4 DNA damage response regulates RAG1/2 expression through ATM-FOXO1 | 105 In a recent study, it was shown that RAG2 is also affected by DNA damage, triggering its nuclear export. However, only a modest fraction of RAG2 was shown to undergo subcellular redistribution, making it unlikely that this mechanism is involved in regulating V(D)J recombination60. Previously, in severe combined immune deficient (SCID) mice it was shown that irradiation promotes the aberrant joining of RAG1/2-dependent DNA breaks to random DNA breaks, leading to chromosomal translocations that promote thymic lymphomagenesis61. We speculate that the rapid downregulation of RAG1 upon DNA damage may be important in preventing such aberrant recombinations in pro- and pre-B cells that have initiated V(D) J recombination, by limiting the co-existence of RAG-dependent and RAG-independent DNA breaks. Our data suggest that ATM imposes an important barrier for the generation of RAG-dependent DNA damage not only by regulating DNA repair of these lesions62,63 but also by transcriptional regulation of RAG1, thereby preventing excessive and inappropriate RAG activity. Conflict of interest statement The authors declare that there are no conflicts of interest. Acknowledgements We thank Dr. Craig Bassing (University of Pennsylvania School of Medicine, Philadelphia, PA), Drs. Inês Trancoso and Jocelyne Demengeot (Instituto Gulbenkian, Oeiras, Portugal); Prof. Mark Schlissel (University of Michigan, Ann Arbor, MI) and Dr. Mirjam van der Burg (Erasmus Medical Center, Rotterdam, The Netherlands) for providing reagents and cell lines, and Yanís Pelinski Carmona for excellent technical assistance.
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