ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes

Elsa Callén, Mila Jankovic, Simone Difilippantonio, Jeremy A. Daniel, Hua Tang Chen, Arkady Celeste, Manuela Pellegrini, Kevin McBride, Danny Wangsa, Andrea L. Bredemeyer, Barry P. Sleckman, Thomas Ried, Michel Nussenzweig, André Nussenzweig

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146 Scopus citations

Abstract

DNA double-strand breaks (DSBs) induce a signal transmitted by the ataxia-telangiectasia mutated (ATM) kinase, which suppresses illegitimate joining of DSBs and activates cell-cycle checkpoints. Here we show that a significant fraction of mature ATM-deficient lymphocytes contain telomere-deleted ends produced by failed end joining during V(D)J recombination. These RAG-1/2 endonuclease-dependent, terminally deleted chromosomes persist in peripheral lymphocytes for at least 2 weeks in vivo and are stable over several generations in vitro. Restoration of ATM kinase activity in mature lymphocytes that have transiently lost ATM function leads to loss of cells with terminally deleted chromosomes. Thus, maintenance of genomic stability in lymphocytes requires faithful end joining as well a checkpoint that prevents the long-term persistence and transmission of DSBs. Silencing this checkpoint permits DNA ends produced by V(D)J recombination in a lymphoid precursor to serve as substrates for translocations with chromosomes subsequently damaged by other means in mature cells.

Original languageEnglish
Pages (from-to)63-75
Number of pages13
JournalCell
Volume130
Issue number1
DOIs
StatePublished - Jul 13 2007

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    Callén, E., Jankovic, M., Difilippantonio, S., Daniel, J. A., Chen, H. T., Celeste, A., Pellegrini, M., McBride, K., Wangsa, D., Bredemeyer, A. L., Sleckman, B. P., Ried, T., Nussenzweig, M., & Nussenzweig, A. (2007). ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes. Cell, 130(1), 63-75. https://doi.org/10.1016/j.cell.2007.06.016