Heterozygosity for the mouse Apex gene results in phenotypes associated with oxidative stress.
Apurinic/apyrimidinic endonuclease is a key enzyme in the process of base excision repair, required for the repair of spontaneous base damage that arises as a result of oxidative damage to DNA. In mice, this endonuclease is coded by the Apex gene, disruption of which is incompatible with embryonic life. Here we confirm the embryonic lethality of Apex-null mice and report the phenotypic characterization of mice that are heterozygous mutants for the Apex gene (Apex+/-). We show that Apex heterozygous mutant cells and animals are abnormally sensitive to increased oxidative stress. Additionally, such animals manifest elevated levels of oxidative stress markers in serum, and we show that dietary supplementation with antioxidants restores these to normal levels. Apex+/- embryos and pups manifest reduced survival that can also be partially rescued by dietary supplementation with antioxidants. These results are consistent with a proposed role for this enzyme in protection against the deleterious effects of oxidative stress and raise the possibility that humans with heterozygous mutations in the homologous HAP1 gene may be at increased risk for the phenotypic consequences of oxidative stress in cells.
Meira
L B
LB
Laboratory of Molecular Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072, USA.
Devaraj
S
S
Kisby
G E
GE
Burns
D K
DK
Daniel
R L
RL
Hammer
R E
RE
Grundy
S
S
Jialal
I
I
Friedberg
E C
EC
D000231:Adenocarcinoma, Papillary / Q000235:genetics / Q000473:pathology; D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage; D019757:Carbon-Oxygen Lyases / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D019587:Dietary Supplements; D015237:Dinoprost / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005838:Genotype; D006579:Heterozygote; D008054:Lipid Peroxides / Q000097:blood; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000235:genetics*; D010269:Paraquat / Q000494:pharmacology; D010641:Phenotype; D014810:Vitamin E / Q000008:administration & dosage; D014812:Vitamin K / Q000494:pharmacology
D008054:Lipid Peroxides; D014812:Vitamin K; D014810:Vitamin E; D015237:Dinoprost; D019757:Carbon-Oxygen Lyases; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D010269:Paraquat; D001205:Ascorbic Acid