Studies Of Immunoglobulin Gene Rearrangement

Diabetes, Digestive, Kidney Diseases

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Abstract

During lymphoid development, functional immunoglobulin and T cell receptor genes are assembled from gene segments by a process called V(D)J recombination, which is essential for generating the diversity of the immune response. In the first stage of this reaction, specific double-strand breaks are made at the target sites (RSS) by the RAG1/RAG2 protein complex. The later steps necessary for rejoining employ many protein factors that are also used for repair of X-ray damage. Our recent work has concentrated on the RAG proteins. We show that the whole RAG1/2 assembly necessary to start recombination binds to a single recognition sequence, and the complementary sequence enters this complex as naked DNA. Formation of this synaptic complex is forced to go by this route; it is inhibited if RAG1/2 binds the two sequences separately prior to mixing. This pathway helps to ensure that correct pairs of sites are used for recombination. A RAG-DNA complex is known to be capable of transposing its recognition sequences into a second DNA. We have now found a new kind of ?inverse transposition?, in which non-specific DNA is cleaved and subsequently used to attack a recognition sequence. Although non-specific DNA is bound only weakly by RAG1/2, it is in such excess in cells over the recognition sequences that this reaction may happen occasionally, providing another possible mechanism for chromosomal translocations present in lymphoid tumors.