title: A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.
abstract: Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decision remain elusive. Here we exposed cultured cells and mice to different doses and dose rates of γ-irradiation, which revealed cell-type-specific sensitivities to chronic, but not acute, γ-irradiation. Among tested cell types, human fibroblasts were associated with the highest levels of growth inhibition in response to chronic γ-irradiation. In this context, fibroblasts exhibited a reversible G1 cell-cycle arrest or an irreversible senescence-like growth arrest, depending on the irradiation dose rate or the rate of DNA damage. Remarkably, when the same dose of γ-irradiation was delivered chronically or acutely, chronic delivery induced considerably more cellular senescence. A similar effect was observed with primary cells isolated from irradiated mice. We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate. Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells. Together these results provide insights into the mechanisms governing cell-fate determination in response to different rates of DNA damage.
authors.affiliation: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Lili
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Kawai
authors.affiliation: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Sasatani
authors.affiliation: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iizuka
authors.affiliation: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; Department of Genome Dynamics, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Masuda
authors.affiliation: Department of Molecular Oncology & Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Radiation Biology and Health, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ootsuyama
authors.affiliation: Radioisotope Research Center, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Umata
authors.affiliation: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kamiya
authors.affiliation: Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000528:radiation effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D016922:Cellular Senescence / Q000235:genetics / Q000528:radiation effects; D003114:Colony-Forming Units Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D059585:G1 Phase Cell Cycle Checkpoints; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins
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