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[Cancer Research 61, 5552-5557, July 15, 2001]
© 2001 American Association for Cancer Research

Molecular Biology and Genetics

Heterozygosity for the Mouse Apex Gene Results in Phenotypes Associated with Oxidative Stress1

Lisiane B. Meira, Sridevi Devaraj, Glen E. Kisby, Dennis K. Burns, Russel L. Daniel, Robert E. Hammer, Scott Grundy, Ishwarlal Jialal and Errol C. Friedberg2

Laboratory of Molecular Pathology [L. B. M., D. K. B., R. L. D., E. C. F.], Division of Clinical Biochemistry and Human Metabolism, Department of Pathology [S. D., I. J.], The Center for Human Nutrition [S. G.], and Department of Biochemistry and HHMI [R. E. H.], University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072, and Center for Research on Occupational and Environmental Technology, Oregon Health Sciences University, Portland, Oregon 97201 [G. E. K.]

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.




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