Nuclear ferritin‐mediated protection of corneal epithelial cells from oxidative damage to DNA

Cai, Cindy X.; Ching, Anna; Lagace, Christopher J.; Linsenmayer, Thomas F.

doi:10.1002/dvdy.21494

Cited by 33 publications

(29 citation statements)

References 38 publications

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“…ROS toxicity and its involvement in different human pathologies underline the need to identify new pathways and proteins that can mitigate the adverse effects of ROS accumulation (16,(33)(34)(35)(36)(37). It is surprising that, despite the widely assumed involvement of ROS in DNA damage in plants, no transcriptional DDR has been observed in various genome-wide transcript profiling studies that directly monitored ROS-or abiotic stress-mediated responses in Arabidopsis (38, 39).…”

Section: Resultsmentioning

confidence: 99%

Extranuclear protection of chromosomal DNA from oxidative stress

Vanderauwera

Suzuki

Miller

et al. 2011

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

197

138

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Eukaryotic organisms evolved under aerobic conditions subjecting nuclear DNA to damage provoked by reactive oxygen species (ROS). Although ROS are thought to be a major cause of DNA damage, little is known about the molecular mechanisms protecting nuclear DNA from oxidative stress. Here we show that protection of nuclear DNA in plants requires a coordinated function of ROS-scavenging pathways residing in the cytosol and peroxisomes, demonstrating that nuclear ROS scavengers such as peroxiredoxin and glutathione are insufficient to safeguard DNA integrity. Both catalase (CAT2) and cytosolic ascorbate peroxidase (APX1) play a key role in protecting the plant genome against photorespiratory-dependent H 2 O 2 -induced DNA damage. In apx1/ cat2 double-mutant plants, a DNA damage response is activated, suppressing growth via a WEE1 kinase-dependent cell-cycle checkpoint. This response is correlated with enhanced tolerance to oxidative stress, DNA stress-causing agents, and inhibited programmed cell death.Arabidopsis | stress tolerance | hydrogen peroxide R eactive oxygen species (ROS) are toxic molecules continuously produced in cells during aerobic metabolism. In plants ROS are produced mainly in peroxisomes during photorespiration, in chloroplasts during photosynthesis, and in mitochondria during respiration (1, 2). Unless detoxified by specialized enzymes and low molecular antioxidants, ROS can lead to protein, lipid, and DNA oxidation and to cell death (1, 2). Plants contain a large network of genes encoding different pathways involved in ROS scavenging and production, with a key role in managing the overall steady-state level of ROS in cells (2). Similar to genotoxic agents or ionizing radiation, ROS-derived DNA oxidation leads to altered bases and damaged sugar residues, resulting in DNA single-and double-strand breaks (3, 4). Strand breaks trigger a DNA damage response (DDR) by inducing the expression of molecular markers associated with DNA damage repair, such as poly(ADP ribose) polymerase (PARP), RAD51, and BREAST CANCER (BRCA) family members (5-8). Upon DNA stress, the ataxia telangiectasia-mutated (ATM) and the ataxia telangiectasia and Rad3-related (ATR) signaling kinases are activated and lead, via the WEE1 serine/ threonine kinase, to a transient cell-cycle arrest that allows cells to repair DNA before proceeding into mitosis (9). Although oxidative DNA base damage has been shown to initiate a DDR in mammalian and yeast cells (10, 11), reports in plants on either the sources of oxidative stress that cause DNA damage or the subsequent induction of a DDR directly through ROS remain scarce (3,12,13). Until now, DNA damage and DDR in plants were studied mainly in response to exogenously applied DNAdamaging agents such as bleomycin and hydroxyurea or ionizing irradiation (9, 14, 15).Protection against damage caused by ROS traditionally has been attributed to enzymes with ROS-detoxifying activities (16), and mutants lacking a particular ROS-scavenging enzyme were considered more sensitive to oxidative stress ...

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Section: Resultsmentioning

confidence: 99%

Extranuclear protection of chromosomal DNA from oxidative stress

Vanderauwera

Suzuki

Miller

et al. 2011

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

197

138

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“…Nuclear ferritin is distributed nonrandomly, with preferential association with heterochromatin, which suggests that it might be involved in facilitating DNA synthesis (9,10). Ferritin in the nucleus has a protective function, as shown by its ability to protect DNA of corneal epithelial cells from UV damage and oxidative stress (11)(12)(13). Ferritin may also play a role in drug resistance mechanisms, as repeated exposure of cells to hydroxyurea results in an increased resistance to this toxic agent and an increase in ferritin mRNA (14).…”

Section: Introductionmentioning

confidence: 99%

Heavy Chain Ferritin siRNA Delivered by Cationic Liposomes Increases Sensitivity of Cancer Cells to Chemotherapeutic Agents

et al. 2011

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Approximately half of all gliomas are resistant to chemotherapy, and new therapeutic strategies are urgently needed to treat this cancer. We hypothesized that disrupting iron homeostasis in glioma cells could block tumor growth, based on an acute requirement for high levels of iron to meet energy requirements associated with their rapid growth. Ferritin is best known as an intracellular iron storage protein, but it also localizes to tumor cell nuclei where it seems to protect DNA from oxidative damage and to promote transcription. In this study, we hypothesize that silencing the H-ferritin (heavy chain ferritin) gene could increase tumor sensitivity to chemotoxins. To test this hypothesis, H-ferritin siRNA was delivered to several human cancer cell lines by using cationic liposomes (C-liposome). H-ferritin siRNA decreased protein expression by 80% within 48 hours, and this decrease was associated with more than 50% decrease in the LD 50 for DNA-alkylating agent carmustine (BCNU), which is commonly used to treat glioma in clinic. In a subcutaneous mouse model of human glioma, intratumoral injections of liposomes containing H-ferritin siRNA reduced the effective dose of BCNU needed for tumor suppression by more than 50%. A plasmid supercoil relaxation assay showed that H-ferritin specifically and directly protected DNA from BCNU treatment. H-ferritin siRNA additionally seemed to increase apoptosis in glioma cells in vitro upon H-ferritin knockdown. Overall, our results illustrate how silencing H-ferritin can effectively sensitize tumors to chemotherapy and also show the ability of C-liposomes to serve as a novel in vivo delivery tool for siRNAs. Cancer Res; 71(6); 2240-9. Ó2011 AACR.

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“…Further, chelatable iron that can favor a Fenton reaction has also been found in the nucleus (280), and other metal ions such as Cu 2 + are thought to be present on the chromosomes and might also accelerate the production of ROS (285). In line, nuclear ferritin known to sequester free iron was found to ameliorate oxidative damage in embryonic avian corneal epithelial cells (51). Thus, each compartment is involved in ROS generation and therefore may be involved to a different extend in the modulation of cell growth, differentiation, senescence, and apoptosis, and thus in carcinogenesis.…”

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confidence: 96%

Nutritional Countermeasures Targeting Reactive Oxygen Species in Cancer: From Mechanisms to Biomarkers and Clinical Evidence

Samoylenko

Hossain²,

Mennerich³

et al. 2013

Antioxidants & Redox Signaling

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Reactive oxygen species (ROS) exert various biological effects and contribute to signaling events during physiological and pathological processes. Enhanced levels of ROS are highly associated with different tumors, a Western lifestyle, and a nutritional regime. The supplementation of food with traditional antioxidants was shown to be protective against cancer in a number of studies both in vitro and in vivo. However, recent largescale human trials in well-nourished populations did not confirm the beneficial role of antioxidants in cancer, whereas there is a well-established connection between longevity of several human populations and increased amount of antioxidants in their diets. Although our knowledge about ROS generators, ROS scavengers, and ROS signaling has improved, the knowledge about the direct link between nutrition, ROS levels, and cancer is limited. These limitations are partly due to lack of standardized reliable ROS measurement methods, easily usable biomarkers, knowledge of ROS action in cellular compartments, and individual genetic predispositions. The current review summarizes ROS formation due to nutrition with respect to macronutrients and antioxidant micronutrients in the context of cancer and discusses signaling mechanisms, used biomarkers, and its limitations along with large-scale human trials.

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Nuclear ferritin‐mediated protection of corneal epithelial cells from oxidative damage to DNA

Cited by 33 publications

References 38 publications

Extranuclear protection of chromosomal DNA from oxidative stress

Extranuclear protection of chromosomal DNA from oxidative stress

Heavy Chain Ferritin siRNA Delivered by Cationic Liposomes Increases Sensitivity of Cancer Cells to Chemotherapeutic Agents

Nutritional Countermeasures Targeting Reactive Oxygen Species in Cancer: From Mechanisms to Biomarkers and Clinical Evidence

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