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.
Highlights
XRCC4-like factor (XLF) functions in classical non-homologous end-joining but is dispensable for the repair of DNA double-strand breaks (DSBs) generated during V(D)J recombination
The repair of RAG-induced DSB is known to be fully dependent on core classical non-homologous end-joining (cNHEJ) factors (Ku70/80, XRCC4 and Ligase IV) and DNA-PKcs/Artemis in the context of coding joint (CJ) formation[3,4,5]
We find that the RAG complex and XLF functionally overlap in the repair of DNA breaks during antigen receptor assembly
Summary
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. XLF/p53-deficient animals, unlike other cNHEJ/p53 double-deficient mice, rarely die of pro-B cell lymphomas but instead develop T-cell lymphomas characteristic of p53 deficiency[20] These results are consistent with normal overall V(D)J recombination in developing XLF-deficient lymphocytes and led to the speculation that lymphocyte-specific factors/pathways compensate for XLF function during V(D)J recombination[3,19,20]. Single deficiencies for XLF or individual DDR factors generally have little effect on V(D)J recombination, these deficiencies have been demonstrated to have a profound effect on non-V(D)J cNHEJ-mediated DSB repair (for example, irradiation or activation-induced cytidine deaminase (AID)-induced DSBs during the process of class switch recombination)[8,22], indicating that such compensatory functions are specific to the repair of RAG-mediated DNA breaks. The nature of the mechanism(s) underlying these discrepancies is unknown
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