Coupling of V(D)J recombination to the cell cycle suppresses genomic instability and lymphoid tumorigenesis.
Journal:
Immunity 2011 FebAuthors:
Zhang L, Reynolds TL, Shan X, Desiderio S
Abstract
V(D)J gene segment recombination is linked to the cell cycle by the periodic phosphorylation and destruction of the RAG-2 protein at the G1-to-S cell cycle transition. To examine the function of this coupling, we constructed mice in which the phosphorylation site at threonine 490 of RAG-2 was mutated to alanine. The RAG-2(T490A) mutation uncoupled DNA cleavage from cell cycle and promoted aberrant recombination. Similar aberrant recombination products were observed in mice deficient in the Skp2
...[more]ubiquitin ligase subunit, which is required for periodic destruction of RAG-2. On a p53-deficient background, the RAG-2(T490A) mutation induced lymphoid malignancies characterized by clonal chromosomal translocations involving antigen receptor genes. Taken together, these observations provide a direct link between the periodic destruction of RAG-2 and lymphoid tumorigenesis. We infer that cell cycle control of the V(D)J recombinase limits the potential genomic damage that could otherwise result from RAG-mediated DNA cleavage.[less]
Mesh Headings:
Amino Acid Substitution, Animals, Base Sequence, Cell Cycle, DNA Breaks, Double-Stranded, DNA Repair, DNA-Binding Proteins, Female, Gene Knock-In Techniques, Gene Rearrangement, Genes, p53, Genomic Instability, Lymphoma, Non-Hodgkin, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphorylation, Protein Processing, Post-Translational, Receptors, Antigen, T-Cell, S-Phase Kinase-Associated Proteins, Specific Pathogen-Free Organisms, T-Lymphocytes, Translocation, Genetic