Cyclin A/CDK2 regulates V(D)J recombination by coordinating RAG-2 accumulation and DNA repair

Accumulation of the V(D)J recombinase protein RAG-2 is restricted to G0/G1 cells by phosphorylation-mediated degradation at the G1-S boundary. Here cyclin A/CDK2 is shown to oppose RAG-2 accumulation; conversely, RAG-2 is induced by p27(Kip1) and related CDK inhibitors. Coinduction of RAG-2 and G1 delay by p27(Kip1) is accompanied by strong stimulation of V(D)J recombination. Unexpectedly, induction of RAG-2 accumulation in the absence of G1 delay has no effect on recombination frequency, p27(Kip1) may stimulate V(D)J recombination by coordinating accumulation of RAG-2 with prolongation of G1, when nonhomologous end joining is preferentially active. Consistent with this, enforced expression of RAG-2 throughout cell cycle is associated with accumulation of aberrant recombination products reminiscent of those formed in the absence of nonhomologous end joining.