V(D)J recombination: how to tame a transposase

Since the discovery that the recombination-activating gene (RAG) proteins were capable of transposition in vitro, investigators have been trying to uncover instances of transposition in vivo and understand how this transposase has been harnessed to do useful work while being inhibited from causing deleterious chromosome rearrangements. How to preserve the capacity of the recombinase to promote a certain class of rearrangements while curtailing its ability to catalyze others is an interesting problem. In this review, we examine the progress that has been made toward understanding the regulatory mechanisms that prohibit transposition in order to formulate a model that takes into account the diverse observations that have been made over the last 15 years. First, we touch on the striking mechanistic similarities between transposition and V(D)J recombination and review evidence suggesting that the RAG proteins may be members of the retroviral integrase superfamily. We then dispense with an old theory that certain standard products of V(D)J recombination called signal joints protect against deleterious transposition events. Finally, we discuss the evidence that target capture could serve a regulatory role and close with an analysis of hairpins as preferred targets for RAG-mediated transposition. These novel strategies for harnessing the RAG transposase not only shed light on V(D)J recombination but also may provide insight into the regulation of other transposases.