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Immunoglobulins
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Immunoglobulin gene rearrangement is regulated by complex interactions between special DNA sequences, DNA-binding factors, and DNA-modifying enzymes. V, D, and J genes all have flanking regions called recombination signal sequences. These are important in the mechanism of rearrangement. The heptamer (seven base pairs, or bp) and nonamer (nine bp) sequences are separated by a spacer of either 12 or 23 bp (Figure 4–5). A gene with a flanking sequence containing a 12 bp spacer may only join to a gene whose flanking sequence has a 23 bp spacer. This is called the 12–23 base pair rule. Presumably, these sequences are recognized by DNA-binding proteins focusing the activity of endonucleases and ligases performing the splicing. The conservation of these flanking sequences in many species indicates their importance in the rearrangement mechanism. Although not firmly established, the heptamer and nonamer are thought to direct rearrangement via interaction with specific binding proteins, rather than through DNA-DNA interaction.
Genetics of immunoglobulins: Ontogenic, biological, and clinical implications
Published in Gabriel Virella, Medical Immunology, 2019
The VDJ joining is regulated by two proteins encoded by two closely linked recombination-activating genes, RAG-1 and RAG-2, localized on the short arm of human chromosome 11. These genes have at least two unusual characteristics not shared by most eukaryotic genes: they are devoid of introns and, although adjacent in location and synergistic in function, they have no sequence homology. The latter implies that, unlike the immunoglobulin and major histocompatibility complex genes, RAG-1 and RAG-2 did not arise by gene duplication. Recent studies suggest that these genes may be evolutionarily related to transposons, genetic elements that can be transposed in the genome from one location to the other. Conserved recombination signal sequences (RSSs) serve as substrate for the enzymes coded by the RAG genes. These enzymes introduce a break between the RSS and the coding sequence. Mechanisms involved in subsequent rejoining to form a mature coding segment are not completely understood.
Expression and clinical significance of RAG1 in myelodysplastic syndromes
Published in Hematology, 2022
Xiaoke Huang, Xiaolin Liang, Shanhu Zhu, Qiongni Xie, Yibin Yao, Zeyan Shi, Zhenfang Liu
The plasticity of the acquired immune system in recognizing millions of possible antigens is largely due to the combinatorial joining of variable (V), diversity (D), and joining (J) gene segments that encode the antigen-binding regions of T cell receptors (TCRs) in T cells and B cell receptors (BCRs) in B cells, and the junctional diversity that can be introduced during the process of V(D)J recombination[5]. RAG1 and RAG2 proteins form a complex and initiate V(D)J recombination by introducing DNA double-strand breaks (DSBs) between the recombination signal sequences and the flanking V, D, or J gene segment. The human RAG1 protein consists of 1,043 amino acids, and the catalytic core (amino acids 387–1011) contains a nonamer-binding domain, a dimerization and DNA binding domain, a pre-RNase H and catalytic RNase H domain, 2 zinc-binding domains, and the carboxy-terminal domain, which are all crucial for V(D)J recombination[6, 7].
Approaches to patients with variants in RAG genes: from diagnosis to timely treatment
Published in Expert Review of Clinical Immunology, 2019
Adeeb A. Bulkhi, Joseph F. Dasso, Catharina Schuetz, Jolan E. Walter
The adaptive immune system is unique due to the capability to recognize millions of antigens in a pre-immune state before environmental exposure. This diversity stems from a process where T and B lymphocytes break their own DNA in the regions coding the antigen receptor genes, reshuffles the segments (recombination), and create a unique construct of variable (V), diversity (D), and joining (J) gene to form the antigen-binding site of the variable region of T and B cell receptors (TCR and BCR) [1,2]. This process, termed V(D)J recombination, generates a highly diverse BCR (in the bone marrow) and TCR (in the thymus) that can recognize millions of antigens [3]. Each gene segment of V, D, and J is flanked by recombination signal sequences (RSSs) [1,4]. As a first step in the V(D)J recombination process, a DNA breakage occurs in a synaptic complex just before RSS by a heterotetramer endonuclease complex with recombination-activating genes 1 (RAG1) and 2 (RAG2). Specifically, RAG2 reads the histone codes of active DNA, RAG1 recognizes the RSS, and RAG2 directs RAG1 to nick DNA [5]. Together they create a DNA break and secure the blunt end to recruit the non-homologous end joining (NHEJ) complex for repair and further diversification of junctional regions [6]. The RAG enzyme complex is restricted to lymphocytes and only expressed during early T and B cell development, whereas NHEJ is ubiquitous. RAG enzyme expression is high during the G0/G1 phase, during which V(D)J rearrangement largely occurs, and is low during the rest of the cell cycle [7].
Ionizing radiation does not impair the mechanisms controlling genetic stability during T cell receptor gene rearrangement in mice
Published in International Journal of Radiation Biology, 2018
Serge M. Candéias, Sylwia Kabacik, Ann-Karin Olsen, Dag M. Eide, Dag A. Brede, Simon Bouffler, Christophe Badie
T lymphocytes express a TR composed of either an α and a β or a γ and a δ chain. The V, D, and J genes coding for the TRβ chain are located in the TRB locus on the murine chromosome 6, while the genes coding for the TRγ chains are located within the TRG locus on the chromosome 13, and the genes coding for the TRα and TRδ chains share the TRAD locus on the chromosome 14 [see IMGT®, the international ImMunoGeneTics information system®http://www.imgt.org for nomenclature and information (Lefranc et al. 2015)]. The activity of the RAG recombinase is targeted to recombination signal sequences (RSSs) flanking these genes and generates asymmetrical DNA ends: the signal ends, bearing the RSS, are blunt and phosphorylated, while the gene coding ends are sealed by a hairpin (Lieber et al. 1994; Gellert 2002). The RAG proteins remain associated with these DNA ends to insure proper repair and prevent unwanted, potentially mutagenic recombination events (Lee et al. 2004; Deriano et al. 2011). In addition to this lymphoid specific mechanism, the ubiquitously expressed ATM protein also plays an essential role in the surveillance of genetic integrity during V(D)J recombination.