TY - JOUR
T1 - A Novel Hypomorphic Apex1 Mouse Model Implicates Apurinic/Apyrimidinic Endonuclease 1 in Oxidative DNA Damage Repair in Gastric Epithelial Cells
AU - Rios-Covian, David
AU - Butcher, Lindsay D.
AU - Ablack, Amber L.
AU - Den Hartog, Gerco
AU - Matsubara, Mason T.
AU - Ly, Hong
AU - Oates, Andrew W.
AU - Xu, Guorong
AU - Fisch, Kathleen M.
AU - Ahrens, Eric T.
AU - Toden, Shusuke
AU - Brown, Corrie C.
AU - Kim, Kenneth
AU - Le, Dzung
AU - Eckmann, Lars
AU - Dhar, Bithika
AU - Izumi, Tadahide
AU - Ernst, Peter B.
AU - Crowe, Sheila E.
N1 - Publisher Copyright:
© Copyright 2023, Mary Ann Liebert, Inc., publishers 2023.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - 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.
AB - 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.
KW - APE1
KW - Apex1
KW - DNA damage
KW - cell differentiation
KW - embryonic development
KW - oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85146484667&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85146484667&partnerID=8YFLogxK
U2 - 10.1089/ars.2021.0119
DO - 10.1089/ars.2021.0119
M3 - Article
C2 - 35754343
AN - SCOPUS:85146484667
SN - 1523-0864
VL - 38
SP - 183
EP - 197
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 1-3
ER -