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Nat Commun. 2016 Feb 2;7:10529. doi: 10.1038/ncomms10529.

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

Author information

1
Departments of Immunology and Genomes and Genetics, Institut Pasteur, CNRS-URA 1961, Paris 75015, France.
2
Laboratory of Genome Dynamics in the Immune System, INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
3
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

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 (Rag2(c/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, Rag2(c/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.

PMID:
26833222
PMCID:
PMC4740868
DOI:
10.1038/ncomms10529
[Indexed for MEDLINE]
Free PMC Article

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