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DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress

By Harald Krenzlin, Ilja Demuth, Bastian Salewsky, Petra Wessendorf, Kathrin Weidele, Alexander Bürkle and Martin Digweed


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

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  7. (2001). An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele.
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  16. (2008). Constitutive phosphorylation of MDC1 physically links the MRE11-RAD50-NBS1 complex to damaged chromatin.
  17. (1983). Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay.
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  19. (1982). DNA fragmentation and NAD depletion. Their relation to the turnover of endogenous mono(ADP-ribosyl) and poly(ADP-ribosyl) proteins.
  20. (1995). Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome.
  21. (2006). Impaired elimination of DNA double-strand break-containing lymphocytes in ataxia telangiectasia and Nijmegen breakage syndrome.
  22. (2001). Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice. Cancer Res 61: 1849–1854. 4 . Z i vS ,B r e n n e rO ,A m a r i g l i oN ,S m o r o d i n s k yN I ,G a l r o nR ,e ta l
  23. (1999). Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs.
  24. (1976). Malignant neoplasms in the families of patients with ataxia-telangiectasia.
  25. (1995). Methods for the quantification of DNA double-strand breaks determined from the distribution of DNA fragment sizes measured by pulsed-field gel electrophoresis.
  26. (2006). NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity.
  27. (2001). NAD(P)H, a directly operating antioxidant?
  28. (2007). NAD+ metabolism in health and disease.
  29. (2002). NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain.
  30. (2005). Nibrin functions in Ig class-switch recombination.
  31. (2000). Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group.
  32. (1999). Poly(ADP-ribose) polymerase activity is not affected in ataxia telangiectasia cells and knockout mice.
  33. (2010). Poly(ADP-ribose) polymerase is hyperactivated in homologous recombinationdefective cells.
  34. (2005). Poly(ADP-ribose). The most elaborate metabolite of NAD+.
  35. (1976). Pyridine nucleotide levels as a function of growth in normal and transformed 3T3 cells.
  36. (1999). Reaction of peroxynitrite with reduced nicotinamide nucleotides, the formation of hydrogen peroxide.
  37. (2004). Role of oxygen radicals in DNA damage and cancer incidence.
  38. (2003). Role of PARP under stress conditions: cell death or protection?
  39. (1965). Synthesis of Diacetyldichlorofluorescin: a Stable Reagent for Fluorometric Analysis.
  40. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
  41. (2007). The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex.
  42. (2007). The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome.
  43. (2008). The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases.
  44. (2010). The Fanconi anemia protein, FANCG, binds to the ERCC1-XPF endonuclease via its tetratricopeptide repeats and the central domain of ERCC1.
  45. (1965). The Fluorometric Analysis of Ultramicro Quantities of Hydrogen Peroxide.
  46. (1990). Transition metals as catalysts of ‘‘autoxidation’’ reactions.
  47. (2008). Working together and apart: the twisted relationship of the Mre11 complex and Chk2 in apoptosis and tumor suppression.

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