- mice conferred immunity to Rag1-/- mice [1].
  • Analysis of GF and conventionally raised Rag1-/- mice disclosed that mature lymphocytes are not required for the development of lethal radiation enteritis or the microbiota-associated enhancement of endothelial radiosensitivity [2].
  • In contrast to these findings, it was recently reported that Rag1(-/-) Atm(-/-) mice do not develop thymic lymphomas, a finding that was interpreted as demonstrating a requirement for RAG-dependent recombination in the susceptibility to tumors in Atm-deficient mice [3].
  • Furthermore, CD40L-induced FHF depended on competent lymphocytes, because inflammatory reactions were strongly decreased in SCID and Rag1(-/-) mice [4].
  • Expression of the antiangiogenic factor 16K hPRL in human HCT116 colon cancer cells inhibits tumor growth in Rag1(-/-) mice [5].
 

Psychiatry related information on Rag1

  • Compared to control mice, RAG-1-knockout mice exhibited increased locomotor activity in an open field under both dim and bright lighting conditions and decreased habituation (reduction in the expected decline in locomotor activity with increasing familiarity with the novel environment in a 1-h test session) in bright lighting [6].
  • Rag-1 mice which underwent CLP did not die prematurely and there were no apparent observable differences in the physical response (tachypnea, piloerection, lethargy, etc), or intra-abdominal bowel inflammation/adhesions compared with CLP mice with normal T and B cells [7].
 

High impact information on Rag1

  • Thus, mere membrane deposition of Ig, even with concomitant expression of bcl-2, terminates neither expression of RAG-1 and 2, nor secondary L chain gene rearrangements, nor does it allow the development of mature B cells [8].
  • Complicon formation is initiated by recombination of RAG1/2-catalyzed IgH locus double-strand breaks with sequences downstream of c-myc, generating a dicentric (15;12) chromosome as an amplification intermediate [9].
  • RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination [10].
  • Primarily, these mice have few B220+ IgM+ mature B or B220+ CD43- pre-B cells in the bone marrow, reduced frequencies of V(D)J and V kappa J kappa recombination of the immunoglobulin loci, and lower expression levels of the immunoglobulin, RAG-1, RAG-2, and lambda 5 genes [11].
  • We have generated TCR transgenic mice (T/R+) specific for myelin basic protein (MBP) and crossed them to RAG-1-deficient mice to obtain mice (T/R-) that have T cells expressing the transgenic TCR but no other lymphocytes [12].
 

Chemical compound and disease context of Rag1

 

Biological context of Rag1

  • A congenic strain (called 'ZORI' here) with defects in Rag1 and Rag2 expression, thymocyte maturation and peripheral T cell homeostasis has been developed [15].
  • Using a mouse model, we show that expression of an inducible muHC transgene in Rag2-/- pro-B cells induces down-regulation of the following: (a) TdT protein, (b) a transgenic green fluorescent protein reporter reflecting endogenous Rag2 expression, and (c) Rag1 primary transcripts [16].
  • It has been suggested that pre-B cell receptor (pre-BCR) signals are responsible for down-regulation of the VDJH-recombinase machinery (Rag1, Rag2, and terminal deoxynucleotidyl transferase [TdT]), thereby preventing further rearrangement on the second HC allele [16].
  • Using a transient transfection assay, we demonstrate that the recombination activating genes Rag1 and Rag2 direct site-specific rearrangement on an artificial substrate in poorly differentiated as well as in differentiated nonlymphoid cell lines [17].
  • This distinctly restricted phylogenetic distribution has led to the hypothesis that one or both of the Rag genes were coopted after horizontal gene transfer and assembled into a Rag1/2 gene cluster in a common jawed vertebrate ancestor [18].
 

Anatomical context of Rag1

 

Associations of Rag1 with chemical compounds

  • Pregnant NOD- Rag1 null Prf1 null dams were treated with busulfan 22.5 mg/kg [22].
  • To search for additional catalytic amino acids and to better define the functional anatomy of RAG-1, we mutated all 86 conserved basic amino acids to alanine and evaluated the mutant proteins for DNA binding, nicking, hairpin formation, and joining [23].
  • No therapeutic effect was observed in immunodeficient RAG-1(-/-) mice, or when the contact sensitizer DNCB was replaced by skin irritants (croton oil or tributyltin) [24].
  • Based on this information, we have identified two aspartic acid residues in RAG1 (D600 and D708) that function specifically in catalysis [25].
  • We tested this hypothesis by introducing a point mutation on the Rag-1 cDNA, transforming the tyrosine codon into a phenylalanine codon [26].
 

Physical interactions of Rag1

 

Regulatory relationships of Rag1

  • We also show that IL-7 induced RAG-1 and RAG-2 mRNA expression by FL cells [28].
  • Additional separation of CD4(+) T cells into CD4(+)CD25(+) and CD4(+)CD25(-) subpopulations before their adoptive transfer into Rag1(-/-) mice showed that CD4(+)CD25(+) T cells were capable of reducing TLR-stimulated cytokine production levels to WT levels, whereas CD4(+)CD25(-) T cells had no regulatory effect [29].
  • TCRhi, CD8+CD4+ cells have lost RAG-2 mRNA but continue to express significant levels of RAG-1 mRNA, providing molecular evidence that this cell type is transitional between the TCRlo, CD4+CD8+ and the TCRhi, CD4+CD8-, or CD4-CD8+ phenotypes [30].
  • In line, pulmonary macrophages from RAG-1(-/-) C. pneumoniae-infected mice expressed IFN-gamma mRNA [31].
  • In adoptive transfer experiments, T-DAP12 cells enhanced the survival of NK cell-depleted RAG-1-deficient mice inoculated with RMA-S-Rae-1beta but not parental RMA-S tumors [32].
 

Other interactions of Rag1

  • The recombination activating genes, RAG-1 and RAG-2, are likely to encode components of the V(D)J site-specific recombination machinery [33].
  • By introducing a RAG-1 deficiency into Atm-/- mice in the presence of a TCR transgene, we show that V(D)J recombination is critical for thymoma development in these mice [34].
  • These cells are B lineage precursors based on their capacity to generate B lineage cells rapidly in stromal-dependent culture and their expression of high levels of germline IgH transcripts in the absence of Rag-1/2 [35].
  • Furthermore, when lethally irradiated recombination activating gene (RAG)-1-deficient (RAG-1(-/-)) mice that had received spleen cells from LT-alpha-/- mice were immunized with sheep red blood cells, they failed to generate PNA+ clusters in the reconstituted spleen but showed robust PNA+ clusters in the reconstituted LNs [36].
  • Recombination-activating gene (RAG) deficiencies were introduced into both p53-/- mice and TgTDeltaN transgenic mice, a strain in which 100% of the mice develop thymoma due to thymocyte-specific inactivation of p53 by a simian virus 40 T-antigen variant [37].
 

Analytical, diagnostic and therapeutic context of Rag1

References

  1. B1b lymphocytes confer T cell-independent long-lasting immunity. Alugupalli, K.R., Leong, J.M., Woodland, R.T., Muramatsu, M., Honjo, T., Gerstein, R.M. Immunity (2004) [Pubmed]
  2. Microbial regulation of intestinal radiosensitivity. Crawford, P.A., Gordon, J.I. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  3. RAG-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice. Petiniot, L.K., Weaver, Z., Vacchio, M., Shen, R., Wangsa, D., Barlow, C., Eckhaus, M., Steinberg, S.M., Wynshaw-Boris, A., Ried, T., Hodes, R.J. Mol. Cell. Biol. (2002) [Pubmed]
  4. Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure. Schmitz, V., Dombrowski, F., Prieto, J., Qian, C., Diehl, L., Knolle, P., Sauerbruch, T., Caselmann, W.H., Spengler, U., Leifeld, L. Hepatology (2006) [Pubmed]
  5. Expression of the antiangiogenic factor 16K hPRL in human HCT116 colon cancer cells inhibits tumor growth in Rag1(-/-) mice. Bentzien, F., Struman, I., Martini, J.F., Martial, J., Weiner, R. Cancer Res. (2001) [Pubmed]
  6. Neurobehavioral changes resulting from recombinase activation gene 1 deletion. Cushman, J., Lo, J., Huang, Z., Wasserfall, C., Petitto, J.M. Clin. Diagn. Lab. Immunol. (2003) [Pubmed]
  7. Apoptosis in lymphoid and parenchymal cells during sepsis: findings in normal and T- and B-cell-deficient mice. Hotchkiss, R.S., Swanson, P.E., Cobb, J.P., Jacobson, A., Buchman, T.G., Karl, I.E. Crit. Care Med. (1997) [Pubmed]
  8. Roles of IgH and L chains and of surrogate H and L chains in the development of cells of the B lymphocyte lineage. Melchers, F., Haasner, D., Grawunder, U., Kalberer, C., Karasuyama, H., Winkler, T., Rolink, A.G. Annu. Rev. Immunol. (1994) [Pubmed]
  9. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Zhu, C., Mills, K.D., Ferguson, D.O., Lee, C., Manis, J., Fleming, J., Gao, Y., Morton, C.C., Alt, F.W. Cell (2002) [Pubmed]
  10. RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination. Agrawal, A., Schatz, D.G. Cell (1997) [Pubmed]
  11. Constitutive expression of the Id1 gene impairs mouse B cell development. Sun, X.H. Cell (1994) [Pubmed]
  12. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Lafaille, J.J., Nagashima, K., Katsuki, M., Tonegawa, S. Cell (1994) [Pubmed]
  13. CD4+ and CD8+ T cells mediate adoptive immunity to aerosol infection of Mycobacterium bovis bacillus Calmette-Guérin. Feng, C.G., Britton, W.J. J. Infect. Dis. (2000) [Pubmed]
  14. Injury in renal ischemia-reperfusion is independent from immunoglobulins and T lymphocytes. Park, P., Haas, M., Cunningham, P.N., Bao, L., Alexander, J.J., Quigg, R.J. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  15. Control of thymocyte development and recombination-activating gene expression by the zinc finger protein Zfp608. Zhang, F., Thomas, L.R., Oltz, E.M., Aune, T.M. Nat. Immunol. (2006) [Pubmed]
  16. Surface mu heavy chain signals down-regulation of the V(D)J-recombinase machinery in the absence of surrogate light chain components. Galler, G.R., Mundt, C., Parker, M., Pelanda, R., Mårtensson, I.L., Winkler, T.H. J. Exp. Med. (2004) [Pubmed]
  17. Three lymphoid-specific factors account for all junctional diversity characteristic of somatic assembly of T-cell receptor and immunoglobulin genes. Kallenbach, S., Doyen, N., Fanton d'Andon, M., Rougeon, F. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  18. An ancient evolutionary origin of the Rag1/2 gene locus. Fugmann, S.D., Messier, C., Novack, L.A., Cameron, R.A., Rast, J.P. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Willenbring, H., Bailey, A.S., Foster, M., Akkari, Y., Dorrell, C., Olson, S., Finegold, M., Fleming, W.H., Grompe, M. Nat. Med. (2004) [Pubmed]
  20. Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells. Han, S., Zheng, B., Schatz, D.G., Spanopoulou, E., Kelsoe, G. Science (1996) [Pubmed]
  21. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Pull, S.L., Doherty, J.M., Mills, J.C., Gordon, J.I., Stappenbeck, T.S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  22. An assay for human hematopoietic stem cells based on transplantation into nonobese diabetic recombination activating gene-null perforin-null mice. Minamiguchi, H., Wingard, J.R., Laver, J.H., Mainali, E.S., Shultz, L.D., Ogawa, M. Biol. Blood Marrow Transplant. (2005) [Pubmed]
  23. Mutational analysis of all conserved basic amino acids in RAG-1 reveals catalytic, step arrest, and joining-deficient mutants in the V(D)J recombinase. Huye, L.E., Purugganan, M.M., Jiang, M.M., Roth, D.B. Mol. Cell. Biol. (2002) [Pubmed]
  24. Chemoimmunotherapy for melanoma with dacarbazine and 2,4-dinitrochlorobenzene elicits a specific T cell-dependent immune response. Wack, C., Kirst, A., Becker, J.C., Lutz, W.K., Bröcker, E.B., Fischer, W.H. Cancer Immunol. Immunother. (2002) [Pubmed]
  25. Identification of two catalytic residues in RAG1 that define a single active site within the RAG1/RAG2 protein complex. Fugmann, S.D., Villey, I.J., Ptaszek, L.M., Schatz, D.G. Mol. Cell (2000) [Pubmed]
  26. Rag-1: a topoisomerase? Kallenbach, S., Brinkmann, T., Rougeon, F. Int. Immunol. (1993) [Pubmed]
  27. A dimer of the lymphoid protein RAG1 recognizes the recombination signal sequence and the complex stably incorporates the high mobility group protein HMG2. Rodgers, K.K., Villey, I.J., Ptaszek, L., Corbett, E., Schatz, D.G., Coleman, J.E. Nucleic Acids Res. (1999) [Pubmed]
  28. Interleukin 7-induced expression of specific T cell receptor gamma variable region genes in murine fetal liver cultures. Appasamy, P.M., Kenniston, T.W., Weng, Y., Holt, E.C., Kost, J., Chambers, W.H. J. Exp. Med. (1993) [Pubmed]
  29. CD4+CD25+ regulatory T cells control innate immune reactivity after injury. Murphy, T.J., Choileain, N.N., Zang, Y., Mannick, J.A., Lederer, J.A. J. Immunol. (2005) [Pubmed]
  30. Recombinase activating gene expression in thymic subpopulations. A transitional cell type has lost RAG-2 but not RAG-1. Campbell, J.J., Hashimoto, Y. J. Immunol. (1993) [Pubmed]
  31. Macrophages, CD4+ or CD8+ cells are each sufficient for protection against Chlamydia pneumoniae infection through their ability to secrete IFN-gamma. Rothfuchs, A.G., Kreuger, M.R., Wigzell, H., Rottenberg, M.E. J. Immunol. (2004) [Pubmed]
  32. T cells gene-engineered with DAP12 mediate effector function in an NKG2D-dependent and major histocompatibility complex-independent manner. Teng, M.W., Kershaw, M.H., Hayakawa, Y., Cerutti, L., Jane, S.M., Darcy, P.K., Smyth, M.J. J. Biol. Chem. (2005) [Pubmed]
  33. The recombination activating gene-1 (RAG-1) transcript is present in the murine central nervous system. Chun, J.J., Schatz, D.G., Oettinger, M.A., Jaenisch, R., Baltimore, D. Cell (1991) [Pubmed]
  34. Critical role for Atm in suppressing V(D)J recombination-driven thymic lymphoma. Liao, M.J., Van Dyke, T. Genes Dev. (1999) [Pubmed]
  35. Identification of the earliest B lineage stage in mouse bone marrow. Li, Y.S., Wasserman, R., Hayakawa, K., Hardy, R.R. Immunity (1996) [Pubmed]
  36. Independent signals regulate development of primary and secondary follicle structure in spleen and mesenteric lymph node. Fu, Y.X., Huang, G., Matsumoto, M., Molina, H., Chaplin, D.D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  37. No requirement for V(D)J recombination in p53-deficient thymic lymphoma. Liao, M.J., Zhang, X.X., Hill, R., Gao, J., Qumsiyeh, M.B., Nichols, W., Van Dyke, T. Mol. Cell. Biol. (1998) [Pubmed]
  38. Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8+ thymocytes. Ilangumaran, S., Ramanathan, S., Ning, T., La Rose, J., Reinhart, B., Poussier, P., Rottapel, R. Blood (2003) [Pubmed]
  39. Allograft rejection requires STAT5a/b-regulated antiapoptotic activity in T cells but not B cells. Zhang, Y., Kirken, R.A., Furian, L., Janczewska, S., Qu, X., Hancock, W.W., Wang, M., Tejpal, N., Kerman, R., Kahan, B.D., Stepkowski, S.M. J. Immunol. (2006) [Pubmed]
  40. Interaction between the innate and adaptive immune systems is required to survive sepsis and control inflammation after injury. Shelley, O., Murphy, T., Paterson, H., Mannick, J.A., Lederer, J.A. Shock (2003) [Pubmed]
  41. Role of T lymphocytes and interferon-gamma in ischemic stroke. Yilmaz, G., Arumugam, T.V., Stokes, K.Y., Granger, D.N. Circulation (2006) [Pubmed]
 
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