DNA damage responses to oxidative stress

Barzilai, Ari; Yamamoto, Ken

doi:10.1016/j.dnarep.2004.03.002

Cited by 670 publications

(465 citation statements)

References 71 publications

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“…3,8 Although the neurodegenerative phenotype in A-T has been attributed to a defective DDR in pre-and postmitotic neurons, 1 oxidative stress and endoplasmic reticulum stress may also play a causative role. 11 Data from ATM-null mice support the notion that the cerebellar degeneration arises from a defective DDR, 12 but consequent to oxidative stress. [13][14][15] As developing neurons are rapidly proliferating and potentially generating high levels of oxidants, which favor the accumulation of DNA lesions, genetic defects of the DDR, by exacerbating genomic instability, may eventually compromise neuron survival particularly at postmitotic level.…”

supporting

confidence: 61%

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

et al. 2009

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Ataxia-telangiectasia (A-T) is a neurodegenerative disorder caused by defects in the ATM kinase, a component of the DNA-damage response (DDR). Here, we employed an immortalized human neural stem-cell line (ihNSC) capable of differentiating in vitro into neurons, oligodendrocytes and astrocytes to assess the ATM-dependent response and outcome of ATM ablation. The time-dependent differentiation of ihNSC was accompanied by an upregulation of ATM and DNA-PK, sharp downregulation of ATR and Chk1, transient induction of p53 and by the onset of apoptosis in a fraction of cells. The response to ionizing radiation (IR)-induced DNA lesions was normal, as attested by the phosphorylation of ATM and some of its substrates (e.g., Nbs1, Smc1, Chk2 and p53), and by the kinetics of c-H2AX nuclear foci formation. Depletion in these cells of ATM by shRNA interference (shATM) attenuated the differentiation-associated apoptosis and response to IR, but left unaffected the growth, self-renewal and genomic stability. shATM cells generated a normal number of MAP2/b-tubulin III þ neurons, but a reduced number of GalC þ oligodendrocytes, which were nevertheless more susceptible to oxidative stress. Altogether, these findings highlight the potential of ihNSCs as an in vitro model system to thoroughly assess, besides ATM, the role of DDR genes in neurogenesis and/or neurodegeneration.

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supporting

confidence: 61%

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

et al. 2009

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“…KG1 cells were treated for 1 h with or without 100 mM H 2 O 2 , a well-known donor of reactive oxygen species that can induce DNA damage (Barzilai and Yamamoto, 2004). Then the cells were rinsed and cultured in fresh medium.…”

Section: Resultsmentioning

confidence: 99%

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

et al. 2008

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The anti-apoptotic transcription factor nuclear factor-jB (NF-jB) is constitutively activated in CD34 þ myeloblasts from high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Inhibition of NF-jB by suppressing the canonical NF-jB activation pathway, for instance by knockdown of the three subunits of the inhibitor of NF-jB (IjB) kinase (IKK) complex (IKK1, IKK2 and NEMO) triggers apoptosis in such cells. Here, we show that an MDS/AML model cell line exhibits a constitutive interaction, within the nucleus, of activated, S1981-phosphorylated ataxia telangiectasia mutated (ATM) with NEMO. Inhibition of ATM with two distinct pharmacological inhibitors suppressed the activating autophosphorylation of ATM, blocked the interaction of ATM and NEMO, delocalized NEMO as well as another putative NF-jB activator, PIDD, from the nucleus, abolished the activating phosphorylation of the catalytic proteins of the IKK complex (IKK1/2 on serines 176/180), enhanced the expression of IjBa and caused the relocalization of NF-jB from the nucleus to the cytoplasm, followed by apoptosis. Knockdown of ATM with small-interfering RNAs had a similar effect that could not be enhanced by knockdown of NEMO, PIDD and the p65 NF-jB subunit, suggesting that an ATM inhibition/ depletion truly induced apoptosis through inhibition of the NF-jB system. Pharmacological inhibition of ATM also induced the nucleocytoplasmic relocalization of p65 in malignant myeloblasts purified from patients with highrisk MDS or AML, correlating with the induction of apoptosis. Altogether, these results support the contention that constitutively active ATM accounts for the activation of NF-jB in high-risk MDS and AML.

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“…In the present study, CaE inhibited the damage of the supercoiled form of the plasmid DNA due to exposure to hydrogen peroxide and UV light, and thus prevented the formation of single-strand or double-strand breaks. The single-strand breaks in DNA are very often transformed into double-strand breaks that can cause apoptosis, directly inactivate important genes, or can result in chromosomal aberrations (Barzilai and Yamamoto, 2004). The limitation of amyloid β neurotoxicity and free radical induced damage such as lipid peroxidation and DNA modification present a potential mechanism of action for anti-Alzheimer's therapies.…”

Section: Discussionmentioning

confidence: 99%

Centella asiatica extract selectively decreases amyloid β levels in hippocampus of Alzheimer's disease animal model

Dhanasekaran

Holcomb

Hitt

et al. 2008

Phytotherapy Research

166

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PSAPP mice expressing the 'Swedish' amyloid precursor protein and the M146L presenilin 1 mutations are a well-characterized model for spontaneous amyloid β β β β β plaque formation. Centella asiatica has a long history of use in India as a memory enhancing drug in Ayurvedic literature. The study investigated whether Centella asiatica extract (CaE) can alter the amyloid pathology in PSAPP mice by administering CaE (2.5 or 5.0 g/kg/day) starting at 2 months of age prior to the onset of detectable amyloid deposition and continued for either 2 months or 8 months. A significant decrease in amyloid β β β β β 1-40 and 1-42 was detectable by ELISA following an 8 month treatment with 2.5 mg/kg of CaE. A reduction in Congo Red stained fibrillar amyloid plaques was detected with the 5.0 mg/kg CaE dose and long-term treatment regimen. It was also confirmed that CaE functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation and protecting against DNA damage. The data indicate that CaE can impact the amyloid cascade altering amyloid β β β β β pathology in the brains of PSAPP mice and modulating components of the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimer's disease.

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DNA damage responses to oxidative stress

Cited by 670 publications

References 71 publications

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

DNA-damage response, survival and differentiation in vitro of a human neural stem cell line in relation to ATM expression

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

Centella asiatica extract selectively decreases amyloid β levels in hippocampus of Alzheimer's disease animal model

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