V(D)J recombination

Definition

Target type: biologicalprocess

The process in which immune receptor V, D, and J, or V and J gene segments, depending on the specific receptor, are recombined within a single locus utilizing the conserved heptamer and nonomer recombination signal sequences (RSS). [GOC:add, ISBN:0781700221, ISBN:0781735149]

V(D)J recombination is a critical process in the development of a functional immune system. It occurs in developing lymphocytes, specifically B cells and T cells, and is responsible for generating the vast diversity of antigen receptors, known as immunoglobulins (antibodies) in B cells and T cell receptors (TCRs) in T cells. This diversity is essential for the immune system to recognize and respond to a wide range of pathogens.

The process involves the rearrangement of gene segments called variable (V), diversity (D), and joining (J) segments. These segments are located in different loci on the genome: the V locus, the D locus (only present in the immunoglobulin heavy chain and TCR beta chain), and the J locus.

Here is a step-by-step breakdown of V(D)J recombination:

1. **DNA Cleavage:** The first step is the precise cleavage of DNA at the junctions between the V, D, and J segments. This cleavage is mediated by a specialized enzyme complex called the V(D)J recombinase, which consists of two key proteins: RAG1 and RAG2. RAG1 recognizes and binds to specific DNA sequences called recombination signal sequences (RSSs) flanking the V, D, and J segments. RAG2 then assists RAG1 in creating double-stranded breaks in the DNA.

2. **Hairpin Formation:** After cleavage, the broken DNA ends form hairpin structures. These hairpins are important for ensuring that the correct segments are joined together.

3. **Exonucleolytic Processing:** The hairpin structures are then processed by exonucleases, which remove nucleotides from the ends of the DNA. This processing can lead to the loss of nucleotides, resulting in deletions and variations in the sequence of the rearranged gene.

4. **Nucleotide Addition:** Once the hairpins have been processed, terminal deoxynucleotidyl transferase (TdT) can add non-templated nucleotides (N-nucleotides) to the ends of the DNA. This addition of N-nucleotides further contributes to the diversity of the rearranged gene.

5. **Joining:** The processed DNA ends are then joined together by the enzyme DNA ligase IV. This step completes the rearrangement of the V, D, and J segments, generating a functional VDJ exon.

6. **Transcription and Translation:** The rearranged gene is transcribed into messenger RNA (mRNA) and translated into a protein, which forms part of the antigen receptor.

V(D)J recombination is a highly regulated process that involves several factors, including:

* **Specificity of Recombination:** The process is highly specific, ensuring that only the correct V, D, and J segments are joined together. This specificity is mediated by the RSSs flanking each segment.
* **Accessibility of DNA:** The accessibility of the DNA in the V, D, and J loci is regulated by chromatin modifications, which control the packaging and accessibility of DNA.
* **Timing and Location:** V(D)J recombination occurs at specific stages of lymphocyte development and in specific locations within the cell.

Errors in V(D)J recombination can lead to a variety of immune disorders, including immunodeficiency and autoimmunity. These errors can arise from defects in the recombinase complex or other factors involved in the process.

In summary, V(D)J recombination is a complex and tightly regulated process that generates the vast diversity of antigen receptors required for an effective adaptive immune response. It is essential for the immune system to recognize and respond to a wide range of pathogens and for maintaining immune homeostasis.'
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Proteins (3)

Compounds (26)