title: Radiosensitivity in Nijmegen Breakage Syndrome cells is attributable to a repair defect and not cell cycle checkpoint defects.
abstract: Cells derived from Nijmegen Breakage Syndrome (NBS) patients display radiosensitivity and cell cycle checkpoint defects. Here, we examine whether the radiosensitivity of NBS cells is the result of a repair defect or whether it can be attributed to impaired checkpoint arrest. We report a small increased fraction of unrejoined double strand breaks and, more significantly, increased chromosome breaks in noncycling NBS cells at 24 h after irradiation. One of the NBS lines examined (347BR) was atypical in showing a nearly normal checkpoint response. In contrast to the mild checkpoint defect, 347BR displays marked y-ray sensitivity similar to that shown by other NBS lines. Thus, the gamma-ray sensitivity correlates with the repair defect rather than impaired checkpoint control. Taken together, the results provide direct evidence for a repair defect in NBS cells and are inconsistent with the suggestion that the radiosensitivity is attributable only to impaired checkpoint arrest. 347BR also displays elevated spontaneous damage that cannot be attributed to impaired G2-M arrest, suggesting a function of Nbsl in decreasing or limiting the impact of spontaneously arising double strand breaks.
authors.affiliation: Medical Research Council Cell Mutation Unit, University of Sussex, Falmer, Brighton, United Kingdom.
authors.forename: P M
authors.initials: PM
authors.lastname: Girard
authors.forename: N
authors.initials: N
authors.lastname: Foray
authors.forename: M
authors.initials: M
authors.lastname: Stumm
authors.forename: A
authors.initials: A
authors.lastname: Waugh
authors.forename: E
authors.initials: E
authors.lastname: Riballo
authors.forename: R S
authors.initials: RS
authors.lastname: Maser
authors.forename: W P
authors.initials: WP
authors.lastname: Phillips
authors.forename: J
authors.initials: J
authors.lastname: Petrini
authors.forename: C F
authors.initials: CF
authors.lastname: Arlett
authors.forename: P A
authors.initials: PA
authors.lastname: Jeggo
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D019457:Chromosome Breakage; D002877:Chromosomes, Human / Q000528:radiation effects; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D007399:Interphase / Q000235:genetics; D008938:Mitosis / Q000235:genetics; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology*; D013577:Syndrome; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D016159:Tumor Suppressor Protein p53; D004247:DNA; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases