title: Impaired elimination of DNA double-strand break-containing lymphocytes in ataxia telangiectasia and Nijmegen breakage syndrome.
abstract: The repair of DNA double-strand breaks is critical for genome integrity and tumor suppression. Here we show that following treatment with the DNA-intercalating agent actinomycin D (ActD), normal quiescent T cells accumulate double-strand breaks and die, whereas T cells from ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) patients are resistant to this death pathway despite a comparable amount of DNA damage. We demonstrate that the ActD-induced death pathway in quiescent T lymphocytes follows DNA damage and H2AX phosphorylation, is ATM- and NBS1-dependent and due to p53-mediated cellular apoptosis. In response to genotoxic 2-Gy gamma-irradiation, on the other hand, quiescent T cells from normal donors survive following complete resolution of the damage thus induced. T cells from AT and NBS patients also survive, but retain foci of phosphorylated H2AX due to a subtle double-strand break (DSB) repair defect. A common consequence of these two genetic defects in the DSB response is the apparent tolerance of cells containing DNA breaks. We suggest that this tolerance makes a major contribution to the oncogenic risk of patients with chromosome instability syndromes.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Porcedda
authors.forename: Valentina
authors.initials: V
authors.lastname: Turinetto
authors.forename: Erica
authors.initials: E
authors.lastname: Lantelme
authors.forename: Enrico
authors.initials: E
authors.lastname: Fontanella
authors.forename: Krystyna
authors.initials: K
authors.lastname: Chrzanowska
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ragona
authors.forename: Mario
authors.initials: M
authors.lastname: De Marchi
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Claudia
authors.initials: C
authors.lastname: Giachino
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001260:Ataxia Telangiectasia / Q000235:genetics*; D004249:DNA Damage; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D003609:Dactinomycin / Q000633:toxicity; D005434:Flow Cytometry; D005720:Gamma Rays; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D049932:Nijmegen Breakage Syndrome / Q000235:genetics*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects*
chemical_list: D017931:DNA Primers; C468783:H2AX protein, human; D006657:Histones; D003609:Dactinomycin