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

Archana Unnikrishnan, Julian J. Raffoul, Hiral V. Patel, Thomas M. Prychitko, Njwen Anyangwe, Lisiane B. Meira, Errol C. Friedberg, Diane C. Cabelof, Ahmad R. Heydari

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1488-1499
Number of pages12
JournalFree Radical Biology and Medicine
Volume46
Issue number11
DOIs
StatePublished - Jun 1 2009

Keywords

  • Apoptosis
  • Apurinic/apyrimidinic endonuclease 1/redox factor-1
  • Base excision repair
  • Free radicals
  • Liver
  • NF-κB
  • Oxidative DNA damage
  • Redox activity

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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