title: ATM-dependent hyper-radiosensitivity in mammalian cells irradiated by heavy ions.
abstract: OBJECTIVE
  Low-dose hyper-radiosensitivity (HRS) and the later appearing radioresistance (termed induced radioresistance [IRR]) was mainly studied in low linear energy transfer (LET) radiation with survival observation. The aim of this study was to find out whether equivalent hypersensitivity occurred in high LET radiation, and the roles of ataxia telangiectasia mutated (ATM) kinase.
  
  
  METHODS
  Survival and mutation were measured by clonogenic assay and HPRT mutation assay. ATM Ser1981 activation was detected by Western blotting and immunofluorescent staining. Pretreatment of specific ATM inhibitor (10 microM KU55933) and activator (20 microg/mL chloroquine) before carbon radiation were adopted to explore the involvement of ATM. The roles of ATM were also investigated in its G2/M checkpoint function with histone H3 phosphorylation analysis and flow cytometric assay, and DNA double strand break (DSB) repair function measured using gamma-H2AX foci assay.
  
  
  RESULTS
  HRS/IRR was observed with survival and mutation in normal human skin fibroblast cells by carbon ions, while impaired in cells with intrinsic ATM deficiency or normal cells modified with specific ATM activator or inhibitor before irradiation. The dose-response pattern of ATM kinase activation was concordant with the transition from HRS to IRR. The ATM-dependent "early" G2 checkpoint arrest and DNA DSB repair efficiency could explain the difference between HRS and IRR.
  
  
  CONCLUSIONS
  These data demonstrate that the HRS/IRR by carbon ion radiation is an ATM-dependent phenomenon in the cellular response to DNA damage.
authors.affiliation: School of Radiation Medicine and Public Health, Medical College of Soochow University, Suzhou, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Xue
authors.forename: Dong
authors.initials: D
authors.lastname: Yu
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Furusawa
authors.forename: Jianping
authors.initials: J
authors.lastname: Cao
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okayasu
authors.forename: Saijun
authors.initials: S
authors.lastname: Fan
mesh_terms: D000465:Algorithms; D064007:Ataxia Telangiectasia Mutated Proteins; D002244:Carbon / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D002470:Cell Survival; D002738:Chloroquine / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D020450:Heavy Ions; D006657:Histones / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000528:radiation effects; D018499:Linear Energy Transfer / Q000502:physiology*; D008938:Mitosis / Q000528:radiation effects; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011753:Pyrones / Q000494:pharmacology; D011836:Radiation Tolerance / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D009025:Morpholines; D011753:Pyrones; D025521:Tumor Suppressor Proteins; D002244:Carbon; D002738:Chloroquine; D007041:Hypoxanthine Phosphoribosyltransferase; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases