V(D)J Recombination

This chapter focuses on V(D)J recombination, but other mechanisms also contribute to antigen receptor diversity. Although in mice and humans V(D)J recombination is the major source of diversity, this is not true of all vertebrates. Terminal deoxynucleotidyltransferase (TdT) is normally expressed only in early lymphoid cells, so these insertions are relatively specific to V(D)J recombination (compared with other types of double-strand break repair). Work of the past several years has shown that V(D)J recombination has two distinct stages. In the first stage, the RAG1 protein and RAG2 protein act together to recognize the RSSs and their correct 12/23 pairing, and make double-strand breaks at the border between each heptamer and the neighboring coding sequence. In the second stage, an array of factors also used in other types of “nonhomologous end joining” acts to assemble the coding joints and signal joints. The RAG1 and RAG2 proteins are the only lymphoid-specific factors needed for V(D)J recombination. RAG1 and RAG2 are normally coexpressed only in early lymphoid cells, where V(D)J recombination takes place. Transcription of the two neighboring RAG genes is convergent, and it has been shown that the control region of both genes is located upstream of RAG2. As for the regulation of V(D)J recombination, several new experimental systems should soon lead to a better understanding of locus accessibility, and make experimental modification of rearrangement possible.