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 p27Kip1 and related CDK inhibitors. Coinduction of RAG-2 and G1 delay by p27Kip1 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. p27Kip1 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.
Lee
J
J
Department of Molecular Biology and Genetics and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Desiderio
S
S
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D002461:Cell Line, Transformed; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004254:DNA Nucleotidyltransferases; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011995:Recombination, Genetic; D045567:VDJ Recombinases
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases