DNA fragmentation factor 40 expression in T cells confers sensibility to tributyltin-induced apoptosis
| Autor: | Merve Kulbay, Jacques Bernier, Bruno Johnson |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Apoptosis Toxicology Jurkat cells Histones 03 medical and health sciences chemistry.chemical_compound Endonuclease Gene Knockout Techniques Jurkat Cells 0302 clinical medicine Cell Line Tumor Humans Viability assay Phosphorylation Poly-ADP-Ribose Binding Proteins Nuclease Deoxyribonucleases biology Chemistry Molecular biology 030104 developmental biology Caspases Toxicity biology.protein Tributyltin DNA fragmentation Trialkyltin Compounds Reactive Oxygen Species 030217 neurology & neurosurgery DNA Damage |
| Zdroj: | Toxicology. 426 |
| ISSN: | 1879-3185 |
| Popis: | DNA fragmentation factor 40 (DFF40), an endonuclease, mediates the final and irreversible step of apoptosis by conducting oligonucleosomal DNA fragmentation. New emerging studies have proposed a role of DFF40 in genomic stability, besides its nuclease activity. Overexpression of DFF40 in tumoral cells increases their sensitivity to chemotherapeutic drugs. In this study, we sought to determine if DFF40 expression influences the toxicity of tributyltin (TBT), a well-known immunotoxic and apoptosis-inducing compound. The strategy used was to knockout DFF40 expression by CRISPR-cas9 method in Jurkat T cells and to determine the toxicity of TBT in DFF40 KO cells and DFF40 WT Jurkat cells. DFF40 KO Jurkat cells show an increase of cell viability following a 24-h TBT exposure (p 0.05). There is a resistance to TBT-induced apoptosis determined by annexin V/PI am labeling (p 0.05). Interestingly, the basal level of ROS rises in DFF40 KO Jurkat cells, but ROS production levels after TBT exposure remains at the same basal level. Other apoptosis or DNA damage makers (procaspase-3, caspase-6, and PARP cleavage) are significantly delayed and decreased. DFF40 deficient cells do not present histone H2AX phosphorylation, whereas wild-type cells present a phosphorylation following a 6-h exposure to TBT (p 0.001). The re-expression of DFF40 in DFF40 KO cells restores the cytotoxic effects of TBT. Overall, these data suggest a role of DFF40 in cells sensitivity to TBT and possibly in DNA stability. |
| Databáze: | OpenAIRE |
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