Aims: Though 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 (HM) mouse with decreased APE1 expression throughout the body was generated using a construct containing a neomycin resistance (NeoR) cassette knocked into the Apex1 site. Offspring were assessed for APE1 expression, breeding efficiency, and morphology with a focused examination of DNA damage in the stomach. Heterozygotic breeding pairs yielded 50% fewer HM mice than predicted by Mendelian genetics. APE1 expression was reduced up to 90% in the lungs, heart, stomach, and spleen. The HM offspring were typically smaller, and most had a malformed tail. Oxidative DNA damage was increased spontaneously in the stomachs of HM mice. Further, all changes were reversed when the NeoR cassette was removed. Primary gastric epithelial cells from HM 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 HM mouse with decreased APE1 expression throughout the body was generated and extensively characterized. Conclusion: The results suggest that HM mice enable studies of APE1's multiple functions throughout the body. The detailed characterization of the stomach showed that gastric epithelial cells from HM were more susceptible to DNA damage. Antioxid. Redox Signal. 38, 183-197.
|Number of pages||15|
|Journal||Antioxidants and Redox Signaling|
|State||Published - Jan 1 2023|
Bibliographical noteFunding Information:
Research reported in this publication was supported by the National Institutes of Health under Awards: R01-AI079145, P30-DK120515 and UL-1TR001442, T35-OD010956, R03CA249111 as well as the Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccine Development. This research was also supported by the Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558). The microscopy facility was supported by the UCSD Cancer Center Specialized Support Grant P30 CA23100 and NS047101. The authors are grateful for the technical support, products, and/or services provided to their research by the Mouse Biology Program (MBP) at the University of California Davis funded by U42OD012210 and the Animal Care Program at UCSD.
© Copyright 2023, Mary Ann Liebert, Inc., publishers 2023.
- cell differentiation
- DNA damage
- embryonic development
- oxidative stress
ASJC Scopus subject areas
- Molecular Biology
- Clinical Biochemistry
- Cell Biology