Oxidative stress alters base excision repair pathway and increases apoptotic response in apurinic/apyrimidinic endonuclease 1/redox factor-1 haploinsufficient mice.
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.
Unnikrishnan
Archana
A
Department of Nutrition & Food Science, College of Liberal Arts and Sciences, Wayne State University, Detroit, MI 48202, USA.
Raffoul
Julian J
JJ
Patel
Hiral V
HV
Prychitko
Thomas M
TM
Anyangwe
Njwen
N
Meira
Lisiane B
LB
Friedberg
Errol C
EC
Cabelof
Diane C
DC
Heydari
Ahmad R
AR
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009595:Nitroparaffins / Q000633:toxicity; D018384:Oxidative Stress / Q000235:genetics*; D011407:Propane / Q000031:analogs & derivatives / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051981:Uracil-DNA Glycosidase / Q000378:metabolism; D000097642:GADD45 Proteins
D002352:Carrier Proteins; D020169:Caspases; D045647:DNA Glycosylases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009595:Nitroparaffins; D011407:Propane; D016159:Tumor Suppressor Protein p53; D051981:Uracil-DNA Glycosidase; C121373:Gadd45g protein, mouse; D000097642:GADD45 Proteins; C485990:Ogg1 protein, mouse; C486216:Apex1 protein, mouse; C016617:2-nitropropane