Oxidative damage induced genotoxic effects in human fibroblasts from Xeroderma Pigmentosum group A patients

Low, Grace Kah Mun; Fok, Edwin Dan Zhihao; Ting, Aloysius Poh Leong; Hande, M. Prakash

doi:10.1016/j.biocel.2008.05.009

Cited by 24 publications

(24 citation statements)

References 49 publications

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“…The latter study also demonstrated that XPA-deficient human brain tissue and liver tissue of Xpa mice contained higher levels of G [8-5 m]T lesions than the corresponding normal controls (93). In addition, an increased susceptibility to oxidative stress-induced genotoxicity was detected in primary fibroblasts from an XP-A patient after treatment with sodium arsenite and H 2 O 2 (53). A recent report shows that fibroblasts derived from XP-C and XP-A patients are deficient in the repair of both bulky photoproducts and oxidative DNA damage.…”

Section: Fig 3 Picture Of a Patient With Cockayne Syndrome (Cs)mentioning

confidence: 60%

Oxidative DNA Damage and Nucleotide Excision Repair

Melis

Steeg

Luijten

2013

Antioxidants & Redox Signaling

188

150

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Significance: Oxidative DNA damage is repaired by multiple, overlapping DNA repair pathways. Accumulating evidence supports the hypothesis that nucleotide excision repair (NER), besides base excision repair (BER), is also involved in neutralizing oxidative DNA damage. Recent Advances: NER includes two distinct sub-pathways: transcription-coupled NER (TC-NER) and global genome repair (GG-NER). The CSA and CSB proteins initiate the onset of TC-NER. Recent findings show that not only CSB, but also CSA is involved in the repair of oxidative DNA lesions, in the nucleus as well as in mitochondria. The XPG protein is also of importance for the removal of oxidative DNA lesions, as it may enhance the initial step of BER. Substantial evidence exists that support a role for XPC in NER and BER. XPC deficiency not only results in decreased repair of oxidative lesions, but has also been linked to disturbed redox homeostasis. Critical Issues: The role of NER proteins in the regulation of the cellular response to oxidative (mitochondrial and nuclear) DNA damage may be the underlying mechanism of the pathology of accelerated aging in Cockayne syndrome patients, a driving force for internal cancer development in XP-A and XP-C patients, and a contributor to the mixed exhibited phenotypes of XP-G patients. Future Directions: Accumulating evidence indicates that DNA repair factors can be involved in multiple DNA repair pathways. However, the distinct detailed mechanism and consequences of these additional functions remain to be elucidated and can possibly shine a light on clinically related issues.

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Section: Fig 3 Picture Of a Patient With Cockayne Syndrome (Cs)mentioning

confidence: 60%

Oxidative DNA Damage and Nucleotide Excision Repair

Melis

Steeg

Luijten

2013

Antioxidants & Redox Signaling

188

150

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“…Comet Assay-The extent of single and double strand breaks after 4 days of iron treatment was measured using the comet assay procedure described by Low et al (24). Harvested cells were trypsinized, resuspended in Hanks' balanced salt solution (Sigma), mixed with low melting point agarose (Trevigen, Gaithersburg, MD), and spread on Comet slides (Trevigen).…”

Section: Generation Of Plasmids and Stablementioning

confidence: 99%

Enhanced Autophagy from Chronic Toxicity of Iron and Mutant A53T α-Synuclein

Chew

Ang

Tai

et al. 2011

Journal of Biological Chemistry

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Parkinson disease (PD), a prevalent neurodegenerative motor disorder, is characterized by the rather selective loss of dopaminergic neurons and the presence of ␣-synuclein-enriched Lewy body inclusions in the substantia nigra of the midbrain. Although the etiology of PD remains incompletely understood, emerging evidence suggests that dysregulated iron homeostasis may be involved. Notably, nigral dopaminergic neurons are enriched in iron, the uptake of which is facilitated by the divalent metal ion transporter DMT1. To clarify the role of iron in PD, we generated SH-SY5Y cells stably expressing DMT1 either singly or in combination with wild type or mutant ␣-synuclein. We found that DMT1 overexpression dramatically enhances Fe 2؉ uptake, which concomitantly promotes cell death. This Fe 2؉ -mediated toxicity is aggravated by the presence of mutant ␣-synuclein expression, resulting in increased oxidative stress and DNA damage. Curiously, Fe 2؉ -mediated cell death does not appear to involve apoptosis. Instead, the phenomenon seems to occur as a result of excessive autophagic activity. Accordingly, pharmacological inhibition of autophagy reverses cell death mediated by Fe 2؉ overloading. Taken together, our results suggest a role for iron in PD pathogenesis and provide a mechanism underlying Fe 2؉ -mediated cell death.Parkinson disease (PD) 3 is the most common motor neurodegenerative disorder, affecting 1-2% of the population over the age of 65. Pathologically, it is characterized by selective dopaminergic neuron loss and the presence of Lewy bodies immunoreactive for ␣-synuclein in the substantia nigra pars compacta. To date, the leading causes for the sporadic form of the disease remain unclear, although there is accumulating evidence implicating oxidative stress (1), including the finding that PD brains have increased levels of oxidative damage to DNA, proteins, and lipids (2-4). One potential player contributing to increased oxidative stress is iron, which can convert hydrogen peroxide to highly reactive hydroxyl radicals via the Fenton reaction. Indeed, increased deposition of iron was found in microglia, astrocytes, oligodendrocytes, and dopaminergic neurons of the substantia nigra pars compacta of post-mortem PD brains (5, 6). The total iron content was found to be significantly higher in the substantia nigra pars compacta of PD patients together with a corresponding increase in divalent metal transporter-1 (DMT1) transcripts in the same region (7). This suggests a close association among DMT1 expression, iron overload, and PD.Mutations in a number of genes have also been implicated in the pathogenesis of PD (8) of which the first to be discovered was ␣-synuclein. Besides the A53T, A30P, and E46K missense mutations (9 -11), duplication (12, 13) and triplication (14) of the ␣-synuclein gene have also been linked to familial forms of PD. It has been suggested that the tendency of ␣-synuclein to undergo misfolding and aggregation may underlie its involvement in Lewy body formation and hence PD (15). Given that i...

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“…Because PAF is a potent trigger for skin inflammation, including the production of tumor necrosis factor-␣ (TNF-␣) associated with photosensitivity (36 -39), and there is evidence that XPA-deficient cells have decreased antioxidant defenses (11)(12)(13)(14), we hypothesized that the PAF system could be involved in the photosensitivity associated with XPA deficiency. In the present study, we investigated the role of the PAF system in the photosensitivity of XPA using XPA-deficient cells and mice.…”

mentioning

confidence: 99%

Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity

Yao

Harrison

Al-Hassani

et al. 2012

Journal of Biological Chemistry

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Background: Deficiency of the nucleotide excision repair protein xeroderma pigmentosum type A (XPA) is characterized by photosensitivity. Results: XPA-deficient cells and mice generate increased platelet-activating factor (PAF), oxidized glycerophosphocholines, and skin inflammation following ultraviolet B radiation with the skin inflammation blocked by PAF antagonists. Conclusion: PAF-R signaling mediates photosensitivity seen in XPA deficiency. Significance: These studies provide important insights into the mechanisms of photosensitivity.

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Oxidative damage induced genotoxic effects in human fibroblasts from Xeroderma Pigmentosum group A patients

Cited by 24 publications

References 49 publications

Oxidative DNA Damage and Nucleotide Excision Repair

Oxidative DNA Damage and Nucleotide Excision Repair

Enhanced Autophagy from Chronic Toxicity of Iron and Mutant A53T α-Synuclein

Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity

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