{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRAG2 is an essential component of the RAG1/2 recombinase complex that initiates V(D)J recombination, a process critical for assembling the diverse antigen receptor repertoire in developing B and T lymphocytes. Working in concert with RAG1, RAG2 ensures site‐specific DNA cleavage at recombination signal sequences, and its malfunction—via hypomorphic or inactivating mutations—is closely linked to human immunodeficiency disorders such as severe combined immunodeficiency (SCID) and Omenn syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA key regulatory element of RAG2 is its C-terminal plant homeodomain (PHD) finger, which “reads” epigenetic marks by specifically binding histone H3 trimethylated at lysine 4 (H3K4me3). This chromatin interaction directs recombinase activity to accessible antigen receptor gene segments and augments catalysis of DNA cleavage, while point mutations within this domain can severely impair V(D)J recombination and lead to profound immunodeficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its chromatin‐associating function, RAG2 is subject to rigorous cell cycle–dependent regulation. An intrinsic nuclear localization signal (as revealed by its binding to importin proteins) ensures that RAG2 reaccumulates in the nucleus after mitosis, while its targeted degradation at the G1–S transition—mediated by cell cycle–regulated ubiquitin ligases—restricts recombinase activity to appropriate phases. Furthermore, post‐translational modifications, including phosphorylation, help enforce feedback control; in settings of DNA damage, RAG2 relocalizes from the nucleus to the cytoplasm (often to centrosomal regions), thereby limiting off‐target cleavage and preserving genomic integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence also points to broader roles for RAG2 in modulating immune receptor editing and peripheral tolerance. In mature lymphocytes, RAG2 expression is re‐induced during receptor revision processes, and its misregulation can contribute to autoimmune phenomena. Moreover, additional layers of transcriptional control—including bidirectional promoter activity shared with adjacent genes—underscore the multifaceted regulatory network governing RAG2 function. Clinically, the vast spectrum of immunodeficiency and immune dysregulation phenotypes associated with RAG2 mutations emphasizes its indispensable role in ensuring both effective antigen receptor assembly and genome stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jeroen G Noordzij, Sandra de Bruin-Versteeg, Nicole S Verkaik, et al. 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