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Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway.
Redox Biol. 2018 09; 18:158-172.RB

Abstract

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.

Authors+Show Affiliations

Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada; Department of Neurology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, China.Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.Department of Neurology, Jinling Hospital, Southern Medical University, Nanjing, Jiangsu 210002, China.Department of Neurology, Jinling Clinical College of Nanjing Medical University, Nanjing, Jiangsu 210002, China.Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China. Electronic address: xfliu2@vip.163.com.Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China. Electronic address: gelinxu@nju.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30014904

Citation

Xu, Pengfei, et al. "Breast Cancer Susceptibility Protein 1 (BRCA1) Rescues Neurons From Cerebral Ischemia/reperfusion Injury Through NRF2-mediated Antioxidant Pathway." Redox Biology, vol. 18, 2018, pp. 158-172.
Xu P, Liu Q, Xie Y, et al. Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway. Redox Biol. 2018;18:158-172.
Xu, P., Liu, Q., Xie, Y., Shi, X., Li, Y., Peng, M., Guo, H., Sun, R., Li, J., Hong, Y., Liu, X., & Xu, G. (2018). Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway. Redox Biology, 18, 158-172. https://doi.org/10.1016/j.redox.2018.06.012
Xu P, et al. Breast Cancer Susceptibility Protein 1 (BRCA1) Rescues Neurons From Cerebral Ischemia/reperfusion Injury Through NRF2-mediated Antioxidant Pathway. Redox Biol. 2018;18:158-172. PubMed PMID: 30014904.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway. AU - Xu,Pengfei, AU - Liu,Qian, AU - Xie,Yi, AU - Shi,Xiaolei, AU - Li,Yunzi, AU - Peng,Mengna, AU - Guo,Hongquan, AU - Sun,Rui, AU - Li,Juanji, AU - Hong,Ye, AU - Liu,Xinfeng, AU - Xu,Gelin, Y1 - 2018/07/07/ PY - 2018/06/02/received PY - 2018/06/27/revised PY - 2018/06/30/accepted PY - 2018/7/18/pubmed PY - 2018/11/6/medline PY - 2018/7/18/entrez KW - BRCA1 KW - DNA damage KW - Ischemia/Reperfusion KW - NRF2 KW - Oxidative stress SP - 158 EP - 172 JF - Redox biology JO - Redox Biol VL - 18 N2 - 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. SN - 2213-2317 UR - https://www.unboundmedicine.com/medline/citation/30014904/Breast_cancer_susceptibility_protein_1__BRCA1__rescues_neurons_from_cerebral_ischemia/reperfusion_injury_through_NRF2_mediated_antioxidant_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2317(18)30473-7 DB - PRIME DP - Unbound Medicine ER -