title: An imperfect G2M checkpoint contributes to chromosome instability following irradiation of S and G2 phase cells.
abstract: DNA double strand break (DSB) repair and checkpoint control represent two major mechanisms that function to reduce chromosomal instability following ionizing irradiation (IR). Ataxia telangiectasia (A-T) cells have long been known to have defective checkpoint responses. Recent studies have shown that they also have a DSB repair defect following IR raising the issue of how ATM's repair and checkpoint functions interplay to maintain chromosomal stability. A-T and Artemis cells manifest an identical and epistatic repair defect throughout the cell cycle demonstrating that ATM's major repair defect following IR represents Artemis-dependent end-processing. Artemis cells show efficient G(2)/M checkpoint induction and a prolonged arrest relative to normal cells. Following irradiation of G(2) cells, this checkpoint is dependent on ATM and A-T cells fail to show checkpoint arrest. In contrast, cells irradiated during S phase initiate a G(2)/M checkpoint which is independent of ATM and, significantly, both Artemis and A-T cells show a prolonged arrest at the G(2)/M checkpoint likely reflecting their repair defect. Strikingly, the G(2)/M checkpoint is released before the completion of repair when approximately 10-20 DSBs remain both for S phase and G(2) phase irradiated cells. This defined sensitivity level of the G(2)/M checkpoint explains the prolonged arrest in repair-deficient relative to normal cells and provides a conceptual framework for the cooperative phenotype between checkpoint and repair functions in maintaining chromosomal stability.
authors.affiliation: Fachrichtung Biophysik, Universität des Saarlandes, Homburg/Saar, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Krempler
authors.forename: Dorothee
authors.initials: D
authors.lastname: Deckbar
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
authors.forename: Markus
authors.initials: M
authors.lastname: Löbrich
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D043171:Chromosomal Instability; D004247:DNA / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases; D016195:G2 Phase / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D016196:S Phase / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C426344:DCLRE1C protein, human; D004720:Endonucleases