DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress

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2012
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Krenzlin, Harald
Demuth, Ilja
Salewsky, Bastian
Wessendorf, Petra
Digweed, Martin
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PLoS Genetics ; 8 (2012), 3. - e1002557. - ISSN 1553-7390. - eISSN 1553-7404
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.
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ISO 690KRENZLIN, Harald, Ilja DEMUTH, Bastian SALEWSKY, Petra WESSENDORF, Kathrin WEIDELE, Alexander BÜRKLE, Martin DIGWEED, 2012. DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress. In: PLoS Genetics. 8(3), e1002557. ISSN 1553-7390. eISSN 1553-7404. Available under: doi: 10.1371/journal.pgen.1002557
BibTex
@article{Krenzlin2012damag-21715,
  year={2012},
  doi={10.1371/journal.pgen.1002557},
  title={DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress},
  number={3},
  volume={8},
  issn={1553-7390},
  journal={PLoS Genetics},
  author={Krenzlin, Harald and Demuth, Ilja and Salewsky, Bastian and Wessendorf, Petra and Weidele, Kathrin and Bürkle, Alexander and Digweed, Martin},
  note={Article Number: e1002557}
}
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