1. The RAG2 C terminus suppresses genomic instability and lymphomagenesis
- Author
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Yi-Fan Chou, Sandy Chang, Jane A. Skok, Marc Coussens, Ludovic Deriano, Alexander V. Alekseyenko, Asha S. Multani, David Roth, Julie Chaumeil, New York University School of Medicine (NYU), New York University School of Medicine, Department of Genetics, University of Texas M.D. Anderson Cancer Center, Yale University School of Medicine, Yale School of Medicine, University College of London [London], University of Pennsylvania [Philadelphia], NYU System (NYU)-NYU System (NYU), The University of Texas M.D. Anderson Cancer Center [Houston], and University College of London [London] (UCL)
- Subjects
Genome instability ,MESH: Chromosomes, Mammalian ,Lymphoma ,Mammalian/genetics ,MESH: Genes, p53 ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Kaplan-Meier Estimate ,MESH: Genes, Immunoglobulin Heavy Chain ,Translocation, Genetic ,Mice ,0302 clinical medicine ,Receptors ,Recombinase ,MESH: Animals ,MESH: In Situ Hybridization, Fluorescence ,Lymphoma/*genetics/*pathology ,p53/genetics ,MESH: Ataxia Telangiectasia Mutated Proteins ,In Situ Hybridization, Fluorescence ,In Situ Hybridization ,Recombination, Genetic ,Gene Rearrangement ,0303 health sciences ,Multidisciplinary ,Tumor Suppressor Proteins/chemistry/deficiency/genetics/metabolism ,MESH: Genomic Instability ,MESH: Receptors, Antigen, T-Cell ,hemic and immune systems ,MESH: Gene Rearrangement, T-Lymphocyte ,MESH: Translocation, Genetic ,DNA-Binding Proteins ,T-Lymphocyte/genetics ,Antigen ,Disease Progression ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,MESH: Recombination, Genetic ,MESH: Disease Progression ,Chromosome Deletion ,Thymus Gland/cytology ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,DNA damage ,MESH: Chromosome Deletion ,Genes, Immunoglobulin Heavy Chain ,Receptors, Antigen, T-Cell ,Translocation ,chemical and pharmacologic phenomena ,Thymus Gland ,Protein Serine-Threonine Kinases ,Biology ,Gene Rearrangement, T-Lymphocyte ,DNA-Binding Proteins/*chemistry/deficiency/genetics/*metabolism ,MESH: Protein-Serine-Threonine Kinases ,Article ,Genomic Instability ,Chromosomes ,Fluorescence ,Recombination-activating gene ,03 medical and health sciences ,MESH: Cell Cycle Proteins ,RAG2 ,Animals ,MESH: Tumor Suppressor Proteins ,MESH: Mice ,Gene ,MESH: Kaplan-Meier Estimate ,Genetic/genetics ,030304 developmental biology ,Cell Cycle Proteins/genetics ,Tumor Suppressor Proteins ,Protein-Serine-Threonine Kinases/deficiency/genetics ,MESH: Thymus Gland ,Gene rearrangement ,Genes, p53 ,Chromosomes, Mammalian ,Molecular biology ,Recombination ,Genes ,T-Cell/genetics ,MESH: Lymphoma ,MESH: DNA-Binding Proteins ,Immunoglobulin Heavy Chain/genetics ,030215 immunology - Abstract
International audience; Misrepair of DNA double-strand breaks produced by the V(D)J recombinase (the RAG1/RAG2 proteins) at immunoglobulin (Ig) and T cell receptor (Tcr) loci has been implicated in pathogenesis of lymphoid malignancies in humans and in mice. Defects in DNA damage response factors such as ataxia telangiectasia mutated (ATM) protein and combined deficiencies in classical non-homologous end joining and p53 predispose to RAG-initiated genomic rearrangements and lymphomagenesis. Although we showed previously that RAG1/RAG2 shepherd the broken DNA ends to classical non-homologous end joining for proper repair, roles for the RAG proteins in preserving genomic stability remain poorly defined. Here we show that the RAG2 carboxy (C) terminus, although dispensable for recombination, is critical for maintaining genomic stability. Thymocytes from 'core' Rag2 homozygotes (Rag2(c/c) mice) show dramatic disruption of Tcrα/δ locus integrity. Furthermore, all Rag2(c/c) p53(-/-) mice, unlike Rag1(c/c) p53(-/-) and p53(-/-) animals, rapidly develop thymic lymphomas bearing complex chromosomal translocations, amplifications and deletions involving the Tcrα/δ and Igh loci. We also find these features in lymphomas from Atm(-/-) mice. We show that, like ATM-deficiency, core RAG2 severely destabilizes the RAG post-cleavage complex. These results reveal a novel genome guardian role for RAG2 and suggest that similar 'end release/end persistence' mechanisms underlie genomic instability and lymphomagenesis in Rag2(c/c) p53(-/-) and Atm(-/-) mice.
- Published
- 2011