Abstract
V(D)J recombination is a process specific to developing B- and T- lymphocytes in which double strand breaks (DSBs) are introduced into germline DNA and upon repair generate rearranged gene segments. This recombination event is cell cycle regulated and is confined to the noncycling G0/G1 phase of cell cycle. The protein kinase Ataxia Telangiectasia Mutated (ATM) is a vital mediator in both the DNA damage response and cell cycle. ATM was found localized at V(D)J mediated break sites, suggesting an additional function for ATM in recombination. In the absence of ATM, mice develop thymic lymphomas with chromosomal translocations. Therefore, we hypothesize a role for ATM in the cell cycle control of V(D)J recombination. Thymic lymphomas from Atm null mice revealed cells harbored multiple chromosomal translocations near sites of recombination. Wildtype and Atm null thymocytes were separated into cell cycle fractions of G0/G1 and S/G2/M. V(D)J mediated DSBs, indicative of recombination, were observed at the T cell receptor α, δ, and β loci in both cell cycle fractions of Atm null thymocytes but were found only in the G0/G1 fraction of wildtype thymocytes. Together, these results indicate the involvement of ATM in the cell cycle control of V(D)J recombination. Loss of this control can lead to sustained DNA DSBs and translocations, which could contribute to tumorigenesis.