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Gene Review

RAG1  -  recombination activating gene 1

Homo sapiens

Synonyms: MGC43321, RAG-1, RING finger protein 74, RNF74, V(D)J recombination-activating protein 1
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Disease relevance of RAG1


High impact information on RAG1

  • 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].
  • RAG1/2 catalyzes hairpin formation on target DNA adjacent to transposed RSS ends in a manner consistent with a model leading to chromosome translocations [7].
  • Recombinant RAG1 protein greatly increases activity and complements an inactive extract from a RAG1 (-/-) pre-B cell line [8].
  • PML contains a cysteine-rich region present in a new family of apparent DNA-binding proteins that includes a regulator of the interleukin-2 receptor gene (Rpt-1) and the recombination-activating gene product (RAG-1) [9].
  • The expression of the V(D)J [variable (diversity) joining elements] recombination activating genes, RAG-1 and RAG-2, has been examined during T cell development in the thymus [10].

Chemical compound and disease context of RAG1


Biological context of RAG1

  • We report here a novel clinical and immunological phenotype associated with recessive RAG1 hypomorphic mutations in 4 patients from 4 different families [1].
  • A single promoter region was used for RAG1 transcription [13].
  • Two new 5'-untranslated region (5'UTR) exons were identified in the human gene for the lymphocyte-specific endonuclease recombination activating gene-1 (RAG1) required for the somatic recombination yielding functional Ag receptors [14].
  • 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 [13].
  • Here we report the location of a human recombination activating gene (RAG2), in addition to RAG1, on chromosome 11, band p13, thereby formally demonstrating linkage of these genes in humans and showing that they are not linked to the known locus responsible for the A-T syndrome [2].

Anatomical context of RAG1


Associations of RAG1 with chemical compounds

  • The extremely restricted T-cell repertoire and the lack of circulating B cells prompted analysis of the RAG1 gene, which revealed a novel homozygous thymine to cytosine substitution at nucleotide position 2686 [18].
  • N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains [19].
  • Separately from its role in V(D)J cleavage, the DDE motif of the RAG1/2 active site is specifically required for target DNA capture [20].
  • These signal end complexes were distinct from various precleavage RAG1/2 signal complexes in that they were resistant to treatment with heparin [21].
  • Here we subject RAG1, covalently cross-linked to DNA substrates, to partial cyanogen bromide degradation or trypsin proteolysis in order to map contacts on the protein [22].

Physical interactions of RAG1


Regulatory relationships of RAG1

  • In this study, we present evidence that activated mature CD5-positive human tonsil B cells coexpress both RAG1 and RAG2 mRNA and protein, and display DNA cleavage resulting from their recombinase activity [24].
  • RAG-2 promotes heptamer occupancy by RAG-1 in the assembly of a V(D)J initiation complex [25].

Other interactions of RAG1

  • 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].
  • Rch1, a protein that specifically interacts with the RAG-1 recombination-activating protein [27].
  • All 39 V(H) elements (with their adjacent heptamer/nonamer signal) were tested for site-specific cleavage with purified human core RAG1 and RAG2, and HMG1 proteins in a 12/23-coupled cleavage reaction [28].
  • The contig spanning 8 Mb from RAG1 to KCNA4 has been assembled by STS and probe content mapping for 76 loci with an average spacing of about 100 kb [29].
  • Expression of TdT and the lymphoid-associated genes Ig beta and RAG-1, but not PAX-5, was detected in this fraction, although at lower levels than in the IL-7R alpha+ progenitors [30].

Analytical, diagnostic and therapeutic context of RAG1


  1. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. de Villartay, J.P., Lim, A., Al-Mousa, H., Dupont, S., Déchanet-Merville, J., Coumau-Gatbois, E., Gougeon, M.L., Lemainque, A., Eidenschenk, C., Jouanguy, E., Abel, L., Casanova, J.L., Fischer, A., Le Deist, F. J. Clin. Invest. (2005) [Pubmed]
  2. 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]
  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. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. Katakura, K., Lee, J., Rachmilewitz, D., Li, G., Eckmann, L., Raz, E. J. Clin. Invest. (2005) [Pubmed]
  6. RAGs and regulation of autoantibodies. Jankovic, M., Casellas, R., Yannoutsos, N., Wardemann, H., Nussenzweig, M.C. Annu. Rev. Immunol. (2004) [Pubmed]
  7. RAG1/2-mediated resolution of transposition intermediates: two pathways and possible consequences. Melek, M., Gellert, M. Cell (2000) [Pubmed]
  8. Initiation of V(D)J recombination in a cell-free system. van Gent, D.C., McBlane, J.F., Ramsden, D.A., Sadofsky, M.J., Hesse, J.E., Gellert, M. Cell (1995) [Pubmed]
  9. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Kakizuka, A., Miller, W.H., Umesono, K., Warrell, R.P., Frankel, S.R., Murty, V.V., Dmitrovsky, E., Evans, R.M. Cell (1991) [Pubmed]
  10. Thymocyte expression of RAG-1 and RAG-2: termination by T cell receptor cross-linking. Turka, L.A., Schatz, D.G., Oettinger, M.A., Chun, J.J., Gorka, C., Lee, K., McCormack, W.T., Thompson, C.B. Science (1991) [Pubmed]
  11. Adherence of Acinetobacter calcoaceticus RAG-1 to human epithelial cells and to hexadecane. Rosenberg, M., Perry, A., Bayer, E.A., Gutnick, D.L., Rosenberg, E., Ofek, I. Infect. Immun. (1981) [Pubmed]
  12. Emulsifier of Arthrobacter RAG-1: isolation and emulsifying properties. Rosenberg, E., Zuckerberg, A., Rubinovitz, C., Gutnick, D.L. Appl. Environ. Microbiol. (1979) [Pubmed]
  13. 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]
  14. Extrathymic TCR gene rearrangement in human small intestine: identification of new splice forms of recombination activating gene-1 mRNA with selective tissue expression. Bas, A., Hammarström, S.G., Hammarström, M.L. J. Immunol. (2003) [Pubmed]
  15. 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]
  16. Expression of recombination activating genes 1 and 2 in peripheral B cells of patients with systemic lupus erythematosus. Girschick, H.J., Grammer, A.C., Nanki, T., Vazquez, E., Lipsky, P.E. Arthritis Rheum. (2002) [Pubmed]
  17. Differential expression of inducible costimulator-ligand splice variants: lymphoid regulation of mouse GL50-B and human GL50 molecules. Ling, V., Wu, P.W., Miyashiro, J.S., Marusic, S., Finnerty, H.F., Collins, M. J. Immunol. (2001) [Pubmed]
  18. 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]
  19. N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. Santagata, S., Gomez, C.A., Sobacchi, C., Bozzi, F., Abinun, M., Pasic, S., Cortes, P., Vezzoni, P., Villa, A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  20. Ordered DNA release and target capture in RAG transposition. Matthews, A.G., Elkin, S.K., Oettinger, M.A. EMBO J. (2004) [Pubmed]
  21. Intermediates in V(D)J recombination: a stable RAG1/2 complex sequesters cleaved RSS ends. Jones, J.M., Gellert, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  22. A C-terminal region of RAG1 contacts the coding DNA during V(D)J recombination. Mo, X., Bailin, T., Sadofsky, M.J. Mol. Cell. Biol. (2001) [Pubmed]
  23. 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]
  24. Expression of RAGs in peripheral B cells outside germinal centers is associated with the expression of CD5. Hillion, S., Saraux, A., Youinou, P., Jamin, C. J. Immunol. (2005) [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. Rch1, a protein that specifically interacts with the RAG-1 recombination-activating protein. Cuomo, C.A., Kirch, S.A., Gyuris, J., Brent, R., Oettinger, M.A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  28. The cleavage efficiency of the human immunoglobulin heavy chain VH elements by the RAG complex: implications for the immune repertoire. Yu, K., Taghva, A., Lieber, M.R. J. Biol. Chem. (2002) [Pubmed]
  29. An integrated YAC clone contig for the WAGR region on human chromosome 11p13-p14.1. Gawin, B., Klamt, B., König, A., Thäte, C., Le Paslier, D., Chumakov, I., Bhogal, R., Zehetner, G., Bruns, G., Gessler, M. Genomics (1995) [Pubmed]
  30. Expression of interleukin-7 receptor by lineage-negative human bone marrow progenitors with enhanced lymphoid proliferative potential and B-lineage differentiation capacity. Ryan, D.H., Nuccie, B.L., Ritterman, I., Liesveld, J.L., Abboud, C.N., Insel, R.A. Blood (1997) [Pubmed]
  31. RAG1/2 re-expression causes receptor revision in a model B cell line. Da Sylva, T.R., Fong, I.C., Cunningham, L.A., Wu, G.E. Mol. Immunol. (2007) [Pubmed]
  32. 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]
  33. 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]
  34. Recombination activating gene 1 product alone possesses endonucleolytic activity. Kim, D.R. J. Biochem. Mol. Biol. (2003) [Pubmed]
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