Affinage

RAG2

V(D)J recombination-activating protein 2 · UniProt P55895

Length
527 aa
Mass
59.2 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAG2 is an essential subunit of the lymphoid-specific recombinase that initiates V(D)J recombination, the process that assembles antigen-receptor genes, and its expression alone correlates precisely with recombinase activity across cell types (PMID:2360047). RAG2 acts with RAG1 to build a stable, sequence-specific protein-DNA complex at recombination signal sequences (RSSs): RAG2 contributes directly to DNA binding through basic residues, extends and stabilizes contacts through the spacer into the heptamer-proximal region, and suppresses RAG1's promiscuous non-specific binding to sharpen RSS selectivity (PMID:9166431, PMID:9671477, PMID:9697841, PMID:11684024, PMID:19232525). The catalytically active species is an (RAG1-RAG2)2 heterotetramer containing two molecules of each protein, with RAG2 positioned at the tip of each arm; cryo-EM and crystal structures establish base-flipping, RSS distortion, a two-metal-ion cleavage mechanism, and an asymmetric architecture underlying the 12/23 rule (PMID:10373515, PMID:26548953, PMID:25707801). The complex nicks and forms hairpins at coding ends and, after cleavage, holds the broken DNA in a stable post-cleavage synaptic complex with HMG proteins and DNA-PK components (PMID:9019407, PMID:9094713, PMID:10330156). The non-core RAG2 C-terminus is a multilayered genome-stability module: it harbors a noncanonical PHD finger that reads H3K4me3 (and is enhanced by H3R2me2) to license cleavage and target the recombinase to active chromatin genome-wide, while RAG1 binding is confined to RSSs (PMID:15964836, PMID:18033247, PMID:18025461, PMID:20398922, PMID:21149691). This same C-terminus and the adjacent acidic hinge stabilize the post-cleavage complex to channel ends into classical NHEJ, enforce locus accessibility, and suppress transposition; its loss in vivo causes impaired lymphoid development, destabilized post-cleavage complexes, and oncogenic chromosomal translocations (PMID:9707447, PMID:12531919, PMID:12682025, PMID:12682024, PMID:21368836, PMID:23994475, PMID:26833222). RAG2 abundance is restricted to G0/G1 by CDK-dependent Thr-490 phosphorylation that triggers nuclear export and Skp2-SCF-mediated ubiquitin-proteasomal degradation at the G1-to-S transition (PMID:8146183, PMID:8986717, PMID:12205088, PMID:15949444). Mutations clustered in the PHD finger underlie human immunodeficiencies including SCID (PMID:15964836, PMID:18033247, PMID:18025461).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1990 High

    Established that RAG2 is a necessary partner gene whose expression confers V(D)J recombinase activity, answering whether recombination required a dedicated factor beyond RAG1.

    Evidence Co-transfection recombination assay in fibroblasts plus cloning/sequencing

    PMID:2360047

    Open questions at the time
    • Did not define RAG2's biochemical role versus RAG1
    • No mechanism of DNA recognition or cleavage
  2. 1996 High

    Identified CDK-dependent Thr-490 phosphorylation as the timer that restricts RAG2 protein, and thus recombination, to G0/G1 — answering how V(D)J activity is confined to a safe cell-cycle window.

    Evidence Cell-cycle synchronization, immunoblot, CDK assays, and Thr-490 mutagenesis in transgenic mice

    PMID:8146183 PMID:8986717

    Open questions at the time
    • Did not identify the degradation machinery
    • Subcellular route of degradation not defined
  3. 1997 High

    Defined the RAG1-RAG2 stable cleavage complex and the divalent-cation-controlled nick/hairpin chemistry, plus the post-cleavage synaptic complex with HMG and DNA-PK, establishing how the recombinase recognizes RSSs and holds broken ends.

    Evidence EMSA, footprinting, cation-dependent cleavage assays, nuclease-resistance and Co-IP of post-cleavage complex

    PMID:9019407 PMID:9094713 PMID:9166431 PMID:9671477 PMID:9697841

    Open questions at the time
    • Stoichiometry of active complex not yet resolved
    • Atomic structure unknown
  4. 1998 High

    Showed the RAG complex is a transposase capable of strand transfer and hybrid-joint formation, and that the RAG2 C-terminus governs locus-specific access — revealing the system's transposon ancestry and a regulatory role beyond catalysis.

    Evidence In vitro transposition, rejoining, and truncated-RAG2 recombination assays

    PMID:9535663 PMID:9707447 PMID:9723614 PMID:9727489

    Open questions at the time
    • How transposition is suppressed in vivo unaddressed
    • Molecular identity of the C-terminal regulatory element unknown
  5. 1999 High

    Demonstrated intrinsic single-stranded hairpin-nicking activity and a tetrameric active complex, clarifying how RAG proteins open hairpins and hold both DNA products.

    Evidence In vitro hairpin nicking, gel filtration, UV cross-linking, and native gel analysis with purified proteins

    PMID:10330156 PMID:10373515

    Open questions at the time
    • Tetramer assembly pathway not defined
    • Conformational basis of activation unknown
  6. 2001 High

    Proved RAG2 directly contributes to DNA binding rather than merely scaffolding RAG1, via basic residues required for complex-DNA interaction.

    Evidence Systematic mutagenesis with EMSA, in vivo recombination, and RAG1-RAG2 interaction assays

    PMID:11684024

    Open questions at the time
    • Single lab
    • Structural placement of these residues not yet visualized
  7. 2002 Medium

    Connected Thr-490 phosphorylation to nuclear export followed by ubiquitin/proteasome degradation, with p27Kip1 stabilizing nuclear RAG2 — mapping the spatial logic of RAG2 turnover.

    Evidence Subcellular fractionation, phosphorylation inhibition, proteasome inhibitors, immunofluorescence

    PMID:12205088

    Open questions at the time
    • E3 ligase not identified here
    • Single lab
  8. 2003 High

    Established the non-core C-terminus as a genome-stability and transposition-suppression module and identified its PHD finger fold, while in vivo deletion confirmed its role in lymphoid development.

    Evidence NMR structure, transposition and target-capture assays, GTP modulation, and core-RAG2 knock-in mice

    PMID:12531919 PMID:12682024 PMID:12682025 PMID:15964836

    Open questions at the time
    • PHD ligand not yet identified
    • Mechanism linking PHD to recombination activity unresolved
  9. 2005 High

    Identified Skp2-SCF as the E3 ligase ubiquitylating RAG2 at the G1-to-S transition, completing the molecular link between cell-cycle control and recombinase destruction.

    Evidence Cell-free reconstituted ubiquitylation, in vivo degradation assays, Skp2 knockout

    PMID:15949444

    Open questions at the time
    • Substrate recognition determinants on RAG2 not fully mapped
  10. 2007 High

    Established the RAG2 PHD finger as a chromatin reader of H3K4me3 (enhanced by H3R2me2) that licenses cleavage, providing the mechanism by which recombination is targeted to active chromatin and explaining clustered immunodeficiency mutations.

    Evidence Crystal structures of PHD with modified H3 peptides, binding assays, mutagenesis, and in vivo recombination

    PMID:18025461 PMID:18033247

    Open questions at the time
    • How H3K4me3 binding is mechanically transmitted to the catalytic core not yet shown
    • Genome-wide targeting consequences not measured here
  11. 2010 High

    Resolved how the chromatin mark links to cleavage activity: H3K4me3 binding by the PHD relieves C-terminal autoinhibition of hairpinning, and genome-wide RAG2 localizes to thousands of H3K4me3 sites while RAG1 stays at RSSs.

    Evidence In vitro cleavage and transposition with truncations plus peptide supplementation; ChIP-seq in primary lymphocytes

    PMID:20398922 PMID:21149691

    Open questions at the time
    • How RAG1 and RAG2 binding patterns converge at recombination centers in vivo incompletely defined
  12. 2011 High

    Showed the RAG2 C-terminus is essential for genomic stability in vivo by stabilizing the post-cleavage complex, with its loss causing locus disruption and oncogenic translocations.

    Evidence Core-Rag2 knock-in (and p53-/-) mice, cytogenetics/FISH, post-cleavage complex stability assays

    PMID:21368836

    Open questions at the time
    • Repair factors mediating the channeling not fully defined here
  13. 2013 Medium

    Localized post-cleavage-complex stabilization and NHEJ channeling to the RAG2 acidic hinge, whose negative charge suppresses alternative-NHEJ-mediated genomic instability.

    Evidence Acidic-hinge mutagenesis, V(D)J junction analysis, PCC stability and in vivo genomic-stability assays

    PMID:23994475

    Open questions at the time
    • Single lab
    • Structural basis of hinge-mediated PCC stabilization not visualized
  14. 2015 High

    Provided near-atomic structures of the (RAG1-RAG2)2 heterotetramer, defining base-flipping, two-metal-ion catalysis, and the asymmetric architecture enforcing the 12/23 rule.

    Evidence Cryo-EM (up to 3.4 Å) of synaptic complexes and X-ray crystallography (3.2 Å) of the heterotetramer

    PMID:25707801 PMID:26548953

    Open questions at the time
    • Structures of the post-cleavage NHEJ-channeling complex not resolved
    • Dynamics of PHD-to-active-site signaling not captured
  15. 2016 Medium

    Demonstrated RAG2's contribution to 12/23 enforcement using ancestral RAG-like proteins and showed C-terminal RAG2 functionally cooperates with XLF in repairing RAG-induced breaks.

    Evidence Recombination/transposition with ancestral RAG1-like proteins ± RAG2; Rag2c/c XLF-/- double-knockout mouse genetics

    PMID:26833222 PMID:27056670

    Open questions at the time
    • Direct physical RAG2-XLF interaction not established
    • Ancestral-protein findings need extension to modern complex

Open questions

Synthesis pass · forward-looking unresolved questions
  • How H3K4me3 sensing by the PHD finger is allosterically transmitted to the distal catalytic core to license cleavage, and how the post-cleavage complex physically recruits classical NHEJ machinery, remain structurally unresolved.
  • No structure of the post-cleavage NHEJ-channeling complex
  • Allosteric path from PHD to active site not mapped
  • Direct RAG2-NHEJ-factor contacts undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0042393 histone binding 3 GO:0140097 catalytic activity, acting on DNA 3 GO:0098772 molecular function regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-168256 Immune System 3 R-HSA-73894 DNA Repair 3
Partners
HMGB1P27KIP1RAG1SKP2XLF
Complex memberships
(RAG1-RAG2)2 recombinase heterotetramerSkp2-SCF ubiquitin ligase (substrate)post-cleavage synaptic complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 RAG1 and RAG2 together synergistically activate V(D)J recombination when co-transfected into fibroblasts, with at least a 1000-fold increase in recombination frequency over RAG1 alone; RAG2 encodes a 527 amino acid protein whose expression correlates precisely with V(D)J recombinase activity across species. Fibroblast transfection/co-transfection recombination assay; molecular cloning and sequencing Science High 2360047
1994 RAG2 protein is phosphorylated at Thr-490 by cyclin-dependent kinase(s), leading to its rapid degradation; RAG2 accumulates preferentially in G0/G1 and declines by at least 20-fold before S phase entry, restricting V(D)J recombination to G0/G1. Cell cycle synchronization, immunoblot, CDK phosphorylation assay in immature B-cell line and thymocytes Proceedings of the National Academy of Sciences High 8146183
1996 A conserved degradation signal in RAG2, including an essential CDK phosphorylation site at Thr-490, governs periodic destruction of RAG2 during cell division; mutation of Thr-490 to Ala abolishes periodic degradation and relieves restriction of V(D)J recombination intermediates to G0/G1 in transgenic mice. Site-directed mutagenesis of Thr-490, transgenic mouse analysis, V(D)J recombination intermediate accumulation assay by cell-cycle phase Immunity High 8986717
1997 RAG1 and RAG2 form a stable protein-DNA complex (stable cleavage complex) with recombination signal sequences requiring both the conserved heptamer and nonamer motifs and both proteins; this complex can nick or form hairpins depending on divalent cation present (Ca2+ traps pre-cleavage complex, Mg2+ or Mn2+ supports cleavage). Gel retardation/mobility shift assay, DNA cleavage assay with defined divalent cations, protein-DNA complex characterization Cell High 9019407
1997 After DNA cleavage, RAG1, RAG2, HMG-1/HMG-2, and components of DNA-dependent protein kinase (DNA-PK) form a stable post-cleavage synaptic complex with signal ends; this complex is resistant to nuclease and can be immunoprecipitated. Nuclease sensitivity assay, gel mobility shift, immunoprecipitation of post-cleavage complex; in vitro V(D)J cleavage system Cell High 9094713
1997 RAG1 and RAG2 cooperate in RSS binding: RAG1 alone shows only 3–5-fold preference for RSS over random DNA and contacts primarily the nonamer; addition of RAG2 increases specificity and stability of the complex and extends protein contacts through the spacer into the heptamer-proximal region, with DNA distortion near the coding/signal border. Gel retardation (EMSA), 1,10-phenanthroline-copper footprinting, DMS protection footprinting Journal of Experimental Medicine / Molecular and Cellular Biology High 9166431 9671477 9697841
1998 RAG1 and RAG2 together function as a transposase, capable of excising DNA containing recombination signals and inserting it into target DNA with short target DNA duplications flanking the transposed fragment, demonstrating the evolutionary origin of the V(D)J system from a transposable element. In vitro transposition assay with plasmid substrates; analysis of strand-transfer products by sequencing and gel analysis Nature / Cell High 9723614 9727489
1998 RAG1 and RAG2 can reverse the cleavage reaction by joining a recombination signal sequence to a broken coding sequence end, creating hybrid joints in vitro, providing a mechanistic explanation for hybrid joints observed in vivo. In vitro rejoining assay with purified RAG1 and RAG2 proteins Science High 9535663
1998 The C-terminus of RAG2 (non-core region), though dispensable for catalysis and DH-JH joining, is essential for efficient VH-DJH rearrangement at the IgH locus, revealing a dual role for RAG2 in both catalysis and governing access to particular loci. Transfection-based V(D)J recombination assay; analysis of IgH locus rearrangement in cell lines expressing truncated RAG2 EMBO Journal Medium 9707447
1999 RAG1 and RAG2 possess an intrinsic single-stranded nuclease activity capable of nicking hairpin coding ends near the hairpin tip (Mg2+) or 5 nt 5' of the tip (Mn2+), suggesting RAG proteins initiate hairpin opening and contribute to P nucleotide generation in V(D)J recombination. In vitro hairpin nicking assay with purified RAG1/RAG2 proteins and synthetic hairpin substrates; sequencing of nicked products Molecular and Cellular Biology High 10330156
1999 The RAG1/RAG2 complex active in cleavage is a tetramer containing two molecules of each protein; after cleavage, both DNA products (coding and signal ends) remain held together in a stable protein-DNA complex. Biochemical purification, gel filtration, UV cross-linking, native gel analysis of protein-DNA complexes Molecular and Cellular Biology Medium 10373515
2001 RAG2 directly participates in DNA binding: five basic residue mutants of RAG2 are deficient in DNA binding by the RAG1-RAG2 complex while retaining normal RAG1 interaction, demonstrating direct involvement of RAG2 in RSS recognition. Site-directed mutagenesis of 36 conserved residues; DNA binding assay (EMSA); V(D)J recombination assay in vivo; RAG1-RAG2 interaction assay Molecular Cell High 11684024
2002 RAG2 degradation occurs via cytoplasmic sequestration followed by ubiquitin/proteasome-mediated degradation; Thr-490 phosphorylation mediates nuclear-to-cytoplasmic translocation, and inhibition of this phosphorylation by p27Kip1 stabilizes RAG2 in the nucleus. Subcellular fractionation, phosphorylation inhibition, ubiquitin/proteasome inhibitor treatment, immunofluorescence localization Journal of Biological Chemistry Medium 12205088
2002 Assembly of the RAG1/RAG2 synaptic complex on a single recombination signal can occur prior to the arrival of the second signal; this pre-synaptic complex contains a dimer of RAG2 and at least a trimer of RAG1, and remains inactive for double-strand break formation until the second complementary signal activates it, possibly through a conformational change. In vitro V(D)J cleavage assay; native gel analysis; protein stoichiometry determination; coupled cleavage assay Molecular and Cellular Biology Medium 11739723
2003 Deletion of the RAG2 C-terminus leads to impaired lymphoid development in mice with reduced B and T cell numbers and reduced chromosomal V(D)J recombination, demonstrating the in vivo importance of the non-core RAG2 region. Knock-in mouse model expressing only core RAG2 (lacking C-terminal 144 amino acids); flow cytometry; Southern blot for V(D)J recombination Proceedings of the National Academy of Sciences High 12531919
2003 The C-terminal portion of full-length RAG2 suppresses transposition in vitro: unlike core RAG2, full-length RAG2 blocks transposition of signal ends following V(D)J cleavage, suggesting this non-catalytic domain prevents transposition in developing lymphocytes. In vitro transposition assay comparing full-length vs. truncated RAG2 proteins EMBO Journal High 12682024 12682025
2003 RAG-mediated transposition is suppressed by physiological concentrations of GTP and by the full-length RAG2 C-terminus; both GTP and full-length RAG2 block transposition by inhibiting non-covalent capture of target DNA; Ca2+ can stimulate transposition overcoming both inhibitory mechanisms. In vitro transposition assay with defined nucleotides and protein variants; target capture assay EMBO Journal High 12682024
2005 The RAG2 C-terminus contains a noncanonical PHD finger domain (determined by NMR); all non-core RAG2 mutations linked to immunodeficiencies cluster within this PHD finger at zinc-coordinating residues or residues adjacent to an alpha-helix that participates in phosphoinositide binding; PHD finger mutations affect intramolecular interactions and modulate recombination activity. NMR spectroscopy for structure determination; mutagenesis of PHD finger residues; V(D)J recombination assay; phosphoinositide binding assay Journal of Biological Chemistry High 15964836
2005 The Skp2-SCF ubiquitin ligase mediates ubiquitylation of RAG-2 at the G1-to-S transition both in vitro and in vivo, directly linking V(D)J recombination to cell cycle control via the ubiquitin-proteasomal pathway. Cell-free ubiquitylation system reconstitution; in vitro ubiquitylation assay; in vivo degradation assay; Skp2 knockout analysis Molecular Cell High 15949444
2007 The RAG2 C-terminal PHD finger specifically recognizes histone H3 trimethylated at lysine 4 (H3K4me3); crystal structure of RAG2 PHD bound to H3K4me3 reveals the molecular basis of recognition; mutations abrogating H3K4me3 binding severely impair V(D)J recombination in vivo; reducing H3K4me3 levels decreases V(D)J recombination; a conserved tryptophan W453 is essential for binding and is mutated in immunodeficiency patients. Crystal structure (high-resolution); in vitro histone peptide binding assay; site-directed mutagenesis; in vivo V(D)J recombination assay; H3K4me3 level manipulation Nature High 18033247
2007 The RAG2 PHD finger simultaneously recognizes two distinct histone modifications: H3K4me3 and dimethyl-R2 (H3R2me2); unlike other PHD domains, RAG2-PHD substitutes a carboxylate with a Tyr, allowing enhanced rather than inhibited binding when R2 is dimethylated; five residues involved in histone recognition are mutated in SCID patients. Crystal structures of RAG2-PHD alone and complexed with five modified H3 peptides; binding assays Proceedings of the National Academy of Sciences High 18025461
2009 RAG2 suppresses non-sequence-specific DNA binding by RAG1: RAG1 alone exhibits high-affinity non-sequence-specific DNA binding that masks RSS-specific interaction; addition of RAG2 suppresses this non-specific binding, greatly increasing the differential affinity of the RAG complex for RSS over non-RSS sites. Fluorescence anisotropy binding assay; gel mobility shift assay with RSS and non-RSS substrates Journal of Molecular Biology Medium 19232525
2010 RAG2 binds at thousands of sites genome-wide containing H3K4me3, while RAG1 binding is restricted to recombination signal sequences; each RAG protein independently localizes within recombination centers in a developmental stage- and lineage-specific manner in vivo. ChIP-seq (chromatin immunoprecipitation followed by deep sequencing) in primary lymphocytes Cell High 20398922
2010 The C-terminal regions of RAG1 (aa 1009–1040) and RAG2 PHD domain (aa 388–520) collaborate to inhibit the hairpinning stage of DNA cleavage; the RAG2 C-terminus destabilizes the RAG-DNA precleavage complex, and this inhibition is reversed by binding of the PHD domain to H3K4me3; H3K4me3 also alleviates PHD-mediated inhibition of transposition. In vitro cleavage assay with purified full-length and truncated RAG proteins; histone peptide supplementation; transposition assay Proceedings of the National Academy of Sciences High 21149691
2011 The RAG2 C-terminus (non-core region) is critical for maintaining genomic stability: thymocytes from core Rag2 (Rag2c/c) mice show dramatic disruption of Tcrα/δ locus integrity; Rag2c/c p53-/- mice rapidly develop thymic lymphomas with complex chromosomal translocations involving Tcrα/δ and Igh loci; core RAG2 severely destabilizes the RAG post-cleavage complex, similar to ATM deficiency. Knock-in mouse genetics; cytogenetics/FISH; post-cleavage complex stability assay; tumor characterization Nature High 21368836
2013 RAG2's acidic hinge region is critical for stabilizing the post-cleavage complex and directing repair to classical NHEJ; mutations reducing the hinge's negative charge destabilize the PCC, allow alternative NHEJ to repair RAG-mediated DSBs, and reduce genomic stability in developing lymphocytes. Site-directed mutagenesis of acidic hinge; V(D)J junction analysis; post-cleavage complex stability assay; in vivo lymphocyte genomic stability assessment Cell Reports Medium 23994475
2015 Cryo-EM structures of synaptic RAG complexes at up to 3.4 Å resolution reveal: (RAG1-RAG2)2 forms a closed conformation with base flipping and base-specific RSS recognition; distortion at RSS-coding segment junctions and base flipping in coding segments demonstrate a two-metal-ion catalytic mechanism; induced asymmetry via tilting of the nonamer-binding domain dimer of RAG1 upon HMGB1-bent 12-RSS or 23-RSS binding underlies the molecular mechanism for the 12/23 rule. Cryo-electron microscopy structure determination (up to 3.4 Å); biochemical validation Cell High 26548953
2015 Crystal structure of the mouse RAG1-RAG2 complex at 3.2 Å resolution reveals a Y-shaped 230 kDa RAG1-RAG2 heterotetramer with intertwined RAG1 N-terminal domains forming a stalk; each RAG1-RAG2 heterodimer forms one arm with the active site in the middle and RAG2 at its tip; architectural similarity to hairpin-forming transposases Hermes and Tn5 supports evolutionary conservation. X-ray crystallography (3.2 Å resolution) Nature High 25707801
2016 RAG2 enhances transposition by an ancestral Transib transposase and enables V(D)J recombination by RAG1 alone; RAG2 is implicated in imposing the 12/23 rule, as RAG1 alone performs recombination without 12/23 asymmetric substrate requirement. V(D)J recombination assay with ancestral RAG1-like proteins ± RAG2; in vitro transposition assay Genes & Development Medium 27056670
2016 RAG2 (together with XLF/Cernunnos) participates in the DNA repair phase of V(D)J recombination: in Rag2c/c (C-terminus deleted) mice, XLF deficiency causes profound lymphopenia, severe V(D)J recombination defect, and genomic instability at V(D)J sites, revealing a functional interplay between the RAG2 C-terminus and XLF in repairing RAG-induced DSBs. Double-knockout mouse genetics (Rag2c/c XLF-/- ± p53-/-); V(D)J recombination assay; chromosomal instability analysis Nature Communications High 26833222

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science (New York, N.Y.) 1175 2360047
1998 Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 560 9723614
1998 DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations. Cell 414 9727489
2007 RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 383 18033247
1996 The SCID but not the RAG-2 gene product is required for S mu-S epsilon heavy chain class switching. Immunity 324 8885865
1997 RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination. Cell 244 9094713
1991 Thymocyte expression of RAG-1 and RAG-2: termination by T cell receptor cross-linking. Science (New York, N.Y.) 237 1831564
2010 The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci. Cell 234 20398922
1996 Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells. Science (New York, N.Y.) 223 8953043
2006 Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-gamma c-/- mice. Proceedings of the National Academy of Sciences of the United States of America 199 17038503
2011 Transgenic expression of human signal regulatory protein alpha in Rag2-/-gamma(c)-/- mice improves engraftment of human hematopoietic cells in humanized mice. Proceedings of the National Academy of Sciences of the United States of America 184 21788509
1998 Enhanced human cell engraftment in mice deficient in RAG2 and the common cytokine receptor gamma chain. British journal of haematology 180 9827902
1997 A stable RAG1-RAG2-DNA complex that is active in V(D)J cleavage. Cell 174 9019407
2007 The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2. Proceedings of the National Academy of Sciences of the United States of America 172 18025461
2006 A phylogenetic analysis of the major groups of catfishes (Teleostei: Siluriformes) using rag1 and rag2 nuclear gene sequences. Molecular phylogenetics and evolution 169 16876440
1996 A conserved degradation signal regulates RAG-2 accumulation during cell division and links V(D)J recombination to the cell cycle. Immunity 161 8986717
2009 Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 160 19164562
1994 Cell cycle regulation of V(D)J recombination-activating protein RAG-2. Proceedings of the National Academy of Sciences of the United States of America 158 8146183
2004 Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2-/- gammac-/- mice: functional inactivation of p53 in developing T cells. Blood 149 15319293
1997 Characterization and expression of the recombination activating genes (rag1 and rag2) of zebrafish. Immunogenetics 149 9089097
2015 Molecular Mechanism of V(D)J Recombination from Synaptic RAG1-RAG2 Complex Structures. Cell 144 26548953
2006 HIV-1 infection and CD4 T cell depletion in the humanized Rag2-/-gamma c-/- (RAG-hu) mouse model. Retrovirology 139 17078891
2015 Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes Engrafted in Rag2-/-IL2Rγnull Immunodeficient Mice. Cancer research 137 26113085
1999 RAG2:GFP knockin mice reveal novel aspects of RAG2 expression in primary and peripheral lymphoid tissues. Immunity 131 10485655
2015 Crystal structure of the V(D)J recombinase RAG1-RAG2. Nature 130 25707801
2008 Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2-/- gammac -/- (RAG-hu) mice. Virology 116 18207484
1999 Coordinate regulation of RAG1 and RAG2 by cell type-specific DNA elements 5' of RAG2. Science (New York, N.Y.) 116 10446057
1997 V(D)J recombination: modulation of RAG1 and RAG2 cleavage activity on 12/23 substrates by whole cell extract and DNA-bending proteins. The Journal of experimental medicine 116 9166431
1991 Selective expression of RAG-2 in chicken B cells undergoing immunoglobulin gene conversion. Cell 116 1986866
1998 Distinct roles of RAG1 and RAG2 in binding the V(D)J recombination signal sequences. Molecular and cellular biology 113 9671477
2014 Optimized cell transplantation using adult rag2 mutant zebrafish. Nature methods 112 25042784
2013 BLT-humanized C57BL/6 Rag2-/-γc-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. Blood 107 24021673
2005 Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle. Molecular cell 103 15949444
1999 A novel immunodeficient mouse model--RAG2 x common cytokine receptor gamma chain double mutants--requiring exogenous cytokine administration for human hematopoietic stem cell engraftment. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 99 10386866
1998 V(D)J recombination signal recognition: distinct, overlapping DNA-protein contacts in complexes containing RAG1 with and without RAG2. Immunity 99 9697841
2015 Evolution of the RAG1-RAG2 locus: both proteins came from the same transposon. Biology direct 92 25928409
1995 Localization, interaction, and RNA binding properties of the V(D)J recombination-activating proteins RAG1 and RAG2. Immunity 92 8777717
1999 DNA hairpin opening mediated by the RAG1 and RAG2 proteins. Molecular and cellular biology 89 10330156
2007 A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. The Journal of clinical investigation 86 17476358
1998 Rejoining of DNA by the RAG1 and RAG2 proteins. Science (New York, N.Y.) 85 9535663
2004 Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review. Genetics in medicine : official journal of the American College of Medical Genetics 81 14726805
2011 The RAG2 C terminus suppresses genomic instability and lymphomagenesis. Nature 80 21368836
2003 Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice. Proceedings of the National Academy of Sciences of the United States of America 78 12531919
2012 Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. PloS one 75 22737248
2002 Assembly of the RAG1/RAG2 synaptic complex. Molecular and cellular biology 74 11739723
1993 Characterization and expression of recombination activating genes (RAG-1 and RAG-2) in Xenopus laevis. Journal of immunology (Baltimore, Md. : 1950) 74 8376769
1998 Dual role of RAG2 in V(D)J recombination: catalysis and regulation of ordered Ig gene assembly. The EMBO journal 68 9707447
1996 RAG1, RAG2 and pre-T cell receptor alpha chain expression by adult human hepatic T cells: evidence for extrathymic T cell maturation. European journal of immunology 68 8977312
2009 IL-7 enhances thymic human T cell development in "human immune system" Rag2-/-IL-2Rgammac-/- mice without affecting peripheral T cell homeostasis. Journal of immunology (Baltimore, Md. : 1950) 64 19923447
2003 The C-terminal portion of RAG2 protects against transposition in vitro. The EMBO journal 59 12682025
2009 A novel Rag2-/-gammac-/--xenograft model of human CLL. Blood 58 20018917
1999 A RAG1 and RAG2 tetramer complex is active in cleavage in V(D)J recombination. Molecular and cellular biology 58 10373515
1996 The recombination activating gene 2 (RAG2) of the rainbow trout Oncorhynchus mykiss. Immunogenetics 58 8662087
1991 Expression of human recombination activating genes (RAG1 and RAG2) in neoplastic lymphoid cells: correlation with cell differentiation and antigen receptor expression. Blood 58 1832998
2003 Regulation of RAG1/RAG2-mediated transposition by GTP and the C-terminal region of RAG2. The EMBO journal 57 12682024
2005 A PHD finger motif in the C terminus of RAG2 modulates recombination activity. The Journal of biological chemistry 56 15964836
2001 RAG1 and RAG2 expression by B cell subsets from human tonsil and peripheral blood. Journal of immunology (Baltimore, Md. : 1950) 56 11123315
2011 HTLV-1 propels thymic human T cell development in "human immune system" Rag2⁻/⁻ gamma c⁻/⁻ mice. PLoS pathogens 55 21909275
2012 Correction of murine Rag2 severe combined immunodeficiency by lentiviral gene therapy using a codon-optimized RAG2 therapeutic transgene. Molecular therapy : the journal of the American Society of Gene Therapy 54 22692499
2010 Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome. The Journal of experimental medicine 54 20547828
2016 RAG2 and XLF/Cernunnos interplay reveals a novel role for the RAG complex in DNA repair. Nature communications 53 26833222
1995 RAG1 and RAG2 expression in human intestinal epithelium: evidence of extrathymic T cell differentiation. European journal of immunology 53 7774617
2016 Overexpression of the 16-kDa α-amylase/trypsin inhibitor RAG2 improves grain yield and quality of rice. Plant biotechnology journal 51 27775871
2002 Gene therapy of RAG-2-/- mice: sustained correction of the immunodeficiency. Blood 51 12393742
1999 Distinct factors regulate the murine RAG-2 promoter in B- and T-cell lines. Molecular and cellular biology 50 10082526
2010 Autoinhibition of DNA cleavage mediated by RAG1 and RAG2 is overcome by an epigenetic signal in V(D)J recombination. Proceedings of the National Academy of Sciences of the United States of America 49 21149691
1995 Expression of recombination activating genes (RAG-1 and RAG-2) in Epstein-Barr virus-bearing B cells. Blood 49 7858259
2010 Fine mapping of the soybean aphid-resistance gene Rag2 in soybean PI 200538. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 48 20454773
1999 RAG1 and RAG2 cooperate in specific binding to the recombination signal sequence in vitro. The Journal of biological chemistry 48 10066757
2000 Lineage-specific regulation of the murine RAG-2 promoter: GATA-3 in T cells and Pax-5 in B cells. Blood 47 10845919
2009 The roles of the RAG1 and RAG2 "non-core" regions in V(D)J recombination and lymphocyte development. Archivum immunologiae et therapiae experimentalis 46 19333736
1999 Omenn syndrome: a disorder of Rag1 and Rag2 genes. Journal of clinical immunology 46 10226883
2001 Identification of basic residues in RAG2 critical for DNA binding by the RAG1-RAG2 complex. Molecular cell 45 11684024
2003 Cutting edge: CD40-induced expression of recombination activating gene (RAG) 1 and RAG2: a mechanism for the generation of autoaggressive T cells in the periphery. Journal of immunology (Baltimore, Md. : 1950) 44 12646605
2007 Wild-type and interleukin-10-deficient regulatory T cells reduce effector T-cell-mediated gastroduodenitis in Rag2-/- mice, but only wild-type regulatory T cells suppress Helicobacter pylori gastritis. Infection and immunity 43 17353283
2011 Efficient infection, activation, and impairment of pDCs in the BM and peripheral lymphoid organs during early HIV-1 infection in humanized rag2⁻/⁻γ C⁻/⁻ mice in vivo. Blood 42 21505190
2010 Liver xeno-repopulation with human hepatocytes in Fah-/-Rag2-/- mice after pharmacological immunosuppression. The American journal of pathology 42 20651238
2010 Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children. Journal of clinical immunology 42 21184155
1999 RAG2 is regulated differentially in B and T cells by elements 5' of the promoter. Proceedings of the National Academy of Sciences of the United States of America 39 10535988
2018 Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype. The Journal of allergy and clinical immunology 38 29772310
2000 Three-dimensional clustering of human RAG2 gene mutations in severe combined immune deficiency. The Journal of biological chemistry 38 10777560
2021 Gene Editing Rescues In vitro T Cell Development of RAG2-Deficient Induced Pluripotent Stem Cells in an Artificial Thymic Organoid System. Journal of clinical immunology 36 33650026
2016 Generation and characterization of RAG2 knockout pigs as animal model for severe combined immunodeficiency. Veterinary immunology and immunopathology 36 27496741
1992 Activation of V(D)J recombination by RAG1 and RAG2. Trends in genetics : TIG 35 1492366
1997 Cloning and characterization of the human recombination activating gene 1 (RAG1) and RAG2 promoter regions. Journal of immunology (Baltimore, Md. : 1950) 34 9379036
2016 Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination. Genes & development 33 27056670
2013 RAG2's acidic hinge restricts repair-pathway choice and promotes genomic stability. Cell reports 32 23994475
2014 RAG2 mutants alter DSB repair pathway choice in vivo and illuminate the nature of 'alternative NHEJ'. Nucleic acids research 31 24753404
2002 RAG2 is down-regulated by cytoplasmic sequestration and ubiquitin-dependent degradation. The Journal of biological chemistry 31 12205088
2003 DNA mismatches and GC-rich motifs target transposition by the RAG1/RAG2 transposase. Nucleic acids research 30 14576304
2002 Cooperative binding of c-Myb and Pax-5 activates the RAG-2 promoter in immature B cells. Blood 28 11781241
2009 Molecular mechanism underlying RAG1/RAG2 synaptic complex formation. The Journal of biological chemistry 27 19502597
2006 Endogenous T lymphocytes and microglial reactivity in the axotomized facial motor nucleus of mice: effect of genetic background and the RAG2 gene. Journal of neuroimmunology 27 16376435
2015 Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection. Journal of clinical immunology 25 26515615
1994 Engraftment of human lymphocytes and thyroid tissue into scid and rag2-deficient mice: absent progression of lymphocytic infiltration. The Journal of clinical endocrinology and metabolism 25 8077352
2017 Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks. Journal of immunology (Baltimore, Md. : 1950) 24 28213501
2009 A non-sequence-specific DNA binding mode of RAG1 is inhibited by RAG2. Journal of molecular biology 24 19232525
2013 The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage. Nature communications 23 23900513
2007 Strength and corticosteroid responsiveness of mdx mice is unchanged by RAG2 gene knockout. Neuromuscular disorders : NMD 23 17452104
2001 RAG1 and RAG2 in V(D)J recombination and transposition. Immunologic research 23 11417858

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