Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway
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Cellular oxidative stress plays a vital role in the pathological process of neural damage in cerebral ischemia/reperfusion (I/R). The breast cancer susceptibility protein 1 (BRCA1), a tumor suppressor, can modulate cellular antioxidant response and DNA repair. Yet the role of BRCA1 in cerebral I/R injury has not been explored. In this study, we observed that BRCA1 was mainly expressed in neurons and was up-regulated in response to I/R insult. Overexpression of BRCA1 attenuated reactive oxygen species production and lipid peroxidation. Enhanced BRCA1 expression promoted DNA double strand break repair through non-homologous end joining pathway. These effects consequently led to neuronal cell survival and neurological recovery. Mechanically, BRCA1 can interact with the nuclear factor (erythroid-derived 2)-like 2 (NRF2) through BRCA1 C-terminal (BRCT) domain. The cross-talk between BRCT and NRF2 activated the NRF2/Antioxidant Response Element signaling pathway and thus protected injured neurons during cerebral I/R. In conclusion, enhanced BRCA1 after cerebral I/R injury may attenuate or prevent neural damage from I/R via NRF2-mediated antioxidant pathway. The finding may provide a potential therapeutic target against ischemic stroke.
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DPP3 contains a 480ETGE483 motif and interacts with Keap1 by binding to its Kelch domain, thereby inhibiting the Keap1-Nrf2 interaction.
“DPP3, which contains a 480ETGE483 motif, interacts with Keap1 by binding to its Kelch domain, thereby inhibiting the Keap1-Nrf2 interaction [83].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [83]
The BRCT domain of BRCA1 interacts with the ETGE motif in the Neh2 domain of Nrf2, which inhibits Keap1-mediated ubiquitination and increases the response to oxidative stress.
“The BRCT domain of BRCA1 interacts with the ETGE motif in the Neh2 domain of Nrf2, which inhibits Keap1-mediated ubiquitination and increases the response to oxidative stress [82,83].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [83]
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Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
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- Authors
- Xu, P., Liu, Q., Xie, Y., Shi, X., Li, Y., Peng, M., Guo, H., Sun, R., Li, J., Hong, Y., Liu, X., & Xu, G.
- Affiliations
- Nanjing General Hospital of Nanjing Military Command (CN)
- Wannan Medical College (CN)
- Nanjing Medical University (CN)
- Corresponding author
- Liu, Xinfeng
- Xu, Gelin
- ORCID
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 18
- Pages
- 158-172
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC6068089
- OpenAlex
- W2832629985
- Cited by
- 100
- References
- 48
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 19 · 2023: 13 · 2022: 15 · 2021: 16 · 2020: 13 · 2019: 8
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-01-01)
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81571143, 81701230, 81701180)
- Natural Science Foundation of Jiangsu Province (BK20160607)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- BRCA1, cerebral ischemia-reperfusion injury, Nrf2, oxidative stress, reactive oxygen species, lipid peroxidation, DNA double-strand break repair, non-homologous end joining, BRCT domain, neuronal survival, ischemic stroke, neuroprotection
- MeSH terms
- Animals, Brain Ischemia, Male, Mice, Inbred C57BL, Neurons, Signal Transduction, Reperfusion Injury, Apoptosis, Oxidative Stress, BRCA1 Protein, Tumor Suppressor Proteins, NF-E2-Related Factor 2, Antioxidant Response Elements
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