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RAG2 and XLF/Cernunnos interplay reveals a novel role for the RAG complex in DNA repair

Author

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  • Chloé Lescale

    (Institut Pasteur)

  • Vincent Abramowski

    (Laboratory of Genome Dynamics in the Immune System, INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine)

  • Marie Bedora-Faure

    (Institut Pasteur)

  • Valentine Murigneux

    (Institut Pasteur)

  • Gabriella Vera

    (Laboratory of Genome Dynamics in the Immune System, INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine)

  • David B. Roth

    (University of Pennsylvania)

  • Patrick Revy

    (Laboratory of Genome Dynamics in the Immune System, INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine)

  • Jean-Pierre de Villartay

    (Laboratory of Genome Dynamics in the Immune System, INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine)

  • Ludovic Deriano

    (Institut Pasteur)

Abstract

XRCC4-like factor (XLF) functions in classical non-homologous end-joining (cNHEJ) but is dispensable for the repair of DNA double-strand breaks (DSBs) generated during V(D)J recombination. A long-standing hypothesis proposes that, in addition to its canonical nuclease activity, the RAG1/2 proteins participate in the DNA repair phase of V(D)J recombination. Here we show that in the context of RAG2 lacking the C-terminus domain (Rag2c/c mice), XLF deficiency leads to a profound lymphopenia associated with a severe defect in V(D)J recombination and, in the absence of p53, increased genomic instability at V(D)J sites. In addition, Rag2c/c XLF−/− p53−/− mice develop aggressive pro-B cell lymphomas bearing complex chromosomal translocations and gene amplifications involving Igh and c-myc/pvt1 loci. Our results reveal an unanticipated functional interplay between the RAG complex and XLF in repairing RAG-induced DSBs and maintaining genome integrity during antigen receptor gene assembly.

Suggested Citation

  • Chloé Lescale & Vincent Abramowski & Marie Bedora-Faure & Valentine Murigneux & Gabriella Vera & David B. Roth & Patrick Revy & Jean-Pierre de Villartay & Ludovic Deriano, 2016. "RAG2 and XLF/Cernunnos interplay reveals a novel role for the RAG complex in DNA repair," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10529
    DOI: 10.1038/ncomms10529
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    Cited by:

    1. Estelle Vincendeau & Wenming Wei & Xuefei Zhang & Cyril Planchais & Wei Yu & Hélène Lenden-Hasse & Thomas Cokelaer & Juliana Pipoli da Fonseca & Hugo Mouquet & David J. Adams & Frederick W. Alt & Step, 2022. "SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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