Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway.
Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway.
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乳腺癌易感蛋白1（BRCA1）通过NRF2介导的抗氧化途径拯救神经元免受脑缺血/再灌注损伤
DOI：
10.1016/j.redox.2018.06.012
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发表时间：
2018-09
期刊：
影响因子：
11.4
通讯作者：
Xu G
中科院分区：
文献类型：
--
作者：
Xu P;Liu Q;Xie Y;Shi X;Li Y;Peng M;Guo H;Sun R;Li J;Hong Y;Liu X;Xu G
细胞氧化应激在脑缺血/再灌注(I/R)神经损伤的病理过程中起重要作用。乳腺癌易感蛋白1(BRCA1)是一种肿瘤抑制因子，可以调节细胞的抗氧化反应和DNA修复。然而，BRCA1在脑I/R损伤中的作用尚不清楚。在本研究中，我们观察到BRCA1主要在神经元中表达，并在I/R损伤后上调。BRCA1的过表达降低了活性氧的产生和脂质过氧化。BRCA1表达增强通过非同源末端连接途径促进DNA双链断裂修复。这些效应最终导致神经细胞存活和神经功能恢复。从机制上讲，BRCA1可以通过BRCT结构域与核因子(红系衍生的2)样2(NRF2)相互作用。BRCT和NRF2之间的相互作用激活了NRF2/抗氧化剂反应元件信号通路，从而保护了脑I/R损伤的神经元。结论：脑I/R损伤后增强的BRCA1可能通过NRF2介导的抗氧化途径减轻或防止脑I/R所致的神经损伤。这一发现可能为治疗缺血性中风提供一个潜在的治疗靶点。脑缺血再灌注损伤后BRCA1表达上调。上调BRCA1可减轻脑缺血/再灌注损伤和认知功能障碍。BRCA1通过BRCT结构域与NRF2结合，触发NRF2介导的抗氧化反应。BRCA1通过非同源末端连接途径促进双链断裂修复。
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. BRCA1 was up-regulated after cerebral ischemia/reperfusion injury. Up-regulated BRCA1 attenuated cerebral ischemia/reperfusion injury and cognitive impairment. BRCA1 binding to NRF2 via BRCT domain triggered NRF2-mediated antioxidant response. BRCA1 promoted DSBs repair via non-homologous end joining-pathway.
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DNA 损伤及其与神经变性的联系。
影响因子：
16.2
作者：
Madabhushi R;Pan L;Tsai LH
通讯作者：
Tsai LH
DOI：
10.1093/toxsci/kfr089
发表时间：
2011-07
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
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作者：
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DOI：
10.1073/pnas.1707151114
发表时间：
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影响因子：
11.1
作者：
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影响因子：
4.2
作者：
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影响因子：
11.2
作者：
Bae, I;Fan, S;Rosen, EM
通讯作者：
Rosen, EM