In developing lymphocytes, V(D)J recombination is subject to tight spatial and temporal regulation. An emerging body of evidence indicates that some of these constraints, particularly with respect to locus specificity and cell cycle phase, are enforced by regulatory cues that converge directly on the RAG proteins themselves. Active chromatin is bound by RAG-2 through a specific histone modification that may serve the recombinase as an allosteric activator as well as a docking site. RAG-1 possesses intrinsic histone ubiquitin ligase activity, suggesting that the recombinase not only responds to chromatin modification but is itself able to modify chromatin. The cyclin A/Cdk2 component of the cell cycle clock triggers periodic destruction of RAG-2, thereby restricting V(D)J recombination to the G0/G1 cell cycle phases. These examples illustrate that the RAG proteins, in addition to their direct actions on DNA, are able to detect and respond to intracellular signals, thereby coordinating recombinase activity with intracellular processes such as cell division and transcription.
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