The recombinase activating genes: architects of immune diversity during lymphocyte development

Abstract

The mature lymphocyte population of a healthy individual has the remarkable ability to recognise an immense variety of antigens. Instead of encoding a unique gene for each potential antigen receptor, evolution has used gene rearrangements, also known as variable, diversity, and joining gene segment (V(D)J) recombination. This process is critical for lymphocyte development and relies on recombination-activating genes-1 (RAG1) and RAG2, here collectively referred to as RAG. RAG serves as powerful genome editing tools for lymphocytes and is strictly regulated to prevent dysregulation. However, in the case of dysregulation, RAG has been implicated in cases of cancer, autoimmunity and severe combined immunodeficiency (SCID). This review examines functional protein domains and motifs of RAG, describes advances in our understanding of the function and (dys)regulation of RAG, discuss new therapeutic options, such as gene therapy, for RAG deficiencies, and explore in vitro and in vivo methods for determining RAG activity and target specificity.

Development of an in vitro genotoxicity assay to detect retroviral vector-induced lymphoid insertional mutants

“…Of note, the Rag1 and Rag2 genes are involved in the T cell receptor recombination, essential to generate functional T cells. 77 Synergistic effects between the specific transgene and the expression levels of the viral-derived MND promoter in a defined lineage context might account for the differences in scores between branches and could serve as a practical example of how the lymphoid and myeloid assays might complement each other. The results from both the lymphoid and myeloid IVIM/SAGA assays should be interpreted in probabilistic terms on how likely a specific vector design is to induce genotoxicity.…”

RAG1 and RAG2 Non-core Regions Are Implicated in Leukemogenesis and Off-target V(D)J Recombination in BCR-ABL1-driven B-cell Lineage Lym-phoblastic Leukemia

“…The RAGs consist of core and non-core region. Although non-core regions of RAG1/2 are not strictly required for V(D)J recombination, the evolutionarily conserved non-core RAG regions indicate their potential significance in vivo that may involve quantitative or qualitative modifications in RAG activity and expression ( Braams, et al, 2023;Curry and Schlissel, 2008;Liu, et al, 2022;Liu, et al, 2022;Sekiguchi, et al, 2001) . Specifically, the non-core RAG2 region (amino acids 384– 527 of 527 residues) contains a plant homeodomain (PHD) that can recognize histone H3K4 trimethylation, as well as a T490 locus that mediates a cell cycle-regulated protein degradation signal in proliferated pre-B cells stage ( Liu, et al, 2007;…”