DNA repair in neural cells: basic science and clinical implications

Brooks, Philip J.

doi:10.1016/s0027-5107(02)00222-1

Cited by 94 publications

(61 citation statements)

References 133 publications

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“…(5 0 S)-cdA is a transcription blocking lesion and the accumulation of this type of lesions in actively transcribed genes has been associated with neuronal death (Brooks, 2002). This finding supports the notion that, in addition to the defect in TCR, repair of lesions in the overall genome might be affected in CS cells as well (reviewed by Licht et al, 2003).…”

Section: Discussionsupporting

confidence: 65%

The role of CSA in the response to oxidative DNA damage in human cells

et al. 2007

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Cockayne syndrome (CS) is a rare genetic disease characterized by severe growth, mental retardation and pronounced cachexia. CS is most frequently due to mutations in either of two genes, CSB and CSA. Evidence for a role of CSB protein in the repair of oxidative DNA damage has been provided recently. Here, we show that CSA is also involved in the response to oxidative stress. CS-A human primary fibroblasts and keratinocytes showed hypersensitivity to potassium bromate, a specific inducer of oxidative damage. This was associated with inefficient repair of oxidatively induced DNA lesions, namely 8-hydroxyguanine (8-OH-Gua) and (5 0 S)-8,5 0 -cyclo 2 0 -deoxyadenosine. Expression of the wild-type CSA in the CS-A cell line CS3BE significantly decreased the steady-state level of 8-OH-Gua and increased its repair rate following oxidant treatment. CS-A cell extracts showed normal 8-OH-Gua cleavage activity in an in vitro assay, whereas CS-B cell extracts were confirmed to be defective. Our data provide the first in vivo evidence that CSA protein contributes to prevent accumulation of various oxidized DNA bases and underline specific functions of CSB not shared with CSA. These findings support the hypothesis that defective repair of oxidative DNA damage is involved in the clinical features of CS patients.

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Section: Discussionsupporting

confidence: 65%

The role of CSA in the response to oxidative DNA damage in human cells

et al. 2007

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“…Further, neuropathological examinations have revealed various changes in the CNS indicative of neurodegeneration (5,18,20,25). Enhanced oxidative stress caused by xenobiotic exposure combined with CSB deficiency may result in more severe or additional developmental consequences in embryos or fetuses.…”

Section: Discussionmentioning

confidence: 99%

Cockayne Syndrome B Protects Against Methamphetamine-Enhanced Oxidative DNA Damage in Murine Fetal Brain and Postnatal Neurodevelopmental Deficits

McCallum

Wong²,

Wells³

2011

Antioxidants & Redox Signaling

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Methamphetamine (METH) increases the oxidative DNA lesion 8-oxoguanine (8-oxoG) in fetal mouse brain, and causes postnatal motor coordination deficits after in utero exposure. Like oxoguanine glycosylase 1 (OGG1), the Cockayne syndrome B (CSB) protein is involved in the repair of oxidatively damaged DNA, although its function is unclear. Here we used CSB-deficient Csb m=m knockout mice to investigate the developmental role of DNA oxidation and CSB in METH-initiated neurodevelopmental deficits. METH (40 mg=kg intraperitoneally) administration to pregnant Csb females on gestational day 17 increased 8-oxoG levels in Csb m=m fetal brains ( p < 0.05). CSB modulated 8-oxoG levels independent of OGG1 activity, as 8-oxoG incision activity in fetal nuclear extracts was identical in Csb m=m and Csb +=+ mice. This CSB effect was evident despite 7

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“…These changes appears very early in the disease process and represent an interesting target for prevention, because several works showed a protective use of antioxidants in patients and animal and cellular models [71,74]. In this context, effect of oxidative stress on DNA in neurons appears as one of the most interesting mechanisms related to neurodegeneration, because neural cells are terminally differentiated and have less effective DNA repair mechanisms that only function in those genomic regions that are transcribed [75,76]. A recent work showed that in cultured neurons the promoters of genes related to synaptic function, in contrast to other genes, have an increase in the susceptibility to accumulate oxidative stress damage, leading to a down regulation of the synaptic genes [77].…”

Section: Etiologymentioning

confidence: 99%

Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms

et al. 2006

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Alzheimer's disease (AD) is one of the main causes of dementia in the world. Increases in life expectancy in the majority of populations around the world have been associated with a higher rate of AD incidence in different countries in past and future decades [1] AD is clinically characterized by cognitive impairment; there is an initial alteration in recent AbstractIn this paper, we review experimental advances in molecular neurobiology of Alzheimer's disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PS1 and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a "synaptogenomics" approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.

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DNA repair in neural cells: basic science and clinical implications

Cited by 94 publications

References 133 publications

The role of CSA in the response to oxidative DNA damage in human cells

The role of CSA in the response to oxidative DNA damage in human cells

Cockayne Syndrome B Protects Against Methamphetamine-Enhanced Oxidative DNA Damage in Murine Fetal Brain and Postnatal Neurodevelopmental Deficits

Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms

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