A Novel Hypomorphic Apex1 Mouse Model Implicates Apurinic/Apyrimidinic Endonuclease 1 in Oxidative DNA Damage Repair in Gastric Epithelial Cells

David Rios-Covian, Lindsay D. Butcher, Amber L. Ablack, Gerco Den Hartog, Mason T. Matsubara, Hong Ly, Andrew W. Oates, Guorong Xu, Kathleen M. Fisch, Eric T. Ahrens, Shusuke Toden, Corrie C. Brown, Kenneth Kim, Dzung Le, Lars Eckmann, Bithika Dhar, Tadahide Izumi, Peter B. Ernst, Sheila E. Crowe

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)183-197
Number of pages15
JournalAntioxidants and Redox Signaling
Volume38
Issue number1-3
DOIs
StatePublished - Jan 1 2023

Bibliographical note

Publisher Copyright:
© Copyright 2023, Mary Ann Liebert, Inc., publishers 2023.

Keywords

  • APE1
  • Apex1
  • DNA damage
  • cell differentiation
  • embryonic development
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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