1. RAG2 mutants alter DSB repair pathway choice in vivo and illuminate the nature of 'alternative NHEJ'
- Author
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Vered Gigi, Martina Mijušković, Wenzhao Meng, David Roth, Eline T. Luning Prak, Ludovic Deriano, Susanna M. Lewis, Olga Shestova, University of Pennsylvania [Philadelphia], Développement lymphocytaire et Oncogénèse, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health [CA-104588 to D.B.R., 1R21AI097825-01 to S.M.L.]., University of Pennsylvania, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
p53 ,DNA End-Joining Repair ,Lymphoma ,MESH: V(D)J Recombination ,Mutant ,MESH: DNA Breaks, Double-Stranded ,MESH: Genes, p53 ,Genome Integrity, Repair and Replication ,MESH: Mice, Knockout ,Translocation, Genetic ,chemistry.chemical_compound ,Double-Stranded ,Mice ,0302 clinical medicine ,Receptors ,Recombinase ,DNA Breaks, Double-Stranded ,MESH: Animals ,MESH: Ku Autoantigen ,DNA Breaks ,Sequence Deletion ,Mice, Knockout ,Genetics ,0303 health sciences ,DNA-Binding Proteins/*genetics ,V(D)J recombination ,Antigens, Nuclear ,MESH: Receptors, Antigen, T-Cell ,Nuclear/genetics ,MESH: Sequence Deletion ,MESH: Translocation, Genetic ,DNA-Binding Proteins ,030220 oncology & carcinogenesis ,Antigen ,embryonic structures ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Knockout ,Receptors, Antigen, T-Cell ,Lymphoma/genetics ,Translocation ,Biology ,DNA-binding protein ,DNA sequencing ,03 medical and health sciences ,Genetic ,Animals ,Antigens ,Gene ,Ku Autoantigen ,MESH: Antigens, Nuclear ,MESH: Mice ,030304 developmental biology ,fungi ,MESH: DNA End-Joining Repair ,Genes, p53 ,V(D)J Recombination ,enzymes and coenzymes (carbohydrates) ,chemistry ,Genes ,T-Cell/genetics ,MESH: Lymphoma ,DNA ,MESH: DNA-Binding Proteins - Abstract
International audience; DNA double-stranded breaks (DSBs) can be repaired by several mechanisms, including classical NHEJ (c-NHEJ) and a poorly defined, error-prone process termed alternative NHEJ (a-NHEJ). How cells choose between these alternatives to join physiologic DSBs remains unknown. Here, we show that deletion of RAG2's C-terminus allows a-NHEJ to repair RAG-mediated DSBs in developing lymphocytes from both c-NHEJ-proficient and c-NHEJ-deficient mice, demonstrating that the V(D)J recombinase influences repair pathway choice in vivo. Analysis of V(D)J junctions revealed that, contrary to expectation, junctional characteristics alone do not reliably distinguish between a-NHEJ and c-NHEJ. These data suggest that a-NHEJ is not necessarily mutagenic, and may be more prevalent than previously appreciated. Whole genome sequencing of a lymphoma arising in a p53(-/-) mouse bearing a C-terminal RAG2 truncation reveals evidence of a-NHEJ and also of aberrant recognition of DNA sequences resembling RAG recognition sites.
- Published
- 2014
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