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Oxidative stress alters base excision repair pathway and increases apoptotic response in apurinic/apyrimidinic endonuclease 1/redox factor-1 haploinsufficient mice.
- Source :
-
Free radical biology & medicine [Free Radic Biol Med] 2009 Jun 01; Vol. 46 (11), pp. 1488-99. Date of Electronic Publication: 2009 Mar 03. - Publication Year :
- 2009
-
Abstract
- Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is the redox regulator of multiple stress-inducible transcription factors, such as NF-kappaB, 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-kappaB 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.
- Subjects :
- Animals
Apoptosis
Carrier Proteins genetics
Caspases metabolism
DNA Glycosylases metabolism
DNA Repair drug effects
DNA Repair genetics
DNA-(Apurinic or Apyrimidinic Site) Lyase genetics
Enzyme Activation drug effects
Intracellular Signaling Peptides and Proteins
Liver drug effects
Liver pathology
Mice
NF-kappa B metabolism
Nitroparaffins toxicity
Propane analogs & derivatives
Propane toxicity
Protein Binding drug effects
Protein Stability drug effects
Tumor Suppressor Protein p53 metabolism
Uracil-DNA Glycosidase metabolism
Carrier Proteins metabolism
DNA Damage drug effects
DNA-(Apurinic or Apyrimidinic Site) Lyase metabolism
Liver metabolism
Oxidative Stress genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 46
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 19268524
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2009.02.021