Oxidative stress alters base excision repair pathway and increases apoptotic response in apurinic/apyrimidinic endonuclease 1/redox factor-1 haploinsufficient mice

• Published in: Free radical biology & medicine 2009-06, Vol.46 (11), p.1488-1499
• Main Authors: Unnikrishnan, Archana, Raffoul, Julian J., Patel, Hiral V., Prychitko, Thomas M., Anyangwe, Njwen, Meira, Lisiane B., Friedberg, Errol C., Cabelof, Diane C., Heydari, Ahmad R.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apurinic/apyrimidinic endonuclease 1/redox factor-1; Base excision repair; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspases - metabolism; DNA Damage - drug effects; DNA Glycosylases - metabolism; DNA Repair - drug effects; DNA Repair - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Enzyme Activation - drug effects; Free radicals; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Mice; NF-kappa B - metabolism; NF-κB; Nitroparaffins - toxicity; Oxidative DNA damage; Oxidative Stress - genetics; Propane - analogs & derivatives; Propane - toxicity; Protein Binding - drug effects; Protein Stability - drug effects; Redox activity; Tumor Suppressor Protein p53 - metabolism; Uracil-DNA Glycosidase - metabolism
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2009.02.021

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is the redox regulator of multiple stress-inducible transcription factors, such as NF-κB, and the major 5′-endonuclease in base excision repair (BER). We utilized mice containing a heterozygous gene-targeted deletion of APE1/Ref-1 ( Apex +/−) to determine the impact of APE1/Ref-1 haploinsufficiency on the processing of oxidative DNA damage induced by 2-nitropropane (2-NP) in the liver tissue of mice. APE1/Ref-1 haploinsufficiency results in a significant decline in NF-κB DNA-binding activity in response to oxidative stress in liver. In addition, loss of APE1/Ref-1 increases the apoptotic response to oxidative stress, in which significant increases in GADD45g expression, p53 protein stability, and caspase activity are observed. Oxidative stress displays a differential impact on monofunctional (UNG) and bifunctional (OGG1) DNA glycosylase-initiated BER in the liver of Apex +/− mice. APE1/Ref-1 haploinsufficiency results in a significant decline in the repair of oxidized bases (e.g., 8-OHdG), whereas removal of uracil is increased in liver nuclear extracts of mice using an in vitro BER assay. Apex +/− mice exposed to 2-NP displayed a significant decline in 3′-OH-containing single-strand breaks and an increase in aldehydic lesions in their liver DNA, suggesting an accumulation of repair intermediates of failed bifunctional DNA glycosylase-initiated BER.