Sublethal doses of β-amyloid peptide abrogate DNA-dependent protein kinase activity

Alessio Cardinale, Mauro Racaniello, Serena Saladini, Giovanna De Chiara, Cristiana Mollinari, Maria Chiara De Stefano, Maurizio Pocchiari, Enrico Garaci, Daniela Merlo

Research output: Contribution to journalArticlepeer-review

Abstract

Accumulation of DNA damage and deficiency in DNA repair potentially contribute to the progressive neuronal loss in neurodegenerative disorders, including Alzheimer disease (AD). In multicellular eukaryotes, double strand breaks (DSBs), the most lethal form of DNA damage, are mainly repaired by the nonhomologous end joining pathway, which relies on DNA-PK complex activity. Both the presence of DSBs and a decreased end joining activity have been reported in AD brains, but the molecular player causing DNA repair dysfunction is still undetermined. β-Amyloid (Aβ), a potential proximate effector of neurotoxicity in AD, might exert cytotoxic effects by reactive oxygen species generation and oxidative stress induction, which may then cause DNA damage. Here, we show that in PC12 cells sublethal concentrations of aggregated Aβ(25-35) inhibit DNA-PK kinase activity, compromising DSB repair and sensitizing cells to nonlethal oxidative injury. The inhibition of DNA-PK activity is associated with down-regulation of the catalytic subunit DNA-PK (DNA-PKcs) protein levels, caused by oxidative stress and reversed by antioxidant treatment. Moreover, we show that sublethal doses of Aβ(1-42) oligomers enter the nucleus of PC12 cells, accumulate as insoluble oligomeric species, and reduce DNA-PK kinase activity, although in the absence of oxidative stress. Overall, these findings suggest that Aβ mediates inhibition of the DNA-PK-dependent nonhomologous end joining pathway contributing to the accumulation of DSBs that, if not efficiently repaired, may lead to the neuronal loss observed in AD.

Original languageEnglish
Pages (from-to)2618-2631
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number4
DOIs
Publication statusPublished - Jan 20 2012

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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