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Published on: August 9, 2024
Selenite activates the ATM kinase-dependent DNA repair pathway in human osteosarcoma cells with mitochondrial
Marta Wojewoda1, Jarosław Walczak1, Jerzy Duszyński1
1Laboratory of Bioenergetics and Biomembranes, Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur St, 02-993 Warsaw, Poland.
Abstract:
Mitochondrial dysfunction and reactive oxygen species (ROS) induced oxidative damage are implicated in the pathogenesis of several human diseases. Based on our previous findings that ROS level was higher in human osteosarcoma cybrids--Neuropathy, Ataxia and Retinitis Pigmentosa (NARP) and was reduced by selenite treatment, this study was designed to elucidate the effects of selenite administration on oxidative and nitrosative damage to lipids, proteins and DNA. Oxidative and nitrosative damage to lipids and proteins was not increased in NARP cybrids or mitochondrial DNA-lacking Rho0 cells (displaying mitochondrial dysfunction) when compared with control WT cells. However, we found the enhanced formation of DNA double-strand breaks based on the level of histone γH2AX (phosphorylated at Ser 139), which is known to be phosphorylated by ATM (Ataxia Telangiectasia Mutated) kinase in response to DNA damage. Selenite increased the activity of ATM kinase in NARP cybrids and Rho0 cells without concomitant increase in levels of histone γH2AX. Activation of the ATM kinase-dependent DNA repair pathway triggered by selenite could not be associated with enhanced DNA damage but might rather result from selenite-induced activation of ATM-dependent DNA repair mechanisms which could account for protective effects of this agent.
Insights
Selenium (selenite) may protect against DNA damage in certain cells. This study found selenite activated DNA repair mechanisms in cells with mitochondrial dysfunction, suggesting a protective role.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Mitochondrial dysfunction and reactive oxygen species (ROS) contribute to human diseases.
- Previous studies showed increased ROS in NARP cybrids, with selenite reducing ROS levels.
Purpose of the Study:
- To investigate the effects of selenite on oxidative and nitrosative damage in cells with mitochondrial dysfunction.
- To explore selenite's impact on DNA damage and repair pathways.
Main Methods:
- Comparison of NARP cybrids and Rho0 cells (lacking mitochondrial DNA) with control WT cells.
- Assessment of oxidative/nitrosative damage to lipids, proteins, and DNA.
- Measurement of histone γH2AX levels and ATM kinase activity.
Main Results:
- No increased oxidative/nitrosative damage to lipids or proteins was observed in NARP or Rho0 cells.
- Enhanced formation of DNA double-strand breaks, indicated by histone γH2AX, was found in NARP cybrids and Rho0 cells.
- Selenite increased ATM kinase activity in NARP and Rho0 cells, but without a corresponding rise in histone γH2AX levels.
Conclusions:
- Selenite's activation of ATM kinase in NARP and Rho0 cells is not linked to increased DNA damage.
- Selenite may exert protective effects by activating ATM kinase-dependent DNA repair pathways in cells with mitochondrial dysfunction.
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