Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia

Mukhopadhyay, Sudit S.; Leung, Kathryn; Hicks, M. John; Hastings, P. J.; Youssoufian, Hagop; Plon, Sharon E.

doi:10.1083/jcb.200607061

Cited by 121 publications

(108 citation statements)

References 55 publications

(82 reference statements)

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“…Nonn et al (35) overexpressed PRx-3 in WEHI7.2 thymoma cells and found that this overexpression led to decreased levels of cellular H 2 O 2 and that it protected these cells from H 2 O 2 -induced apoptosis. Similarly, Mukhopadhyay et al (34) studied PRx-3 in different cell lines in patients with Fanconi's Anemia (FA). They found that these cells, among other things, had a sevenfold decrease in PRx-3 expression compared with WT control cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of reactive oxygen species by p53: implications for nitric oxide-mediated apoptosis

Popowich

Vavra

Walsh

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Section: Discussionmentioning

confidence: 99%

Regulation of reactive oxygen species by p53: implications for nitric oxide-mediated apoptosis

Popowich

Vavra

Walsh

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Both Prx3 and Prx6 are inactivated after over-oxidation of the catalytic cysteine residue and are the slowest Prx isoforms to be reductively reactivated (34,35). In addition, Prx3 has been shown to be cleaved and inactivated by a calpain-like cysteine protease after oxidant treatment in lymphoblasts (33). Importantly, Prxs are more Several studies have shown that overexpression of Prxs can protect neurons from various forms of toxic stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…Prx activity is regulated by post-translational modifications including oxidation (sulfinylation/sulfonylation), phosphorylation, and proteolytic cleavage (11,32,33). Both control and A␤-treated PC12 cells expressed increased levels of both high and low molecular weight acidic Prx3 and Prx6 isoforms as compared with the A␤-resistant line (Fig.…”

Section: Discussionmentioning

confidence: 99%

Increase in Expression Levels and Resistance to Sulfhydryl Oxidation of Peroxiredoxin Isoforms in Amyloid β-Resistant Nerve Cells

Cumming

Dargusch

Fischer

et al. 2007

Journal of Biological Chemistry

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Peroxiredoxins (Prxs) are a ubiquitously expressed family of thiol peroxidases that reduce hydrogen peroxide, peroxynitrite, and hydroperoxides using a highly conserved cysteine. There is substantial evidence that oxidative stress elicited by amyloid ␤ (A␤) accumulation is a causative factor in the pathogenesis of Alzheimer disease (AD). Here we show that A␤-resistant PC12 cell lines exhibit increased expression of multiple Prx isoforms with reduced cysteine oxidation. A␤-resistant PC12 cells also display higher levels of thioredoxin and thioredoxin reductase, two enzymes critical for maintaining Prx activity. PC12 cells and rat primary hippocampal neurons transfected with wild type Prx1 exhibit increased A␤ resistance, whereas mutant Prx1, lacking a catalytic cysteine, confers no protection. Using an antibody that specifically recognizes sulfinylated and sulfonylated Prxs, it is demonstrated that primary rat cortical nerve cells exposed to A␤ display a time-dependent increase in cysteine oxidation of the catalytic site of Prxs that can be blocked by the addition of the thiol-antioxidant N-acetylcysteine. In support of previous findings, expression of Prx1 is higher in post-mortem human AD cortex tissues than in age-matched controls. In addition, two-dimensional gel electrophoresis and mass spectrometry analysis revealed that Prx2 exists in a more oxidized state in AD brains than in control brains. These findings suggest that increased Prx expression and resistance to sulfhydryl oxidation in A␤-resistant nerve cells is a compensatory response to the oxidative stress initiated by chronic pro-oxidant A␤ exposure.A wide body of evidence has implicated oxidative damage in the pathogenesis of Alzheimer disease (AD) 3 (1). AD, the most common form of dementia in the elderly, is characterized by extracellular neuritic plaques containing the amyloid beta (A␤) peptide 1-42 and intracellular neurofibrillary tangles composed mainly of hyperphosphorylated tau protein. Several studies have shown that A␤ exposure increases levels of hydrogen peroxide (H 2 O 2 ), lipid peroxidation, and protein oxidation (carbonylation) in cultured neurons (2-4). Increased oxidative damage to lipids, DNA, and proteins is also found in AD brains (1). Because the exogenous addition of antioxidants or catalase protects cultured nerve cells from A␤ toxicity (2, 5), it is likely that free radicals play a critical role in A␤ cytotoxicity. Therefore, cellular mechanisms that either prevent or remove reactive oxygen species (ROS) or reverse damage to cellular components after ROS exposure may play a key role in blocking A␤ toxicity. Although widespread nerve cell death occurs in the brains of AD patients, some neurons are spared, indicating that certain populations of cells survive the same conditions that kill neighboring cells. Early studies had shown that low concentrations of A␤ can actually rescue neurons from stressful conditions (6). However, the mechanism of A␤ resistance is only poorly understood. Previously, a series of A␤-resistant clones w...

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“…39 In addition, FANCG interacts with cytochrome P450 2E1, which is associated with the production of reactive oxygen intermediates, and the mitochondrial antioxidant enzyme peroxiredoxin-3. 40,41 Finally, we recently reported that FANCD2 associated with FOXO3a, a master regulator of oxidative stress response. 42 Although these observations point to the involvement of FA proteins in oxidative stress response, the molecular mechanism by which FA proteins function to modulate oxidative stress response has not been defined.…”

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confidence: 99%

The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters

Du¹,

Rani²,

Sipple³

et al. 2012

Blood

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Oxidative stress has been implicated in the pathogenesis of many human diseases including Fanconi anemia (FA), a genetic disorder associated with BM failure and cancer. Here we show that major antioxidant defense genes are downregulated in FA patients, and that gene down-regulation is selectively associated with increased oxidative DNA damage in the promoters of the antioxidant defense genes. Assessment of promoter activity and DNA damage repair kinetics shows that increased initial damage, rather than a reduced repair rate, contributes to the augmented oxidative DNA damage. Mechanistically, FA proteins act in concert with the chromatin-remodeling factor BRG1 to protect the promoters of antioxidant defense genes from oxidative damage. Specifically, BRG1 binds to the promoters of the antioxidant defense genes at steady state. On challenge with oxidative stress, FA proteins are recruited to promoter DNA, which correlates with significant increase in the binding of BRG1 within promoter regions. In addition, oxidative stress-induced FANCD2 ubiquitination is required for the formation of a FA-BRG1-promoter complex. Taken IntroductionOxidative DNA damage is a major source of genomic instability. The most prevalent lesion generated by intracellular reactive oxygen species (ROS) is 8-hydroxydeoxy guanosine (8-oxodG). This lesion causes G:C to T:A transversion mutations and is considered highly mutagenic. 1 There is compelling evidence that 8-oxodG levels are elevated in various human cancers. 2,3 and in animal models of tumors. 4,5 ROS-induced DNA damage can also result in single-or double-strand breaks, which are lethal to the cell if not repaired. 6,7 Although there is a great deal known about DNA repair, we have a limited understanding of the involvement of specific repair pathways in protecting cellular DNA from oxidative damaging agents, particularly ROS. The major pathways involved in DNA repair include repair of single-base damage by the base excision repair (BER) pathway, repair of lesions that distort the DNA helix by the nucleotide excision repair (NER) pathway, and repair of DNA double-strand breaks by homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways. [8][9][10] Although the specificity and efficiency of each of these DNA repair pathways is critical to ensure genome stability, the complexity of ROS-induced oxidative DNA damage may require coordination between these different pathways.Cells have developed a battery of defense mechanisms to protect against damage induced by oxidative stress. Antioxidant defense enzymes, including superoxide dismutases, catalase, glutathione peroxidases and peroxiredoxins, as well as nonenzymatic scavengers such as glutathione and carotenoids can directly eliminate ROS. 11 Other cellular enzymes can repair DNA damage induced by ROS. 12 Moreover, ROS can influence the selective activation of oxidative stress-responsive transcription factors.Indeed, the first line of defense against oxidative damage is the induction of stress-response genes, many of whi...

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Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia

Cited by 121 publications

References 55 publications

Regulation of reactive oxygen species by p53: implications for nitric oxide-mediated apoptosis

Regulation of reactive oxygen species by p53: implications for nitric oxide-mediated apoptosis

Increase in Expression Levels and Resistance to Sulfhydryl Oxidation of Peroxiredoxin Isoforms in Amyloid β-Resistant Nerve Cells

The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters

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