V(D)J recombination is a mechanism of DNA recombination used by humans and other vertebrates for protection against attacks by bacterial, viral, and parasitic invaders. It is a site-specific recombination reaction that generates diverse T-cell receptor (TCR) and immunoglobulin (Ig) molecules that are necessary for the recognition of the greatly diverse foreign antigens.

Background

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Antibody molecules are encoded by three types of genes.

1. Heavy chain gene – located on chromosome 14
2. Light chain kappa (κ)gene – located on chromosome 2
3. Light chain lambda (λ)gene – located chromosome 22

The genes for the variable regions contain three distinct types of segments (Heavy-chain):

• Variable (V) – 200 region genes
• Diversity (D) – 12 region genes
• Joining (J) – 4 region genes

By the mechanism of DNA rearrangement of these regional genes it is possible to generate an antibody repertoire >10⁷ possible combinations. (200 x 12 x 4 = 9600, with addition to the 1000 possible light chain combinations)

Mechanism

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Recognition of the these regional genes (V, D,J) is possible by DNA segment substrates flanking these regional genes called Recombination Signal Sequences (RSSs). RSSs are composed of a heptamer (7 base pairs) and a nonamer (9 base pairs). The heptamer is next to the coding region, which is then followed by the nonamer. The RSSs are present on the 3’ side of a V region and the 5’ side of the J region. These are the sides that will be involved in the joining

The initial steps of VDJ recombination are carried out by critical enzymes, (lymphocyte specific) called RAG1 and RAG2 (recombination activation genes). These enzymes are needed as they associate with each other and recognize the initial RSS sequences and inducing cleavage at the RSS sequences. This cleavage only takes place on one strand on DNA, which leads to a nucleotide attack and creation of a hairpin loop.

• First, the joining a specific D segment to a specific J segment.

This removes the intervening DNA between a particular D segment and a particular J segment

• Second, the joining of a specific V segment to the newly created DJ combination.

Those removes the intervening DNA between the particular V segment and the new DJ combination, and brings the V, D, J gene segments together in translations reading frame at the DNA level.

• Lastly, One V to J rearrangement occurs in either the κ or λ light-chain gene.

The V and J segments of the light chains are combined with a few of the 1000 base pairs separating the J and the C regions which upon transcription, a poly-A tail is added.

References

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1. Leland H Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, Lee M. Silver, Ruth C. Veres (Genetics: From Genes to Genomes, copyright 2000). Chapter 24, Evolution at the molecular level; pages 805-807 ISBN 0-07-540923-2