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

doi:10.1089/ars.2021.0119

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 journal › Article › peer-review

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 language	English
Pages (from-to)	183-197
Number of pages	15
Journal	Antioxidants and Redox Signaling
Volume	38
Issue number	1-3
DOIs	https://doi.org/10.1089/ars.2021.0119
State	Published - Jan 1 2023

Bibliographical note

Funding 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.

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

Keywords

APE1
Apex1
cell differentiation
DNA damage
embryonic development
oxidative stress

ASJC Scopus subject areas

Biochemistry
Physiology
Molecular Biology
Clinical Biochemistry
Cell Biology

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10.1089/ars.2021.0119

Cite this

Rios-Covian, D., Butcher, L. D., Ablack, A. L., Den Hartog, G., Matsubara, M. T., Ly, H., Oates, A. W., Xu, G., Fisch, K. M., Ahrens, E. T., Toden, S., Brown, C. C., Kim, K., Le, D., Eckmann, L., Dhar, B., Izumi, T., Ernst, P. B., & Crowe, S. E. (2023). A Novel Hypomorphic Apex1 Mouse Model Implicates Apurinic/Apyrimidinic Endonuclease 1 in Oxidative DNA Damage Repair in Gastric Epithelial Cells. Antioxidants and Redox Signaling, 38(1-3), 183-197. https://doi.org/10.1089/ars.2021.0119

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

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.",

keywords = "APE1, Apex1, cell differentiation, DNA damage, embryonic development, oxidative stress",

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

note = "Funding 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. Publisher Copyright: {\textcopyright} Copyright 2023, Mary Ann Liebert, Inc., publishers 2023.",

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doi = "10.1089/ars.2021.0119",

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Rios-Covian, D, Butcher, LD, Ablack, AL, Den Hartog, G, Matsubara, MT, Ly, H, Oates, AW, Xu, G, Fisch, KM, Ahrens, ET, Toden, S, Brown, CC, Kim, K, Le, D, Eckmann, L, Dhar, B, Izumi, T, Ernst, PB & Crowe, SE 2023, 'A Novel Hypomorphic Apex1 Mouse Model Implicates Apurinic/Apyrimidinic Endonuclease 1 in Oxidative DNA Damage Repair in Gastric Epithelial Cells', Antioxidants and Redox Signaling, vol. 38, no. 1-3, pp. 183-197. https://doi.org/10.1089/ars.2021.0119

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 - Funding 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. 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 - cell differentiation

KW - DNA damage

KW - embryonic development

KW - oxidative stress

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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