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The RAG2 C terminus suppresses genomic instability and lymphomagenesis

Nature volume 471, pages 119–123 (2011)Cite this article

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Abstract

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 humans1 and in mice2,3,4,5,6,7. 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 lymphomagenesis2,3,4,5,6,7,8,9,10,11. Although we showed previously that RAG1/RAG2 shepherd the broken DNA ends to classical non-homologous end joining for proper repair12,13, roles for the RAG proteins in preserving genomic stability remain poorly defined. Here we show that the RAG2 carboxy (C) terminus, although dispensable for recombination14,15, is critical for maintaining genomic stability. Thymocytes from ‘core’ Rag2 homozygotes (Rag2c/c mice) show dramatic disruption of Tcrα/δ locus integrity. Furthermore, all Rag2c/c p53−/− mice, unlike Rag1c/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-deficiency3, 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 Rag2c/c p53−/− and Atm−/− mice.

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Figure 1: The C terminus of RAG2 is a tumour suppressor in developing thymocytes.
Figure 2: Rag2 c / c p53 −/− thymic lymphomas display recurrent translocations involving chromosomes that harbour antigen-receptor loci.
Figure 3: Rag2c/c p53−/− thymocytes display Tcrα/δ - and Igh -associated genomic instability.
Figure 4: The C terminus of RAG2 stabilizes the RAG post-cleavage complex.

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Acknowledgements

We thank M. Schlissel for the gift of core Rag2 mice, F. Alt for the gift of core Rag1 mice and S. Hewitt for the Igh BAC probes. D.B.R. was supported by National Institutes of Health Roadmap Initiative in Nanomedicine through a Nanomedicine Development Center award (1PN2EY018244), a National Institutes of Health grant CA104588 and the Irene Diamond Fund. L.D. is a Fellow of The Leukemia and Lymphoma Society. A.V.A. was supported in part by grant 1UL1RR029893 from the National Center for Research Resources, National Institutes of Health. J.A.S. was supported by a National Institutes of Health grant R01GM086852, a National Institutes of Health Challenge grant NCI R01CA145746-01, a Leukemia and Lymphoma Scholar Award and a Wellcome trust project grant 085096.

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Authors and Affiliations

  1. Department of Pathology, New York University School of Medicine, New York, 10016, NY, USA

    Ludovic Deriano, Julie Chaumeil, Marc Coussens, YiFan Chou, Jane A. Skok & David B. Roth

  2. Department of Genetics, The M.D. Anderson Cancer Center, Houston, 77030, TX, USA

    Asha Multani

  3. Department of Medicine, Division of Clinical Pharmacology, Center for Health Informatics and Bioinformatics, New York University School of Medicine, NY 10016, USA

    Alexander V. Alekseyenko

  4. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 06520, CT, USA

    Sandy Chang

  5. Department of Immunology and Molecular Pathology, Division of Infection and Immunity, University College London, London W1T 4JF, UK

    Jane A. Skok

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Contributions

L.D. and D.B.R. conceived the study and co-wrote the manuscript. L.D. designed the experiments. L.D., J.C., M.C. and A.M. performed the experiments. Y.C. provided assistance with the mouse colonies. A.V.A. performed the aCGH data analysis. J.A.S. and S.C. provided technical and conceptual support. J.C. and J.A.S revised the manuscript. All the authors read and approved the manuscript.

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Correspondence to David B. Roth.

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Deriano, L., Chaumeil, J., Coussens, M. et al. The RAG2 C terminus suppresses genomic instability and lymphomagenesis. Nature 471, 119–123 (2011). https://doi.org/10.1038/nature09755

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