Mechanistic Insight into DNA Damage and Repair in Ischemic Stroke: Exploiting the Base Excision Repair Pathway as a Model of Neuroprotection

Li, Peiying; Hu, Xiaoming; Gan, Yu; Gao, Yanqin; Li, Weimin; Chen, Jun

doi:10.1089/ars.2010.3451

Cited by 57 publications

(53 citation statements)

References 89 publications

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“…To analyze whether ischemia induces genomic DNA fragmentation in neurons, that might be counteracted by endogenous DNA-repair mechanisms 7 , the degree of DNA breaks was determined by the Comet assay (Fig. 2a-c).…”

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confidence: 99%

The age and genomic integrity of neurons after cortical stroke in humans

et al. 2014

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The age and genomic integrity of neurons after cortical stroke in humans

et al. 2014

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“…Activation of Atm could phosphorylate various protein targets to activate cell cycle check-points and repair the DNA damage [15]. If the damage cannot be repaired, Atm directs the cell to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…It serves as a sensor to bind DNA strand breaks, especially single-strand breaks and activate downstream signaling events. Evidence suggest that post-ischemic activation of Parp1 occurs in practically every cell type of the affected brain region and significantly contributes to the extent of final damage [15]. Translocation of apoptosis inducing factor (AIF) from mitochondria to the nucleus is a key step in the Parp1 cell death process [17][18].…”

Section: Discussionmentioning

confidence: 99%

Stem Cell Treatment after Ischemic Stroke Alters the Expression of DNA Damage Signaling Molecules

Chelluboina

Nalamolu

Klopfenstein

et al. 2016

JSRT

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Accumulating evidence suggests that oxidative DNA damage plays a critical role in cell death associated with ischemic stroke. Endogenous oxidative DNA damage can be detected in the ischemic brain during the stages that precedes the manifestation of cell death and is believed to trigger cell death via various intracellular signaling pathways. Inhibiting the signaling associated with DNA damage induction or facilitating the signaling associated with the DNA repair process can be neuroprotective against brain injury after ischemic stroke. Recent reports demonstrated that human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) prevented the upregulation of apoptotic signaling pathway molecules and thereby attenuated the extent of apoptosis after focal cerebral ischemia as well as improved the neurological recovery. Therefore, we hypothesized that HUCB-MSCs treatment after focal cerebral ischemia prevents the overexpression of molecules associated with DNA damage induction as well as augments the expression of molecules associated with DNA repair process. In order to test our hypothesis, we administered HUCB-MSCs (0.25x10 6 cells/animal) intravenously via tail vein to male Sprague-Dawley rats that were subjected to a two-hour middle cerebral artery occlusion followed by one-day reperfusion. Ischemic brain tissues obtained from various groups seven days' post reperfusion were subjected to DNA damage signaling pathway PCR microarray. Our results demonstrated the induction of both DNA damage inducing and repair genes after focal cerebral ischemia and reperfusion. HUCB-MSCs treatment downregulated the DNA damage inducing genes and upregulated the DNA repair genes without disturbing the endogenous defense mechanisms.

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“…These data suggest that mature oligodendrocytes and neurons represent vulnerable cell populations in the white matter and gray matter of APE1-deficient mice, respectively. DNA damage may activate the protein poly(ADP ribose) polymerase 1 (PARP1), which catalyzes the formation of poly(ADP ribose) polymers (PAR) using NAD + as substrate, thus eliciting intracellular NAD + and ATP depletion (21). PAR is a death signal in neurons after ischemia and reperfusion (23).…”

Section: Ape1 Deficiency Enhances Mitochondrial Translocation Of Puma Inmentioning

confidence: 99%

APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury

Stetler

Gao

Leak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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A major hallmark of oxidative DNA damage after stroke is the induction of apurinic/apyrimidinic (AP) sites and strand breaks. To mitigate cell loss after oxidative DNA damage, ischemic cells rapidly engage the base excision-repair proteins, such as the AP site-repairing enzyme AP endonuclease-1 (APE1), also named redox effector factor-1 (Ref-1). Although forced overexpression of APE1 is known to protect against oxidative stress-induced neurodegeneration, there is no concrete evidence demonstrating a role for endogenous APE1 in the long-term recovery of gray and white matter following ischemic injury. To address this gap, we generated, to our knowledge, the first APE1 conditional knockout (cKO) mouse line under control of tamoxifendependent Cre recombinase. Using a well-established model of transient focal cerebral ischemia (tFCI), we show that induced deletion of APE1 dramatically enlarged infarct volume and impaired the recovery of sensorimotor and cognitive deficits. APE1 cKO markedly increased postischemic neuronal and oligodendrocyte degeneration, demonstrating that endogenous APE1 preserves both gray and white matter after tFCI. Because white matter repair is instrumental in behavioral recovery after stroke, we also examined the impact of APE1 cKO on demyelination and axonal conduction and discovered that APE1 cKO aggravated myelin loss and impaired neuronal communication following tFCI. Furthermore, APE1 cKO increased AP sites and activated the prodeath signaling proteins, PUMA and PARP1, after tFCI in topographically distinct manners. Our findings provide evidence that endogenous APE1 protects against ischemic infarction in both gray and white matter and facilitates the functional recovery of the central nervous system after mild stroke injury.ischemia | neurodegeneration | base excision repair | oxidative DNA damage | white matter injury F ocal ischemic injury in the brain is both a spatial and temporal event, wherein the infarct zone expands gradually over several days (1, 2). However, if the stroke insult is moderate, the periinfarct regions may recover over time. The spontaneous recovery of periinfarct structures and neurological functions creates an opportunity to research the molecular mechanisms underlying endogenous neuroprotection and neural repair, which may accelerate the discovery of rational therapeutic targets for stroke treatment.Oxidative DNA damage (ODD) is an early event following cerebral ischemia and reperfusion (3, 4), and reversal of ODD in penumbral regions is associated with eventual recovery from such insult (4, 5). Repair of ODD by the base excision-repair (BER) pathway targets oxidized DNA base lesions through a multistep process. First, base lesions are recognized by DNA glycosylases, which cleave the damaged bases and form temporary apurinic/ apyrimidinic (AP) sites. The AP sites are then recognized by the critical BER enzyme, AP endonuclease-1/redox effector factor-1 (referred to here as APE1) (6, 7). APE1 repairs AP sites by cleaving the phosphodiester backbone 5′ to the AP ...

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Mechanistic Insight into DNA Damage and Repair in Ischemic Stroke: Exploiting the Base Excision Repair Pathway as a Model of Neuroprotection

Cited by 57 publications

References 89 publications

The age and genomic integrity of neurons after cortical stroke in humans

The age and genomic integrity of neurons after cortical stroke in humans

Stem Cell Treatment after Ischemic Stroke Alters the Expression of DNA Damage Signaling Molecules

APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury

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