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A novel hypomorphic Apex1 mouse model implicates apurinic-apyrimidinic endonuclease 1 in oxidative DNA damage repair in gastric epithelial cells.

AIMS
While best known for its role in oxidative DNA damage repair, apurinic-apyrimidinic endonuclease-1 (APE1) is a multifunctional protein that regulates multiple host responses during oxidative stress including the reductive activation of transcription factors. As knockout of the APE1-encoding gene, Apex1, is embryonically lethal, we sought to create a viable model with generalized inhibition of APE1 expression.


RESULTS
A hypomorphic mouse with decreased APE1 expression throughout the body was generated using a construct containing a NeoR cassette knocked into the Apex1 site. Offspring were assessed for APE1 expression, breeding efficiency, morphology with a focused examination of DNA damage in the stomach. Heterozygotic breeding pairs yielded 50% fewer hypomorphic mice than predicted by Mendelian genetics. APE1 expression was reduced up to 90% in the lungs, heart, stomach and spleen. The hypomorphic offspring were typically smaller and most had a malformed tail. Oxidative DNA damage was increased spontaneously in the stomachs of hypomorphic mice. Further, all changes were reversed when the NeoR cassette was removed. Primary gastric epithelial cells from hypomorphic mice differentiated more quickly and had more evidence of oxidative DNA damage after stimulation with Helicobacter pylori or a chemical carcinogen than control lines from wildtype mice.


INNOVATION
A hypomorphic mouse with decreased APE1 expression throughout the body was generated and extensively characterized.


CONCLUSION
The results suggest hypomorphic mice enable studies of APE1's multiple functions throughout the body. The detailed characterization of the stomach showed that gastric epithelial cells from hypomorphic were more susceptible to DNA damage.