TY - JOUR
T1 - ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes
AU - Callén, Elsa
AU - Jankovic, Mila
AU - Difilippantonio, Simone
AU - Daniel, Jeremy A.
AU - Chen, Hua Tang
AU - Celeste, Arkady
AU - Pellegrini, Manuela
AU - McBride, Kevin
AU - Wangsa, Danny
AU - Bredemeyer, Andrea L.
AU - Sleckman, Barry P.
AU - Ried, Thomas
AU - Nussenzweig, Michel
AU - Nussenzweig, André
N1 - Funding Information:
We thank T. Honjo for AID −/− mice; A.Wynshaw-Boris for Atm −/− mice; J. Chen for 53BP1 −/− mice; F. Alt for DNA-PKcs −/− mice; Seth Steinberg for statistical analysis; L. Granger for flow cytometry; L. Stapleton for chromosome-painting probes; K. Murre and M. Kruhlak for help with the 3D FISH; Y. Xu for ATM −/− ES cells; G. Smith for ATM small-molecule inhibitor KU55933; P. Cortes for anti-RAG antibodies; and E. Besmer, O. Fernandez-Capetillo, and A. Bhandoola for comments. A.N. is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and a grant from the A-T Children's Project. M.C.N. is supported by grants from NIH. M.C.N. is a Howard Hughes Institute Investigator. The authors declare no financial conflict of interest.
PY - 2007/7/13
Y1 - 2007/7/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34447093903&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2007.06.016
DO - 10.1016/j.cell.2007.06.016
M3 - Article
C2 - 17599403
AN - SCOPUS:34447093903
VL - 130
SP - 63
EP - 75
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1
ER -