Nuclear depletion of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is an indicator of energy disruption in neurons
Open accessAbstract
Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is a multifunctional protein critical for cellular survival. Its involvement in adaptive survival responses includes key roles in redox sensing, transcriptional regulation, and repair of DNA damage via the base excision repair (BER) pathway. Ape1 is abundant in most cell types and central in integrating the first BER step catalyzed by different DNA glycosylases. BER is the main process for removal of oxidative DNA lesions in postmitotic brain cells, and after ischemic brain injury preservation of Ape1 coincides with neuronal survival, while its loss has been associated with neuronal death. Here, we report that in cultured primary neurons, diminution of cellular ATP by either oligomycin or H(2)O(2) is accompanied by depletion of nuclear Ape1, while other BER proteins are unaffected and retain their nuclear localization under these conditions. Importantly, while H(2)O(2) induces γH2AX phosphorylation, indicative of chromatin rearrangements in response to DNA damage, oligomycin does not. Furthermore, despite comparable diminution of ATP content, H(2)O(2) and oligomycin differentially affect critical parameters of mitochondrial respiration that ultimately determine cellular ATP content. Taken together, our findings demonstrate that in neurons, nuclear compartmentalization of Ape1 depends on ATP and loss of nuclear Ape1 reflects disruption of neuronal energy homeostasis. Energy crisis is a hallmark of stroke and other ischemic/hypoxic brain injuries. In vivo studies have shown that Ape1 deficit precedes neuronal loss in injured brain regions. Thus, our findings bring to light the possibility that energy failure-induced Ape1 depletion triggers neuronal death in ischemic brain injuries.
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Hydrogen peroxide treatment of primary neuron cells triggers γ-H2AX, indicating double-strand break generation and ATM activation.
“Hydrogen peroxide treatment in primary neuron cells triggers γ-H2AX, indicating DSB generation and ATM activation [69].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [69]
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- Authors
- Singh, S., & Englander, E. W.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Englander, Ella W.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 53
- Issue
- 9
- Pages
- 1782-1790
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC3487712
- OpenAlex
- W1989111051
- Cited by
- 21
- References
- 48
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 2
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (NS039449, ES014613)
- Shriners Hospitals for Children (SHG8670)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- APE1/Ref-1, apurinic/apyrimidinic endonuclease 1, ATP depletion, base excision repair, oxidative DNA damage, mitochondrial respiration, oligomycin, hydrogen peroxide, ischemic brain injury, stroke, neuronal cell death, γH2AX, redox sensing, DNA glycosylase
- MeSH terms
- DNA Ligase ATP, Poly-ADP-Ribose Binding Proteins, X-ray Repair Cross Complementing Protein 1, Adenosine Triphosphate, Animals, Cell Nucleus, Cells, Cultured, DNA Damage, DNA Repair, DNA-Binding Proteins, Energy Metabolism, Hydrogen Peroxide, Mice, Inbred C57BL, Mitochondria, Neurons, Oligomycins, Oxygen Consumption, DNA Ligases, Oxidants, Protein Transport, Mitochondrial Proton-Translocating ATPases, Xenopus Proteins, DNA-(Apurinic or Apyrimidinic Site) Lyase, Mice
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