ATM and p53 are essential in the cell-cycle containment of DNA breaks during V(D)J recombination in vivo

V(D)J recombination is essential for the maturation of lymphocytes. Because of the involvement of cutting and joining DNA double strands, this recombination activity is strictly contained within the noncycling phases of the cell cycle. Such containment is crucial for the maintenance of genomic integrity. The ataxia telangiectasia mutated (ATM) gene is known to have a central role in sensing general DNA damage and mediating cell-cycle checkpoint. In this study, we investigated the role of ATM and its downstream targets in the cell-cycle control of V(D) J recombination in vivo. Our results revealed the persistence of double-strand breaks (DSBs) throughout the cell cycle in ATM(-/-) and p53(-/-) thymocytes, but the cell-cycle regulation of a V(D) J recombinase, Rag-2, was normal. The histone variant H2AX, which is phosphorylated during normal V(D) J recombination, was dispensable for containing DSBs. H2AX was still phosphorylated at V(D) J loci in the absence of ATM. Therefore, V(D) J recombination, a physiological DNA rearrangement process, activates the ATM/p53 pathway to contain DNA breaks within the noncycling cells and surprisingly this pathway is not important for containing Rag-2 activity. This study shows the dynamic multiple functions of ATM in maintaining genomic stability and preventing tumorigenesis in developing lymphocytes. Oncogene (2010) 29, 957-965; doi:10.1038/onc.2009.394; published online 16 November 2009