Role of lipid peroxidation and DNA damage in paraquat toxicity and the interaction of paraquat with ionizing radiation

Ferroptosis is a lipid peroxidation-dependent mechanism of regulated cell death known to suppress tumor proliferation and progression. Although several genetic and protein hallmarks have been identified in ferroptotic cell death, it remains challenging to fully characterize ferroptosis signaling pathways and to find suitable biomarkers. Moreover, changes taking place in the epigenome of ferroptotic cells remain poorly studied. In this context, we aimed to investigate the role of chromatin remodeler forkhead box protein A1 (FOXA1) in RSL3-treated multiple myeloma cells because, similar to ferroptosis, this transcription factor has been associated with changes in the lipid metabolism, DNA damage, and epithelial-to-mesenchymal transition (EMT). RNA sequencing and Western blot analysis revealed that FOXA1 expression is consistently upregulated upon ferroptosis induction in different in vitro and in vivo disease models. In silico motif analysis and transcription factor enrichment analysis further suggested that ferroptosis-mediated FOXA1 expression is orchestrated by specificity protein 1 (Sp1), a transcription factor known to be influenced by lipid peroxidation. Remarkably, FOXA1 upregulation in ferroptotic myeloma cells did not alter hormone signaling or EMT, two key downstream signaling pathways of FOXA1. CUT&RUN genome-wide transcriptional binding site profiling showed that GPX4-inhibition by RSL3 triggered loss of binding of FOXA1 to pericentromeric regions in multiple myeloma cells, suggesting that this transcription factor is possibly involved in genomic instability, DNA damage, or cellular senescence under ferroptotic conditions.

Download Full-text

Induction of DNA breakage in X-irradiated nucleoids selectively stripped of nuclear proteins in two mouse lymphoma cell lines differing in radiosensitivity.

Acta Biochimica Polonica ◽

10.18388/abp.1998_4264 ◽

1998 ◽

Vol 45 (3) ◽

pp. 701-704 ◽

Cited By ~ 2

Author(s):

M Kruszewski ◽

T Iwaneńko

Keyword(s):

Dna Damage ◽

Ionizing Radiation ◽

Cell Lines ◽

Radiation Sensitivity ◽

Lymphoma Cell ◽

Nuclear Proteins ◽

Strand Breaks ◽

Dna Damaging Agents ◽

Mouse Lymphoma

The role of nuclear proteins in protection of DNA against ionizing radiation and their contribution to the radiation sensitivity was examined by an alkaline version of comet assay in two L5178Y (LY) mouse lymphoma cell lines differing in sensitivity to ionizing radiation. LY-S cells are twice more sensitive to ionizing radiation than LY-R cells (D0 values of survival curves are 0.5 Gy and 1 Gy, respectively). Sequential removal of nuclear proteins by extraction with NaCl of different concentrations increased the X-ray induced DNA damage in LY-R nucleoids. In contrast, in the radiation sensitive LY-S cell line, depletion of nuclear proteins practically did not affect DNA damage. Although there is no doubt that the main cause of LYS cells' sensitivity to ionizing radiation is a defect in the repair of double-strand breaks, our data support the concept that nuclear matrix organisation may contribute to the cellular susceptibility to DNA damaging agents.

Download Full-text

Mitochondrial, lysosomal and DNA damages induced by acrylamide attenuate by ellagic acid in human lymphocyte

PLoS ONE ◽

10.1371/journal.pone.0247776 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0247776

Author(s):

Ahmad Salimi ◽

Elahe Baghal ◽

Hassan Ghobadi ◽

Niloufar Hashemidanesh ◽

Farzad Khodaparast ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Dna Damage ◽

Ellagic Acid ◽

Human Lymphocytes ◽

Health Concern ◽

Cytochrome P450 Enzyme ◽

Dna Damages ◽

Ros Formation

Acrylamide (AA), is an important contaminant formed during food processing under high temperature. Due to its potential neurotoxicity, reproductive toxicity, hepatotoxicity, immunotoxicity, genotoxicity and carcinogenicity effects, this food contaminant has been recognized as a human health concern. Previous studies showed that acrylamide-induced toxicity is associated with active metabolite of acrylamide by cytochrome P450 enzyme, oxidative stress, mitochondrial dysfunction and DNA damage. In the current study, we investigated the role of oxidative stress in acrylamide’s genotoxicity and therapeutic potential role of ellagic acid (EA) in human lymphocytes. Human lymphocytes were simultaneously treated with different concentrations of EA (10, 25 and 50 μM) and acrylamide (50 μM) for 4 h at 37°C. After 4 hours of incubation, the toxicity parameters such cytotoxicity, ROS formation, oxidized/reduced glutathione (GSH/GSSG) content, malondialdehyde (MDA) level, lysosomal membrane integrity, mitochondria membrane potential (ΔΨm) collapse and 8-hydroxy-2’-deoxyguanosine (8-OHdG) were analyzed using biochemical and flow cytometry evaluations. It has been found that acrylamide (50 μM) significantly increased cytotoxicity, ROS formation, GSH oxidation, lipid peroxidation, MMP collapse, lysosomal and DNA damage in human lymphocytes. On the other hand, cotreatment with EA (25 and 50 μM) inhibited AA-induced oxidative stress which subsequently led to decreasing of the cytotoxicity, GSH oxidation, lipid peroxidation, MMP collapse, lysosomal and DNA damage. Together, these results suggest that probably the co-exposure of EA with foods containing acrylamide could decrease mitochondrial, lysosomal and DNA damages, and oxidative stress induced by acrylamide in human body.

Download Full-text

Genomic Expression Responses to DNA-damaging Agents and the Regulatory Role of the Yeast ATR Homolog Mec1p

Molecular Biology of the Cell ◽

10.1091/mbc.12.10.2987 ◽

2001 ◽

Vol 12 (10) ◽

pp. 2987-3003 ◽

Cited By ~ 353

Author(s):

Audrey P. Gasch ◽

Mingxia Huang ◽

Sandra Metzner ◽

David Botstein ◽

Stephen J. Elledge ◽

...

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Ionizing Radiation ◽

Cellular Response ◽

Expression Patterns ◽

Wild Type ◽

Data Set ◽

Genomic Expression ◽

Dna Damaging Agents

Eukaryotic cells respond to DNA damage by arresting the cell cycle and modulating gene expression to ensure efficient DNA repair. The human ATR kinase and its homolog in yeast, MEC1, play central roles in transducing the damage signal. To characterize the role of the Mec1 pathway in modulating the cellular response to DNA damage, we used DNA microarrays to observe genomic expression inSaccharomyces cerevisiae responding to two different DNA-damaging agents. We compared the genome-wide expression patterns of wild-type cells and mutants defective in Mec1 signaling, includingmec1, dun1, and crt1 mutants, under normal growth conditions and in response to the methylating-agent methylmethane sulfonate (MMS) and ionizing radiation. Here, we present a comparative analysis of wild-type and mutant cells responding to these DNA-damaging agents, and identify specific features of the gene expression responses that are dependent on the Mec1 pathway. Among the hundreds of genes whose expression was affected by Mec1p, one set of genes appears to represent an MEC1-dependent expression signature of DNA damage. Other aspects of the genomic responses were independent of Mec1p, and likely independent of DNA damage, suggesting the pleiotropic effects of MMS and ionizing radiation. The complete data set as well as supplemental materials is available at http://www-genome.stanford.edu/mec1 .

Download Full-text