title: ATM prevents the persistence and propagation of chromosome breaks in lymphocytes.
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.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1360, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Callén
authors.forename: Mila
authors.initials: M
authors.lastname: Jankovic
authors.forename: Simone
authors.initials: S
authors.lastname: Difilippantonio
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Daniel
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Chen
authors.forename: Arkady
authors.initials: A
authors.lastname: Celeste
authors.forename: Manuela
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Kevin
authors.initials: K
authors.lastname: McBride
authors.forename: Danny
authors.initials: D
authors.lastname: Wangsa
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Bredemeyer
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Michel
authors.initials: M
authors.lastname: Nussenzweig
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000502:physiology* / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019457:Chromosome Breakage; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018816:Genes, cdc; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000502:physiology*; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007136:Immunoglobulins; D008070:Lipopolysaccharides; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; C064658:RAG-1 protein; D015847:Interleukin-4; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases