The Mechanism of V(D)J Recombination

Abstract

During lymphocyte development, the diverse repertoire of functional antigen receptors is created by the process of V(D)J recombination, in which various segments of an antigen receptor locus are brought together by several highly coordinated DNA cleavage and repair steps. In the first phase of this process, double-stranded DNA breaks are generated by the recombinase machinery made up of the lymphocyte lineage-specific proteins recombination-activating gene (RAG) 1 and RAG2, which are aided by the ubiquitously expressed DNA-binding/bending protein high mobility group box protein 1. The second phase of V(D)J recombination, end processing and end joining, involves RAG1 and 2 as well as the DNA-repair proteins of the nonhomologous end-joining pathway. V(D)J recombination is tightly regulated during lymphocyte development, as aberrant V(D)J recombinase activity can lead to chromosomal translocations and genetic instability. In this chapter, we consider in detail what is known about the V(D)J recombination reaction, including the biochemistry of the cleavage reactions, the activities of the RAG proteins, and the regulation of recombination.