Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway

Autor: Hongquan Guo, Xinfeng Liu, Juanji Li, Xiaolei Shi, Yi Xie, Pengfei Xu, Yunzi Li, Qian Liu, Rui Sun, Ye Hong, Mengna Peng, Gelin Xu
Rok vydání: 2018
Předmět:
0301 basic medicine
BRCT
BRCA1 C-terminal
GPX3
glutathione peroxidase 3
4-HNE
4-hydroxynonenol
OGD
oxygen-glucose deprivation
GCLM
glutamate-cysteine ligase regulator subunit
Iba-1
ionized calcium-binding adapter molecule-1
Clinical Biochemistry
SOD1
superoxide dismutase 1
HO-1
heme oxygenase 1
medicine.disease_cause
Biochemistry
NPCs
neural precursor cells
CaMKII
calcium/calmodulin-dependent protein kinase II
Lipid peroxidation
chemistry.chemical_compound
CA1
cornu ammonis 1
NSCs
neural stem cells
3-NT
3-nitrotyrosine
XRE
xenobiotic responsive element
skin and connective tissue diseases
lcsh:QH301-705.5
BER
base excision repair
GFP
green fluorescent protein
PSD95
postsynaptic density protein 95
chemistry.chemical_classification
lcsh:R5-920
DCX
doublecortin
ALS
amyotrophic lateral sclerosis
NRF2
nuclear factor (erythroid-derived 2)-like 2
GPX4
glutathione peroxidase 4
8-OHDG
8-hydroxy-2′-deoxyguanosine
Signal transduction
lcsh:Medicine (General)
Ischemia/Reperfusion
Research Paper
NQO1
NAD(P)H dehydrogenase (quinone 1)
DNA damage
DNA repair
Ischemia
I/R
ischemia/reperfusion
CNS
central nervous system
GCLC
glutamate-cysteine ligase catalytic
NRF2
03 medical and health sciences
ROS
reactive oxygen species
NER
nucleotide excision repair
medicine
MCAO
middle cerebral artery occlusion
SOD2
superoxide dismutase 2
Reactive oxygen species
AD
Alzheimer disease
Organic Chemistry
GFAP
glial fibrillary acidic protein
BRCA1
medicine.disease
ARE
antioxidative response element
030104 developmental biology
lcsh:Biology (General)
chemistry
NHEJ
non-homologous end joining
Oxidative stress
BRCA1
breast cancer susceptibility protein 1
DSBs
double strand breaks
Cancer research
HR
homologous recombination
Reperfusion injury
Zdroj: Redox Biology
Redox Biology, Vol 18, Iss, Pp 158-172 (2018)
ISSN: 2213-2317
DOI: 10.1016/j.redox.2018.06.012
Popis: 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.
Highlights • 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.
Databáze: OpenAIRE
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