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© Deriano Lab / Institut Pasteur
Chromosomes métaphasiques d’une cellule lymphoïde cancéreuse présentant une amplification des gènes Igh et c-myc
Publication : Nature communications

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Nature communications - 02 Feb 2016

Lescale C, Abramowski V, Bedora-Faure M, Murigneux V, Vera G, Roth DB, Revy P, de Villartay JP, Deriano L

Link to Pubmed [PMID] – 26833222

Nat Commun 2016;7:10529

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.

http://www.ncbi.nlm.nih.gov/pubmed/26833222