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

Chloé Lescale, Vincent Abramowski, Marie Bedora-Faure, Valentine Murigneux, Gabriella Vera, David B. Roth, Patrick Revy, Jean-Pierre de Villartay and Ludovic Deriano ()
Additional contact information
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

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10529

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