Journal articles: 'Recombination activating genes'

1

Haines, Brian B., Chun Jeih Ryu, and Jianzhu Chen. "Recombination Activating Genes (RAG) in Lymphoma Development." Cell Cycle 5, no. 9 (April 19, 2006): 913–16. http://dx.doi.org/10.4161/cc.5.9.2732.

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Panchin, Yuri, and Leonid L. Moroz. "Molluscan mobile elements similar to the vertebrate Recombination-Activating Genes." Biochemical and Biophysical Research Communications 369, no. 3 (May 2008): 818–23. http://dx.doi.org/10.1016/j.bbrc.2008.02.097.

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Li, Tong-Tong, Shuhua Han, Mike Cubbage, and Biao Zheng. "Continued expression of recombination-activating genes and TCR gene recombination in human peripheral T cells." European Journal of Immunology 32, no. 10 (October 2002): 2792–99. http://dx.doi.org/10.1002/1521-4141(2002010)32:10<2792::aid-immu2792>3.0.co;2-i.

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Ohmori, Hitoshi, and Masaki Hikida. "Expression and Function of Recombination Activating Genes in Mature В Cells." Critical Reviews™ in Immunology 18, no. 3 (1998): 221–35. http://dx.doi.org/10.1615/critrevimmunol.v18.i3.30.

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Gennery, Andrew R., Elizabeth Hodges, Anthony P. Williams, Susan Harris, Anna Villa, Brian Angus, Andrew J. Cant, and John L. Smith. "Omenn's syndrome occurring in patients without mutations in recombination activating genes." Clinical Immunology 116, no. 3 (September 2005): 246–56. http://dx.doi.org/10.1016/j.clim.2005.04.014.

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Lamb, Teresa M., and Aaron P. Mitchell. "Coupling of Saccharomyces cerevisiae Early Meiotic Gene Expression to DNA Replication Depends Upon RPD3 and SIN3." Genetics 157, no. 2 (February 1, 2001): 545–56. http://dx.doi.org/10.1093/genetics/157.2.545.

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Abstract It has been established that meiotic recombination and chromosome segregation are inhibited when meiotic DNA replication is blocked. Here we demonstrate that early meiotic gene (EMG) expression is also inhibited by a block in replication. Since early meiotic genes are required to promote meiotic recombination and DNA division, the low expression of these genes may contribute to the block in meiotic progression. We have identified three Hur– (HU reduced recombination) mutants that fail to couple meiotic recombination and gene expression with replication. One of these mutations is in RPD3, a gene required to maintain meiotic gene repression in mitotic cells. Complete deletions of RPD3 and the repression adapter SIN3 permitted recombination and early meiotic gene expression when replication was inhibited with hydroxyurea (HU). Biochemical analysis showed that the Rpd3p-Sin3p-Ume6p repression complex does exist in meiotic cells. These observations suggest that repression of early meiotic genes by SIN3 and RPD3 is critical for the normal response to inhibited replication. A second response to inhibited replication has also been discovered. HU-inhibited replication reduced the accumulation of phospho-Ume6p in meiotic cells. Phosphorylation of Ume6p normally promotes interaction with the meiotic activator Ime1p, thereby activating EMG expression. Thus, inhibited replication may also reduce the Ume6p-dependent activation of EMGs. Taken together, our data suggest that both active repression and reduced activation combine to inhibit EMG expression when replication is inhibited.

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Yannoutsos, Nikos, Patrick Wilson, Wong Yu, Hua Tang Chen, Andre Nussenzweig, Howard Petrie, and Michel C. Nussenzweig. "The Role of Recombination Activating Gene (RAG) Reinduction in Thymocyte Development in Vivo." Journal of Experimental Medicine 194, no. 4 (August 20, 2001): 471–80. http://dx.doi.org/10.1084/jem.194.4.471.

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Assembly of T cell receptor (TCR)α/β genes by variable/diversity/joining (V[D]J) rearrangement is an ordered process beginning with recombination activating gene (RAG) expression and TCRβ recombination in CD4−CD8−CD25+ thymocytes. In these cells, TCRβ expression leads to clonal expansion, RAG downregulation, and TCRβ allelic exclusion. At the subsequent CD4+CD8+ stage, RAG expression is reinduced and V(D)J recombination is initiated at the TCRα locus. This second wave of RAG expression is terminated upon expression of a positively selected α/β TCR. To examine the physiologic role of the second wave of RAG expression, we analyzed mice that cannot reinduce RAG expression in CD4+CD8+ T cells because the transgenic locus that directs RAG1 and RAG2 expression in these mice is missing a distal regulatory element essential for reinduction. In the absence of RAG reinduction we find normal numbers of CD4+CD8+ cells but a 50–70% reduction in the number of mature CD4+CD8− and CD4−CD8+ thymocytes. TCRα rearrangement is restricted to the 5′ end of the Jα cluster and there is little apparent secondary TCRα recombination. Comparison of the TCRα genes expressed in wild-type or mutant mice shows that 65% of all α/β T cells carry receptors that are normally assembled by secondary TCRα rearrangement. We conclude that RAG reinduction in CD4+CD8+ thymocytes is not required for initial TCRα recombination but is essential for secondary TCRα recombination and that the majority of TCRα chains expressed in mature T cells are products of secondary recombination.

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Jessen, Jason R., Tammy N. Jessen, Steven S. Vogel, and Shuo Lin. "Concurrent expression of recombination activating genes 1 and 2 in zebrafish olfactory sensory neurons." genesis 29, no. 4 (2001): 156–62. http://dx.doi.org/10.1002/gene.1019.

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Tsai, Albert G., and Michael R. Lieber. "RAGs found “not guilty”: cleared by DNA evidence." Blood 111, no. 4 (February 15, 2008): 1750. http://dx.doi.org/10.1182/blood-2007-09-113381.

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A recent paper from the Alt laboratory shows that recombination activating genes (RAGs) are not responsible for double-strand DNA breaks associated with some chromosomal translocations in pre–T-cell lymphomas.

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Oltz, E. M., F. W. Alt, W. C. Lin, J. Chen, G. Taccioli, S. Desiderio, and G. Rathbun. "A V(D)J recombinase-inducible B-cell line: role of transcriptional enhancer elements in directing V(D)J recombination." Molecular and Cellular Biology 13, no. 10 (October 1993): 6223–30. http://dx.doi.org/10.1128/mcb.13.10.6223-6230.1993.

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Rapid analysis of mechanisms that regulate V(D)J recombination has been hampered by the lack of appropriate cell systems that reproduce aspects of normal prelymphocyte physiology in which the recombinase is activated, accessible antigen receptor loci are rearranged, and rearrangement status is fixed by termination of recombinase expression. To generate such a system, we introduced heat shock-inducible V(D)J recombination-activating genes (RAG) 1 and 2 into a recombinationally inert B-cell line. Heat shock treatment of these cells rapidly induced high levels of RAG transcripts and RAG proteins that were accompanied by a parallel induction of V(D)J recombinase activity, strongly suggesting that RAG proteins have a primary role in V(D)J recombination. Within hours after induction, these cells began to rearrange chromosomally integrated V(D)J recombination substrates but only if the substrates contained an active transcriptional enhancer; substrates lacking an enhancer were not efficiently rearranged. Activities necessary to target integrated substrates for rearrangement were provided by two separate lymphoid-specific transcriptional enhancers, as well as an active nonlymphoid enhancer, unequivocally demonstrating that such elements enhance both transcription and V(D)J recombinational accessibility.

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Oltz, E. M., F. W. Alt, W. C. Lin, J. Chen, G. Taccioli, S. Desiderio, and G. Rathbun. "A V(D)J recombinase-inducible B-cell line: role of transcriptional enhancer elements in directing V(D)J recombination." Molecular and Cellular Biology 13, no. 10 (October 1993): 6223–30. http://dx.doi.org/10.1128/mcb.13.10.6223.

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Rapid analysis of mechanisms that regulate V(D)J recombination has been hampered by the lack of appropriate cell systems that reproduce aspects of normal prelymphocyte physiology in which the recombinase is activated, accessible antigen receptor loci are rearranged, and rearrangement status is fixed by termination of recombinase expression. To generate such a system, we introduced heat shock-inducible V(D)J recombination-activating genes (RAG) 1 and 2 into a recombinationally inert B-cell line. Heat shock treatment of these cells rapidly induced high levels of RAG transcripts and RAG proteins that were accompanied by a parallel induction of V(D)J recombinase activity, strongly suggesting that RAG proteins have a primary role in V(D)J recombination. Within hours after induction, these cells began to rearrange chromosomally integrated V(D)J recombination substrates but only if the substrates contained an active transcriptional enhancer; substrates lacking an enhancer were not efficiently rearranged. Activities necessary to target integrated substrates for rearrangement were provided by two separate lymphoid-specific transcriptional enhancers, as well as an active nonlymphoid enhancer, unequivocally demonstrating that such elements enhance both transcription and V(D)J recombinational accessibility.

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12

Knecht, Hans, Pierre Brousset, Edith Bachmann, Gorm Pallesen, and Bernhard F. Odermatt. "Expression of Human Recombination Activating Genes (RAG-1 and RAG-2) in Lymphoma." Leukemia & Lymphoma 15, no. 5-6 (January 1994): 399–403. http://dx.doi.org/10.3109/10428199409049742.

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13

Amin, Rupesh H., and Mark S. Schlissel. "Foxo1 directly regulates the transcription of recombination-activating genes during B cell development." Nature Immunology 9, no. 6 (May 11, 2008): 613–22. http://dx.doi.org/10.1038/ni.1612.

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14

Willett, Catherine E., Jason J. Cherry, and Lisa A. Steiner. "Characterization and expression of the recombination activating genes (rag1 and rag2) of zebrafish." Immunogenetics 45, no. 6 (April 9, 1997): 394–404. http://dx.doi.org/10.1007/s002510050221.

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15

Fuschiotti, Patrizia, Nagaradona Harindranath, Rose G. Mage, Wayne T. McCormack, Pushparani Dhanarajan, and Kenneth H. Roux. "Recombination activating genes-1 and -2 of the rabbit: Cloning and characterization of germline and expressed genes." Molecular Immunology 30, no. 11 (August 1993): 1021–32. http://dx.doi.org/10.1016/0161-5890(93)90127-w.

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16

Thwaites, Daniel T., Clive Carter, Dylan Lawless, Sinisa Savic, and Joan M. Boyes. "A novel RAG1 mutation reveals a critical in vivo role for HMGB1/2 during V(D)J recombination." Blood 133, no. 8 (February 21, 2019): 820–29. http://dx.doi.org/10.1182/blood-2018-07-866939.

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Abstract The Recombination Activating Genes, RAG1 and RAG2, are essential for V(D)J recombination and adaptive immunity. Mutations in these genes often cause immunodeficiency, the severity of which reflects the importance of the altered residue or residues during recombination. Here, we describe a novel RAG1 mutation that causes immunodeficiency in an unexpected way: The mutated protein severely disrupts binding of the accessory protein, HMGB1. Although HMGB1 enhances RAG cutting in vitro, its role in vivo was controversial. We show here that reduced HMGB1 binding by the mutant protein dramatically reduces RAG cutting in vitro and almost completely eliminates recombination in vivo. The RAG1 mutation, R401W, places a bulky tryptophan opposite the binding site for HMG Box A at both 12- and 23-spacer recombination signal sequences, disrupting stable binding of HMGB1. Replacement of R401W with leucine and then lysine progressively restores HMGB1 binding, correlating with increased RAG cutting and recombination in vivo. We show further that knockdown of HMGB1 significantly reduces recombination by wild-type RAG1, whereas its re-addition restores recombination with wild-type, but not the mutant, RAG1 protein. Together, these data provide compelling evidence that HMGB1 plays a critical role during V(D)J recombination in vivo.

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Nagawa, Fumikiyo, Masami Kodama, Tadashi Nishihara, Kei-ichiro Ishiguro, and Hitoshi Sakano. "Footprint Analysis of Recombination Signal Sequences in the 12/23 Synaptic Complex of V(D)J Recombination." Molecular and Cellular Biology 22, no. 20 (October 15, 2002): 7217–25. http://dx.doi.org/10.1128/mcb.22.20.7217-7225.2002.

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ABSTRACT In V(D)J joining of antigen receptor genes, two recombination signal sequences (RSSs), 12-RSS and 23-RSS, are paired and complexed with the protein products of recombination-activating genes RAG1 and RAG2. Using magnetic beads, we purified the pre- and postcleavage complexes of V(D)J joining and analyzed them by DNase I footprinting. In the precleavage synaptic complex, strong protection was seen not only in the 9-mer and spacer regions but also near the coding border of the 7-mer. This is a sharp contrast to the single RSS-RAG complex where the 9-mer plays a major role in the interaction. We also analyzed the postcleavage signal end complex by footprinting. Unlike what was seen with the precleavage complex, the entire 7-mer and its neighboring spacer regions were protected. The present study indicates that the RAG-RSS interaction in the 7-mer region drastically changes once the synaptic complex is formed for cleavage.

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He, Youdi, Ning Ma, He Xiao, Gencheng Han, Guojiang Chen, Chunmei Hou, Beifen Shen, Yan Li, Renxi Wang, and Wenli Hu. "B cell activating factor (BAFF) induces the transcription of recombination-activating genes in transitional stage 1 B cells." Central European Journal of Immunology 3 (2013): 336–42. http://dx.doi.org/10.5114/ceji.2013.37758.

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19

Goebel, Peter, Noel Janney, Joaquín R. Valenzuela, William J. Romanow, Cornelis Murre, and Ann J. Feeney. "Localized Gene-Specific Induction of Accessibility to V(D)j Recombination Induced by E2a and Early B Cell Factor in Nonlymphoid Cells." Journal of Experimental Medicine 194, no. 5 (September 3, 2001): 645–56. http://dx.doi.org/10.1084/jem.194.5.645.

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Accessibility of immunoglobulin (Ig) gene segments to V(D)J recombination is highly regulated and is normally only achieved in B cell precursors. We previously showed that ectopic expression of E2A or early B cell factor (EBF) with recombination activating gene (RAG) induces rearrangement of IgH and IgL genes in nonlymphoid cells. VκI genes throughout the locus were induced to rearrange after transfection with E2A, suggesting that the entire Vκ locus was accessible. However, here we show that Ig loci are not opened globally but that recombination is localized. Gene families are interspersed in the DH, Vκ, and Vλ loci, and we show that certain families and individual genes undergo high levels of recombination after ectopic expression of E2A or EBF, while other families within the same locus are not induced to rearrange. Furthermore, in some families, induction of germline transcription correlates with the level of induced recombination, while in others there is no correlation, suggesting that recombination is not simply initiated by induction of germline transcription. The induced repertoire seen at 24 hours does not change significantly over time indicating the absence of many secondary rearrangements and also suggesting a direct targeting mechanism. We propose that accessibility occurs in a local manner, and that binding sites for factors facilitating accessibility are therefore likely to be associated with individual gene segments.

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ZOU, Hong-yun, Li MA, Min-jie MENG, Xin-sheng YAO, Ying LIN, Zhen-qiang WU, Xiao-wei HE, Ju-fang WANG, and Xiao-ning WANG. "Expression of recombination-activating genes and T cell receptor gene recombination in the human T cell leukemia cell line." Chinese Medical Journal 120, no. 5 (March 2007): 410–15. http://dx.doi.org/10.1097/00029330-200703010-00013.

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21

Kuhn-Hallek, I., DR Sage, L. Stein, H. Groelle, and JD Fingeroth. "Expression of recombination activating genes (RAG-1 and RAG-2) in Epstein-Barr virus-bearing B cells [see comments]." Blood 85, no. 5 (March 1, 1995): 1289–99. http://dx.doi.org/10.1182/blood.v85.5.1289.bloodjournal8551289.

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Recombination activating genes 1 and 2 (RAG-1 and RAG-2), are the only lymphoid-specific genes required for the site-directed recombination reaction leading to generation of B-cell receptors and T-cell receptors (TCRs). RAGs are normally expressed during a narrow window of precursor lymphocyte development. RAG expression was examined in Epstein-Barr virus (EBV)-infected B cells. No steady-state RAG RNA was found in EBV immortalized cells, including newly established B lymphoblastoid cell lines derived from precursor lymphocytes that transcribed RAGs at the time of infection. RAG RNAs were detected in some endemic (EBV+) and also in some sporadic (EBV-) Burkitt's lymphoma lines that had been infected with EBV in vitro. The RAG+, EBV+ Burkitt's lines were unusual in that they were SIgM+ (one was SIgG+, SIgM-), CD10+, and lacked terminal deoxynucleotidyl transferase. In EBV+ Burkitt's lymphoma lines, transcription of virus latent membrane protein-1 (LMP-1) was correlated with downregulation of RAG-1 and RAG-2. Conversely, absence of LMP-1 in clones of EBV+ tumor lines was associated with increased RAG transcription. Translocation of c-myc into V(D)J loci has been observed in endemic Burkitt's lymphomas, and heptamer-nonamer recombination signal sequences have been identified at some chromosomal breakpoints. Association of RAG transcription with EBV infection raises the possibility that, under certain conditions, virus might predispose to aberrant V(D)J recombination reactions.

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HILLION, SOPHIE, CAROLINE ROCHAS, PIERRE YOUINOU, and CHRISTOPHE JAMIN. "Expression and Reexpression of Recombination Activating Genes: Relevance to the Development of Autoimmune States." Annals of the New York Academy of Sciences 1050, no. 1 (June 2005): 10–18. http://dx.doi.org/10.1196/annals.1313.002.

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23

Knecht, H., DJ Joske, A. Emery-Goodman, E. Bachmann, F. Bachmann, and BF Odermatt. "Expression of human recombination activating genes (RAG-1 and RAG-2) in Hodgkin's disease." Blood 80, no. 11 (December 1, 1992): 2867–72. http://dx.doi.org/10.1182/blood.v80.11.2867.2867.

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Abstract The differentiation status of Sternberg-Reed (SR) cells is still not well defined, primarily because of their scarcity in tumor biopsies of Hodgkin's disease (HD). In this study we have determined the genomic differentiation status of SR cells by quantitation of recombinase activating gene (RAG) expression. RAG genes are selectively transcribed in immature lymphoid cells. In B cells they are silent after genomic rearrangement has occurred, whereas in T cells they are downregulated during positive selection of double-positive thymocytes into single- positive cells. RNA from tumor biopsies either with numerous (11 cases) or a with few SR cells (16 cases) was assessed by a sensitive reverse transcriptase polymerase chain reaction (RT-PCR) and the results compared with established positive and negative controls. In all except two cases levels of RAG expression were within the range of those determined in negative controls. In both positive cases and in the positive control RAG mRNA was further quantitated by competitive PCR. In cases with abundant SR cells RAG expression was still below that observed in 10(-2) dilutions of positive controls. These results suggest that SR cells are derived from lymphoid cells, more differentiated than the pre-B or common thymocyte stage, which have already undergone genomic rearrangement. They show the value of assessing RAG expression by RT-PCR in the characterization of lymphoid malignancies.

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Knecht, H., DJ Joske, A. Emery-Goodman, E. Bachmann, F. Bachmann, and BF Odermatt. "Expression of human recombination activating genes (RAG-1 and RAG-2) in Hodgkin's disease." Blood 80, no. 11 (December 1, 1992): 2867–72. http://dx.doi.org/10.1182/blood.v80.11.2867.bloodjournal80112867.

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The differentiation status of Sternberg-Reed (SR) cells is still not well defined, primarily because of their scarcity in tumor biopsies of Hodgkin's disease (HD). In this study we have determined the genomic differentiation status of SR cells by quantitation of recombinase activating gene (RAG) expression. RAG genes are selectively transcribed in immature lymphoid cells. In B cells they are silent after genomic rearrangement has occurred, whereas in T cells they are downregulated during positive selection of double-positive thymocytes into single- positive cells. RNA from tumor biopsies either with numerous (11 cases) or a with few SR cells (16 cases) was assessed by a sensitive reverse transcriptase polymerase chain reaction (RT-PCR) and the results compared with established positive and negative controls. In all except two cases levels of RAG expression were within the range of those determined in negative controls. In both positive cases and in the positive control RAG mRNA was further quantitated by competitive PCR. In cases with abundant SR cells RAG expression was still below that observed in 10(-2) dilutions of positive controls. These results suggest that SR cells are derived from lymphoid cells, more differentiated than the pre-B or common thymocyte stage, which have already undergone genomic rearrangement. They show the value of assessing RAG expression by RT-PCR in the characterization of lymphoid malignancies.

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Nishana, Mayilaadumveettil, and Sathees C. Raghavan. "Role of recombination activating genes in the generation of antigen receptor diversity and beyond." Immunology 137, no. 4 (November 20, 2012): 271–81. http://dx.doi.org/10.1111/imm.12009.

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Kim, Keun-Yong, Myeong-Hun Ko, Huanzhang Liu, Qiongying Tang, Xianglin Chen, Jun-Ichi Miyazaki, and In-Chul Bang. "Phylogenetic Relationships ofPseudorasbora,Pseudopungtungia, andPungtungia(Teleostei; Cypriniformes; Gobioninae) Inferred from Multiple Nuclear Gene Sequences." BioMed Research International 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/347242.

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Gobionine species belonging to the generaPseudorasbora,Pseudopungtungia, andPungtungia(Teleostei; Cypriniformes; Cyprinidae) have been heavily studied because of problems on taxonomy, threats of extinction, invasion, and human health. Nucleotide sequences of three nuclear genes, that is, recombination activating protein gene 1 (rag1), recombination activating gene 2 (rag2), and early growth response 1 gene (egr1), fromPseudorasbora,Pseudopungtungia, andPungtungiaspecies residing in China, Japan, and Korea, were analyzed to elucidate their intergeneric and interspecific phylogenetic relationships. In the phylogenetic tree inferred from their multiple gene sequences,Pseudorasbora,PseudopungtungiaandPungtungiaspecies ramified into three phylogenetically distinct clades; the “tenuicorpa” clade composed ofPseudopungtungia tenuicorpa, the “parva” clade composed of allPseudorasboraspecies/subspecies, and the “herzi” clade composed ofPseudopungtungia nigra, andPungtungia herzi. The genusPseudorasborawas recovered as monophyletic, while the genusPseudopungtungiawas recovered as polyphyletic. Our phylogenetic result implies the unstable taxonomic status of the genusPseudopungtungia.

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Gennery, Andrew. "Recent advances in understanding RAG deficiencies." F1000Research 8 (February 4, 2019): 148. http://dx.doi.org/10.12688/f1000research.17056.1.

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Recombination-activating genes (RAG)1 and RAG2 initiate the molecular processes that lead to lymphocyte receptor formation through VDJ recombination. Nonsense mutations in RAG1/RAG2 cause the most profound immunodeficiency syndrome, severe combined immunodeficiency (SCID). Other severe and less-severe clinical phenotypes due to mutations in RAG genes are now recognized. The degree of residual protein function may permit some lymphocyte receptor formation, which confers a less-severe clinical phenotype. Many of the non-SCID phenotypes are associated with autoimmunity. New findings into the effect of mutations in RAG1/2 on the developing T- and B-lymphocyte receptor give insight into the development of autoimmunity. This article summarizes recent findings and places the genetic and molecular findings in a clinical context.

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Lange, Miles, Wanqin Xie, Sang Yong Hong, Zhihong Yu, Ti He, Lin Huang, Yangsheng Yu, et al. "The V(D)J recombination machinery is associated with the nuclear matrix (88.3)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 88.3. http://dx.doi.org/10.4049/jimmunol.184.supp.88.3.

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Abstract Somatic recombination of immunoglobulin or T cell antigen receptor genes occurs through recombination activating gene product (RAG)-mediated cleavage at recombination signal sequences (RSS) and subsequently, the broken DNA ends are repaired by non-homologue end joining (NHEJ) enzymes. Here, we show that RAG1, RAG2, and many NHEJ factors in B lineage cells are associated with the nuclear matrix. The core RAG1 and RAG2 proteins have their own nuclear matrix targeting regions. RAG-mediated double stranded DNA breaks at the Jκ4 RSS can be readily detected in the nuclear matrix fraction in Gleevec treated Abelson transformed murine B cells or mouse bone marrow cells, indicating that the recombination reaction is ongoing on the nuclear matrix. In the HEK 293 cell-based recombination system, artificial recombination substrates are recruited to the nuclear matrix for recombination. Moreover, nuclear matrix proteins purified from 293 cells expressing the core RAG proteins or human B lineage cells expressing endogenous RAG proteins support cleavage of RSS substrates in vitro. Based on these results, we propose that the V(D)J recombination machinery is associated with the nuclear matrix.

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Thomson, Daniel, Hezrin Shahrin, Paul Wang, Carol Wadham, Timothy P. Hughes, Andreas Schreiber, and Susan Branford. "High Recombination Activating Gene (RAG) Expression and RAG Mediated Recombination Is Associated with Oncogenic Rearrangement Observed with Tyrosine Kinase Inhibitor Resistant CML." Blood 132, Supplement 1 (November 29, 2018): 3001. http://dx.doi.org/10.1182/blood-2018-99-111212.

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Abstract Background Patients with chronic myeloid leukemia (CML) who develop blast crisis are resistant to TKI therapy. A key focus in CML research is the identification of genetic factors that promote blast crisis and TKI resistance. By using an integrative genomic approach we recently reported frequent structural variation in CML patients, particularly at lymphoid blast crisis (LBC) (Blood, 2018). Developing lymphocytes are uniquely equipped with a molecular toolkit capable of programmed DNA damage and structural variant formation; the V(D)J recombination pathway. Recombination activating genes (RAG1 and RAG2) are involved in cleavage and recombination of immunoglobulin genes to provide diversity in antibodies and T cell receptors. Off target RAG activity is reported to occur in lymphoid malignancies and cause oncogenic structural rearrangements. However, RAG expression and the extent of RAG mediated structural variation in CML are largely uncharacterized. Aim To elucidate the role of RAG mediated recombination as a source of oncogenic structural rearrangement in CML. Methods In a study of samples of 49 patients at chronic phase (CP) diagnosis (Dx), 20 at LBC and 19 at myeloid blast crisis (MBC), we performed whole exome sequencing and/or RNAseq. Bioinformatic analyses included fusion detection (Manta & STAR), gene expression analysis (EdgeR), and copy number variation analysis (in house developed tool). Unsupervised motif detection of sequences surrounding breakpoints was performed with MEME, and fusions were visualized with Jcircos. To identify off target RAG mediated mutation we interrogated the breakpoints of structural variants, excluding those associated with the Philadelphia translocation and those solely involving antigen receptor gene rearrangement. Results 33 structural variants were identified in 22 patients with samples at Dx and/or blast crisis involving genes regularly mutated in hematologic malignancy such as MLL, MECOM, RUNX1 and IKZF1. Differential expression analysis between patients at Dx, MBC and LBC revealed >1000 genes that were differentially expressed, P<0.001. Amongst the most upregulated genes at LBC were RAG1, RAG2 and DNTT, reflected in the most enriched gene ontology: V(D)J recombination. V(D)J recombination genes were sufficient alone in stratifying LBC samples from CP Dx and MBC [Figure 1A]. Furthermore, RAG expression was detectably elevated at Dx in most patients who subsequently developed LBC [Figure 1B]. To identify off target RAG mediated structural variation, we interrogated the sequence surrounding breakpoints of the 33 identified structural variants (66 breakpoints) that were separated into groups of high (n=40) and low (n=26) RAG expression. The canonical heptamer CACAGTG recombination signal sequence (RSS) was enriched only at breakpoints in the high RAG group with sequences from 31/40 breakpoints making up the motif [Figure 1C]. The comparable group of low RAG breakpoints were not enriched for the motif. Another indicator of RAG involvement is the addition of non-template nucleotides at the breakpoint, consistent with DNTT nucleotidyl-transferase activity. This was detected almost exclusively at breakpoints in patients with high RAG, 16/20 structural variants, compared to 1/13 with low RAG. There was an association between high RAG expression and structural variants bearing the RAG RSS motif at breakpoints with nucleotide additions. The most frequently observed of these were intragenic deletions of IKZF1 in 7 patients, including 3 at Dx with subsequent LBC, 3 at LBC and 1 at MBC. A number of novel structural variants also had the RAG recombination signature: IKZF1-IGK fusion, RUNX1 deletion and recurrent HBS1L-MYB intergenic locus deletion. RAG mediated structural variation was further investigated on a genomic level using putative low level fusions identified from RNAseq. By assessing the immunoglobulin/T cell receptor genes, as known sites of RAG activity, we found enrichment of interchromosomal fusions involving these genes in samples with high RAG, compared to Dx and MBC with low RAG [Figure 1D]. An agnostic motif enrichment search at sequences surrounding putative fusions showed enrichment of a motif resembling the recombination signal sequence. Conclusion Our results implicate RAG as a driver of structural variation and the formation of novel oncogenic rearrangements in CML. Figure 1. Figure 1. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cepheid: Honoraria.

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Hikida, M., M. Mori, T. Kawabata, T. Takai, and H. Ohmori. "Characterization of B cells expressing recombination activating genes in germinal centers of immunized mouse lymph nodes." Journal of Immunology 158, no. 6 (March 15, 1997): 2509–12. http://dx.doi.org/10.4049/jimmunol.158.6.2509.

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Abstract Products of recombination activating genes (RAG-1 and RAG-2) involved in the rearrangement of Ig genes have been shown to be expressed only in immature stages of B cells. However, we have recently found that RAG genes were re-expressed in mature mouse B cells activated in vitro and in germinal centers (GCs) of immunized mouse lymph nodes (LNs). Here, we report that RAG transcripts and their proteins were expressed in parallel with the formation of GCs in popliteal LNs from mice immunized in the hind footpads. Immunocytochemical analysis revealed that RAG+ B cells were localized within GCs and were present as apoptotic tingible body cells. RAG expression is not considered a nonspecific result of apoptosis, since apoptotic B cells generated by surface Ig-engagement did not express RAG genes. These results suggest a novel role of RAG products in the differentiation of B cells in GCs.

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Yoshikawa, Genki, Kazuko Miyazaki, Hiroyuki Ogata, and Masaki Miyazaki. "The Evolution of Rag Gene Enhancers and Transcription Factor E and Id Proteins in the Adaptive Immune System." International Journal of Molecular Sciences 22, no. 11 (May 31, 2021): 5888. http://dx.doi.org/10.3390/ijms22115888.

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Adaptive immunity relies on the V(D)J DNA recombination of immunoglobulin (Ig) and T cell receptor (TCR) genes, which enables the recognition of highly diverse antigens and the elicitation of antigen-specific immune responses. This process is mediated by recombination-activating gene (Rag) 1 and Rag2 (Rag1/2), whose expression is strictly controlled in a cell type-specific manner; the expression of Rag1/2 genes represents a hallmark of lymphoid lineage commitment. Although Rag genes are known to be evolutionally conserved among jawed vertebrates, how Rag genes are regulated by lineage-specific transcription factors (TFs) and how their regulatory system evolved among vertebrates have not been fully elucidated. Here, we reviewed the current body of knowledge concerning the cis-regulatory elements (CREs) of Rag genes and the evolution of the basic helix-loop-helix TF E protein regulating Rag gene CREs, as well as the evolution of the antagonist of this protein, the Id protein. This may help to understand how the adaptive immune system develops along with the evolution of responsible TFs and enhancers.

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Livak, F., and D. G. Schatz. "T-cell receptor alpha locus V(D)J recombination by-products are abundant in thymocytes and mature T cells." Molecular and Cellular Biology 16, no. 2 (February 1996): 609–18. http://dx.doi.org/10.1128/mcb.16.2.609.

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In addition to the assembled coding regions of immunoglobulin and T-cell receptor (TCR) genes, the V(D)J recombination reaction can in principle generate three types of by-products in normal developing lymphocytes: broken DNA molecules that terminate in a recombination signal sequence or a coding region (termed signal or coding end molecules, respectively) and DNA molecules containing fused recombination signal sequences (termed reciprocal products). Using a quantitative Southern blot analysis of the murine TCR alpha locus, we demonstrate that substantial amounts of signal end molecules and reciprocal products, but not coding end molecules, exist in thymocytes, while peripheral T cells contain substantial amounts of reciprocal products. At the 5' end of the J alpha locus, 20% of thymus DNA exists as signal end molecules. An additional 30 to 40% of the TCR alpha/delta locus exists as remarkably stable reciprocal products throughout T-cell development, with the consequence that the TCR C delta region is substantially retained in alpha beta committed T cells. The disappearance of the broken DNA molecules occurs in the same developmental transition as termination of expression of the recombination activating genes, RAG-1 and RAG-2. These findings raise important questions concerning the mechanism of V(D)J recombination and the maintenance of genome integrity during lymphoid development.

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Wayne, J., H. Suh, K. A. Sokol, H. T. Petrie, M. Witmer-Pack, S. Edelhoff, C. M. Disteche, and M. C. Nussenzweig. "TCR selection and allelic exclusion in RAG transgenic mice that exhibit abnormal T cell localization in lymph nodes and lymphatics." Journal of Immunology 153, no. 12 (December 15, 1994): 5491–502. http://dx.doi.org/10.4049/jimmunol.153.12.5491.

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Abstract RAG-1 and RAG-2 are developmentally regulated genes that are essential for V(D)J recombination and lymphocyte development. Expression of RAG-1 and RAG-2 by thymocytes is normally limited to cells that have not completed selection. We have previously documented that persistent expression of the recombinase activating genes (RAG) in transgenic mice results in aberrant thymic development, altered lymphatic microanatomy, and a profound immunodeficiency. Here we further document the pathologic changes found in TG.RAG-1,2 mice and examine the role of TCR recombination and positive and negative thymic selection, as well as allelic exclusion, in the etiology of the phenotype. We find that neither selection nor TCR allelic exclusion can be overcome by transgenic expression RAG-1 and RAG-2 under the control of an lck promoter.

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Hikida, Masaki, Yasunori Nakayama, Yumi Yamashita, Yoshio Kumazawa, Shin-Ichi Nishikawa, and Hitoshi Ohmori. "Expression of Recombination Activating Genes in Germinal Center B Cells: Involvement of Interleukin 7 (IL-7) and the IL-7 Receptor." Journal of Experimental Medicine 188, no. 2 (July 20, 1998): 365–72. http://dx.doi.org/10.1084/jem.188.2.365.

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Mouse germinal center (GC) B cells have been shown to undergo secondary V(D)J (V, variable; D, diversity; J, joining) recombination (receptor editing) mediated by the reexpressed products of recombination activating gene (RAG)-1 and RAG-2. We show here that interleukin (IL)-7 as well as IL-4 was effective in inducing functional RAG products in mouse IgD+ B cells activated via CD40 in vitro. Blocking of the IL-7 receptor (IL-7R) by injecting an anti– IL-7R monoclonal antibody resulted in a marked suppression of the reexpression of RAG-2 and subsequent V(D)J recombination in the draining lymph node of immunized mice, whereas RAG-2 expression was not impaired in immunized IL-4–deficient mice. Further, these peripheral B cells activated in vitro or in vivo were found to express IL-7R. These findings indicate a novel role for IL-7 and IL-7R in inducing receptor editing in GC B cells.

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Dorsett, Yair, Davide F. Robbiani, Mila Jankovic, Bernardo Reina-San-Martin, Thomas R. Eisenreich, and Michel C. Nussenzweig. "A role for AID in chromosome translocations between c-myc and the IgH variable region." Journal of Experimental Medicine 204, no. 9 (August 27, 2007): 2225–32. http://dx.doi.org/10.1084/jem.20070884.

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Chromosome translocations between oncogenes and the region spanning the immunoglobulin (Ig) heavy chain (IgH) variable (V), diversity (D), and joining (J) gene segments (Ig V-JH region) are found in several mature B cell lymphomas in humans and mice. The breakpoints are frequently adjacent to the recombination signal sequences targeted by recombination activating genes 1 and 2 during antigen receptor assembly in pre–B cells, suggesting that these translocations might be the result of aberrant V(D)J recombination. However, in mature B cells undergoing activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM), duplications or deletions that would necessitate a double-strand break make up 6% of all the Ig V-JH region–associated somatic mutations. Furthermore, DNA breaks can be detected at this locus in B cells undergoing SHM. To determine whether SHM might induce c-myc to Ig V-JH translocations, we searched for such events in both interleukin (IL) 6 transgenic (IL-6 tg) and AID−/− IL-6 tg mice. Here, we report that AID is required for c-myc to Ig V-JH translocations induced by IL-6.

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Bories, JC, JM Cayuela, P. Loiseau, and F. Sigaux. "Expression of human recombination activating genes (RAG1 and RAG2) in neoplastic lymphoid cells: correlation with cell differentiation and antigen receptor expression." Blood 78, no. 8 (October 15, 1991): 2053–61. http://dx.doi.org/10.1182/blood.v78.8.2053.2053.

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Abstract Regulation of V-(D)-J recombinations that occur in antigen receptor encoding genes remains poorly understood. Recently, two genes, RAG1 and RAG2, that are able to activate rearrangement of synthetic recombination substrates were cloned in mouse and a human gene homologous to RAG1 was described. To define the differentiation stages corresponding to RAG1 and RAG2 RNA expression, we have studied a large number of B- and T-lymphoid neoplasias. First, we show that a human gene homologous to the murine RAG2 is transcribed in humans. Moreover, using a polymerase chain reaction approach, we have shown that RAG are expressed not only in T-cell receptor (TCR)-negative T-cell acute lymphoblastic leukemias (T-ALLs), but also in some cases in which a significant percentage of cells expressed surface TCR. Absence of RAG expression was shown in certain T-ALLs at variable stages of thymic differentiation. Data obtained in B-lineage ALLs show that RAG RNAs are expressed in almost all slg- B-lineage ALLs but are not transcribed in the slg+ B-cell proliferations tested, including Burkitt's ALLs, follicular center cell lymphomas, and chronic leukemias. These findings are consistent with the involvement of RAG in the control of in vivo V- (D)-J recombinations. These findings are also of interest in the delineation of potential regulatory factors acting on RAG transcription and in the understanding of the mechanisms of specific chromosomal abnormalities occurring in immature lymphoid cells.

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Bories, JC, JM Cayuela, P. Loiseau, and F. Sigaux. "Expression of human recombination activating genes (RAG1 and RAG2) in neoplastic lymphoid cells: correlation with cell differentiation and antigen receptor expression." Blood 78, no. 8 (October 15, 1991): 2053–61. http://dx.doi.org/10.1182/blood.v78.8.2053.bloodjournal7882053.

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Regulation of V-(D)-J recombinations that occur in antigen receptor encoding genes remains poorly understood. Recently, two genes, RAG1 and RAG2, that are able to activate rearrangement of synthetic recombination substrates were cloned in mouse and a human gene homologous to RAG1 was described. To define the differentiation stages corresponding to RAG1 and RAG2 RNA expression, we have studied a large number of B- and T-lymphoid neoplasias. First, we show that a human gene homologous to the murine RAG2 is transcribed in humans. Moreover, using a polymerase chain reaction approach, we have shown that RAG are expressed not only in T-cell receptor (TCR)-negative T-cell acute lymphoblastic leukemias (T-ALLs), but also in some cases in which a significant percentage of cells expressed surface TCR. Absence of RAG expression was shown in certain T-ALLs at variable stages of thymic differentiation. Data obtained in B-lineage ALLs show that RAG RNAs are expressed in almost all slg- B-lineage ALLs but are not transcribed in the slg+ B-cell proliferations tested, including Burkitt's ALLs, follicular center cell lymphomas, and chronic leukemias. These findings are consistent with the involvement of RAG in the control of in vivo V- (D)-J recombinations. These findings are also of interest in the delineation of potential regulatory factors acting on RAG transcription and in the understanding of the mechanisms of specific chromosomal abnormalities occurring in immature lymphoid cells.

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Thorey, Irmgard S., Katrin Muth, Andreas P. Russ, Jürgen Otte, Armin Reffelmann, and Harald von Melchner. "Selective Disruption of Genes Transiently Induced in Differentiating Mouse Embryonic Stem Cells by Using Gene Trap Mutagenesis and Site-Specific Recombination." Molecular and Cellular Biology 18, no. 5 (May 1, 1998): 3081–88. http://dx.doi.org/10.1128/mcb.18.5.3081.

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ABSTRACT A strategy employing gene trap mutagenesis and site-specific recombination (Cre/loxP) has been used to identify genes that are transiently expressed during early mouse development. Embryonic stem cells expressing a reporter plasmid that codes for neomycin phosphotransferase and Escherichia coli LacZ were infected with a retroviral gene trap vector (U3Cre) carrying coding sequences for Cre recombinase (Cre) in the U3 region. Activation of Cre expression from integrations into active genes resulted in a permanent switching between the two selectable marker genes and consequently the expression of β-galactosidase (β-Gal). As a result, clones in which U3Cre had disrupted genes that were only transiently expressed could be selected. Moreover, U3Cre-activating cells acquired a cell autonomous marker that could be traced to cells and tissues of the developing embryo. Thus, when two of the clones with inducible U3Cre integrations were passaged in the germ line, they generated spatial patterns of β-Gal expression.

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Zhang, X. L., Y. S. Lu, J. C. Jian, and Z. H. Wu. "Cloning and expression analysis of recombination activating genes (RAG1/2) in red snapper (Lutjanus sanguineus)." Fish & Shellfish Immunology 32, no. 4 (April 2012): 534–43. http://dx.doi.org/10.1016/j.fsi.2012.01.001.

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SHEARD, M., K. SUGAYA, M. FURUTA, S. TSUDA, and Y. TAKAHAMA. "Heterogeneous Expression of Recombination Activating Genes and Surface CD5 in CD3 low CD4 + CD8 + Thymocytes." Scandinavian Journal of Immunology 43, no. 6 (June 1996): 619–25. http://dx.doi.org/10.1046/j.1365-3083.1996.d01-263.x.

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41

Greenhalgh, P., C. E. Olesen, and L. A. Steiner. "Characterization and expression of recombination activating genes (RAG-1 and RAG-2) in Xenopus laevis." Journal of Immunology 151, no. 6 (September 15, 1993): 3100–3110. http://dx.doi.org/10.4049/jimmunol.151.6.3100.

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Abstract The primary repertoire of B and T cells is established by V(D)J recombination. Two closely linked genes, RAG-1 and RAG-2, are essential for this process, and have been identified in mice, humans, and chickens. To study lymphocyte development in Xenopus laevis, we have characterized RAG-1 and RAG-2 in this species and examined their patterns of expression. Degenerate oligonucleotides, based on the known highly conserved RAG-1 sequences, were used to amplify, by the polymerase chain reaction, a segment of Xenopus RAG-1 from genomic DNA. A product of expected size was obtained and used to identify a genomic clone that contained the complete coding region of RAG-1 (1045 codons), and approximately the 3'-half of the coding region of RAG-2. The coding regions of RAG-1 and RAG-2 each lie on a single exon, are in opposite transcriptional orientation, and are separated by approximately 6 kb. The sequence of the remainder of RAG-2 was determined by PCR amplification of genomic DNA, with primers based on sequence analysis of RAG-2 cDNA clones. The predicted Xenopus RAG-1 protein is 71% identical in amino acid sequence to the sequences of each of the mouse, human, and chicken proteins; from position 392 to 1012 the identity is 88%. The coding region of Xenopus RAG-2 (520 codons) is somewhat less conserved among the different species. Tissue-specific expression of Xenopus RAG-1 and RAG-2 was examined both by Northern blotting and by a reverse transcription-polymerase chain reaction assay. In juvenile frogs, the highest levels of RAG-1 and RAG-2 expression were observed in the thymus, with lower levels in liver and spleen, and even lower levels in the kidneys. In adults, the thymus and bone marrow were found to be the principal sites of expression of both genes. RAG-2, but not RAG-1, was expressed in oocytes.

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Dunda, O., and D. Corcos. "Recombining sequence recombination in normal kappa-chain-expressing B cells." Journal of Immunology 159, no. 9 (November 1, 1997): 4362–66. http://dx.doi.org/10.4049/jimmunol.159.9.4362.

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Abstract Recombining sequence (RS) recombination is a DNA rearrangement that deletes one or two C kappa alleles in a large proportion of lambda-expressing B cells. Since its discovery, this recombination has been suggested to play a role in activating lambda gene rearrangements. A model involving a positive signal generated by RS recombination seems to be excluded, but another model that is still under consideration proposes that RS recombination removes DNA sequences within the kappa locus that would interfere with lambda gene assembly. Using PCR assays, we have found that kappa-expressing cells account for the majority of RS rearrangements in mouse spleen. RS rearrangements were also detected by Southern blot in kappa-secreting hybridomas. Quantification of rearrangements indicates that approximately 12% of kappa cells bear an RS recombination. From this finding, we infer that once a cell has performed an RS recombination on one kappa allele, it has a 3 times higher probability of rearranging functionally its other kappa allele rather than one of the lambda genes. These data call into question the role of RS recombination in the switch from kappa to lambda and suggest another function for this nonproductive rearrangement.

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Bashkirov, Vladimir I., Jeff S. King, Elena V. Bashkirova, Jacqueline Schmuckli-Maurer, and Wolf-Dietrich Heyer. "DNA Repair Protein Rad55 Is a Terminal Substrate of the DNA Damage Checkpoints." Molecular and Cellular Biology 20, no. 12 (June 15, 2000): 4393–404. http://dx.doi.org/10.1128/mcb.20.12.4393-4404.2000.

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ABSTRACT Checkpoints, which are integral to the cellular response to DNA damage, coordinate transient cell cycle arrest and the induced expression of DNA repair genes after genotoxic stress. DNA repair ensures cellular survival and genomic stability, utilizing a multipathway network. Here we report evidence that the two systems, DNA damage checkpoint control and DNA repair, are directly connected by demonstrating that the Rad55 double-strand break repair protein of the recombinational repair pathway is a terminal substrate of DNA damage and replication block checkpoints. Rad55p was specifically phosphorylated in response to DNA damage induced by the alkylating agent methyl methanesulfonate, dependent on an active DNA damage checkpoint. Rad55p modification was also observed after gamma ray and UV radiation. The rapid time course of phosphorylation and the recombination defects identified in checkpoint-deficient cells are consistent with a role of the DNA damage checkpoint in activating recombinational repair. Rad55p phosphorylation possibly affects the balance between different competing DNA repair pathways.

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Aidinis, Vassilis, Dora C. Dias, Carlos A. Gomez, Debika Bhattacharyya, Eugenia Spanopoulou, and Sandro Santagata. "Definition of Minimal Domains of Interaction Within the Recombination-Activating Genes 1 and 2 Recombinase Complex." Journal of Immunology 164, no. 11 (June 1, 2000): 5826–32. http://dx.doi.org/10.4049/jimmunol.164.11.5826.

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Faber, C. "Differential expression patterns of recombination-activating genes in individual mature B cells in juvenile idiopathic arthritis." Annals of the Rheumatic Diseases 65, no. 10 (March 28, 2006): 1351–56. http://dx.doi.org/10.1136/ard.2005.047878.

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Ben Yehuda, Arie, Gideon Friedman, Eitan Wirtheim, Loya Abel, and Amiela Globerson. "Checkpoints in thymocytopoiesis in aging: expression of the recombination activating genes RAG-1 and RAG-2." Mechanisms of Ageing and Development 102, no. 2-3 (May 1998): 239–47. http://dx.doi.org/10.1016/s0047-6374(98)00021-9.

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Golubnitchaya-Labudová, O., A. Portele, V. Vaçata, G. Lubec, H. Rink, and M. Höfer. "Recombination activating activity of XRCC1 analogous genes in X-ray sensitive and resistant CHO cell lines." Radiation Physics and Chemistry 50, no. 4 (October 1997): 331–39. http://dx.doi.org/10.1016/s0969-806x(97)00050-9.

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Papavasiliou, F. Nina, and David G. Schatz. "The Activation-induced Deaminase Functions in a Postcleavage Step of the Somatic Hypermutation Process." Journal of Experimental Medicine 195, no. 9 (May 6, 2002): 1193–98. http://dx.doi.org/10.1084/jem.20011858.

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Activation of B cells by antigen fuels two distinct molecular modifications of immunoglobulin (Ig) genes. Class-switch recombination (CSR) replaces the Igμ heavy chain constant region with a downstream constant region gene, thereby altering the effector function of the resulting antibodies. Somatic hypermutation (SHM) introduces point mutations into the variable regions of Ig genes, thereby changing the affinity of antibody for antigen. Mechanistic overlap between the two reactions has been suggested by the finding that both require the activation-induced cytidine deaminase (AID). It has been proposed that AID initiates both CSR and SHM by activating a common nuclease. Here we provide evidence that cells lacking AID, or expressing a dominant negative form of the protein, are still able to incur DNA lesions in SHM target sequences. The results indicate that an intact cytidine deaminase motif is required for AID function, and that AID acts downstream of the initial DNA lesions in SHM.

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Castro-Pérez, Edgardo, Emilio Soto-Soto, Marizabeth Pérez-Carambot, Dawling Dionisio-Santos, Kristian Saied-Santiago, Humberto G. Ortiz-Zuazaga, and Sandra Peña de Ortiz. "Identification and Characterization of the V(D)J Recombination Activating Gene 1 in Long-Term Memory of Context Fear Conditioning." Neural Plasticity 2016 (2016): 1–19. http://dx.doi.org/10.1155/2016/1752176.

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An increasing body of evidence suggests that mechanisms related to the introduction and repair of DNA double strand breaks (DSBs) may be associated with long-term memory (LTM) processes. Previous studies from our group suggested that factors known to function in DNA recombination/repair machineries, such as DNA ligases, polymerases, and DNA endonucleases, play a role in LTM. Here we report data using C57BL/6 mice showing that theV(D)J recombination-activating gene 1(RAG1), which encodes a factor that introduces DSBs in immunoglobulin and T-cell receptor genes, is induced in the amygdala, but not in the hippocampus, after context fear conditioning. Amygdalar induction ofRAG1mRNA, measured by real-time PCR, was not observed in context-only or shock-only controls, suggesting that the context fear conditioning response is related to associative learning processes. Furthermore, double immunofluorescence studies demonstrated the neuronal localization of RAG1 protein in amygdalar sections prepared after perfusion and fixation. In functional studies, intra-amygdalar injections ofRAG1gapmer antisense oligonucleotides, given 1 h prior to conditioning, resulted in amygdalar knockdown ofRAG1mRNA and a significant impairment in LTM, tested 24 h after training. Overall, these findings suggest that theV(D)J recombination-activating gene 1,RAG1, may play a role in LTM consolidation.

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Meru, Nadine, Andreas Jung, Irith Baumann, and Gerald Niedobitek. "Expression of the recombination-activating genes in extrafollicular lymphocytes but no apparent reinduction in germinal center reactions in human tonsils." Blood 99, no. 2 (January 15, 2002): 531–37. http://dx.doi.org/10.1182/blood.v99.2.531.

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Abstract V(D)J recombination in lymphocytes is mediated by 2 recombination-activating genes, RAG1 and RAG2,which are expressed during lymphocyte development in bone marrow and thymus. Prompted by studies reporting re-expression of the RAGs in germinal center B cells, the expression of RAGs and terminal deoxynucleotidyl transferase (TdT) in human lymphoid tissues was examined using in situ hybridization and immunohistochemistry, respectively. Here it is shown that RAGs and TdT are not reinduced in germinal center reactions. However, RAG+/TdT+ cells are frequently present in extrafollicular areas of tonsils mainly at the boundary between lymphoid tissue and fibrous scaffold. Phenotypic analyses suggest that these cells are B cells. Finally, it is shown that RAG+/TdT+ cells are found more frequently in tonsils than in other peripheral lymphoid tissues. This may reflect an increased influx of RAG+/TdT+ cells as a result of higher antigenic stimulation at this site. Alternatively, this observation may indicate that the tonsils are an additional site of lymphocyte ontogeny.

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Journal articles on the topic 'Recombination activating genes'

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