title: DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress.
abstract: Nijmegen Breakage Syndrome (NBS), an autosomal recessive genetic instability syndrome, is caused by hypomorphic mutation of the NBN gene, which codes for the protein nibrin. Nibrin is an integral member of the MRE11/RAD50/NBN (MRN) complex essential for processing DNA double-strand breaks. Cardinal features of NBS are immunodeficiency and an extremely high incidence of hematological malignancies. Recent studies in conditional null mutant mice have indicated disturbances in redox homeostasis due to impaired DSB processing. Clearly this could contribute to DNA damage, chromosomal instability, and cancer occurrence. Here we show, in the complete absence of nibrin in null mutant mouse cells, high levels of reactive oxygen species several hours after exposure to a mutagen. We show further that NBS patient cells, which unlike mouse null mutant cells have a truncated nibrin protein, also have high levels of reactive oxygen after DNA damage and that this increased oxidative stress is caused by depletion of NAD+ due to hyperactivation of the strand-break sensor, Poly(ADP-ribose) polymerase. Both hyperactivation of Poly(ADP-ribose) polymerase and increased ROS levels were reversed by use of a specific Poly(ADP-ribose) polymerase inhibitor. The extremely high incidence of malignancy among NBS patients is the result of the combination of a primary DSB repair deficiency with secondary oxidative DNA damage.
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Krenzlin
authors.forename: Ilja
authors.initials: I
authors.lastname: Demuth
authors.forename: Bastian
authors.initials: B
authors.lastname: Salewsky
authors.forename: Petra
authors.initials: P
authors.lastname: Wessendorf
authors.forename: Kathrin
authors.initials: K
authors.lastname: Weidele
authors.forename: Alexander
authors.initials: A
authors.lastname: Bürkle
authors.forename: Martin
authors.initials: M
authors.lastname: Digweed
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009243:NAD / Q000378:metabolism; D049932:Nijmegen Breakage Syndrome / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D009243:NAD; D001761:Bleomycin; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases