Erschienen:
Springer Science and Business Media LLC, 2016
Erschienen in:Nature Communications
Sprache:
Englisch
DOI:
10.1038/ncomms10529
ISSN:
2041-1723
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>Rag2</jats:italic><jats:sup><jats:italic>c/c</jats:italic></jats:sup> 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, <jats:italic>Rag2</jats:italic><jats:sup><jats:italic>c/c</jats:italic></jats:sup><jats:italic>XLF</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup><jats:italic>p53</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> mice develop aggressive pro-B cell lymphomas bearing complex chromosomal translocations and gene amplifications involving <jats:italic>Igh</jats:italic> and <jats:italic>c-myc</jats:italic>/<jats:italic>pvt1</jats:italic> 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.</jats:p>