Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway
Pengfei Xu,
Qian Liu,
Yi Xie,
Xiaolei Shi,
Yunzi Li,
Mengna Peng,
Hongquan Guo,
Rui Sun,
Juanji Li,
Ye Hong,
Xinfeng Liu,
Gelin Xu
Affiliations
Pengfei Xu
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China
Qian Liu
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China
Yi Xie
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China
Xiaolei Shi
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
Yunzi Li
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China
Mengna Peng
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China
Hongquan Guo
Department of Neurology, Jinling Hospital, Southern Medical University, Nanjing, Jiangsu 210002, China
Rui Sun
Department of Neurology, Jinling Clinical College of Nanjing Medical University, Nanjing, Jiangsu 210002, China
Juanji Li
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China
Ye Hong
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China
Xinfeng Liu
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China; Correspondence to: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu 210002, China
Gelin Xu
Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China; Correspondence to: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu 210002, China
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. Keywords: BRCA1, Ischemia/Reperfusion, Oxidative stress, DNA damage, NRF2
