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

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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

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DNA-(Apurinic or Apyrimidinic Site) Lyase
Oxidative stress
Endonucleases
DNA Repair
Oxidation-Reduction
Oxidative Stress
Repair
Liver
Haploinsufficiency
DNA Glycosylases
DNA
Liver Extracts
Uracil
Protein Stability
Gene Deletion
Caspases
DNA Damage
Assays
Transcription Factors
Genes

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)

Cite this

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

In: Free Radical Biology and Medicine, Vol. 46, No. 11, 01.06.2009, p. 1488-1499.

Research output: Contribution to journalArticle

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. / Oxidative stress alters base excision repair pathway and increases apoptotic response in apurinic/apyrimidinic endonuclease 1/redox factor-1 haploinsufficient mice. In: Free Radical Biology and Medicine. 2009 ; Vol. 46, No. 11. pp. 1488-1499.
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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.",
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