The RAG2 C terminus suppresses genomic instability and lymphomagenesis

Abstract

Misrepair of DNA double-strand breaks (DSBs) produced by the V(D)J recombinase (the RAG1/RAG2 proteins) at immunoglobulin (Ig) and T cell receptor (Tcr) loci has been implicated in pathogenesis of lymphoid malignancies in humans1 and in mice2–7. Defects in DNA damage response factors such as ATM and combined deficiencies in classical nonhomologous end joining (NHEJ) and p53 predispose to RAG-initiated genomic rearrangements and lymphomagenesis2–11. Although we showed previously that RAG1/RAG2 shepherd the broken DNA ends to classical NHEJ for proper repair12,13, roles for the RAG proteins in preserving genomic stability remain poorly defined. Here we show that the RAG2 C-terminus, although dispensable for recombination14,15, is critical for maintaining genomic stability. Thymocytes from “core” Rag2 homozygotes (Rag2c/c mice) show dramatic disruption of Tcrα/δ locus integrity. Furthermore, all Rag2c/c p53−/− mice, unlike Rag1c/c p53−/− and p53−/− animals, rapidly develop thymic lymphomas bearing complex chromosomal translocations, amplifications, and deletions involving the Tcrα/δ and Igh loci. We also find these features in lymphomas from Atm−/− mice. We show that, like ATM-deficiency3, core RAG2 severely destabilizes the RAG post-cleavage complex. These results reveal a novel genome guardian role for RAG2 and suggest that similar “end release/end persistence” mechanisms underlie genomic instability and lymphomagenesis in Rag2c/c p53−/− and Atm−/− mice.