Details

Autor(en) / Beteiligte

• Higgs, Ellen B.
• Godschalk, Roger
• Coltman, Nicholas J.
• Stewart, Grant S.
• van Schooten, Frederik-Jan
• Hodges, Nikolas J.

Titel

Induction of apoptosis in Ogg1-null mouse embryonic fibroblasts by GSH depletion is independent of DNA damage

Ist Teil von

• Toxicology letters, 2020-10, Vol.332, p.27-35

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• •Ogg1-null mouse embryonic fibroblasts (MEFs) are more sensitive to depletion of glutathione.•Ogg1-null MEFs possess increased basal levels of intracellular reactive oxygen species.•Ogg1-null MEFs do not accumulate genomic 8-oxoG lesions.•Glutathione depletion induces apoptosis in Ogg1-null MEFs. Reactive oxygen species (ROS) within the cell are rapidly detoxified by antioxidants such as glutathione. Depletion of glutathione will therefore increase levels of intracellular ROS, which can lead to oxidative DNA damage and the induction of apoptosis. The working hypothesis was that Ogg1 null mouse embryonic fibroblasts (mOgg1−/− MEFs) would be more sensitive in response to GSH depletion due to their deficiency in the removal of the oxidative DNA modification, 8-oxo-7,8-dihydroguanine (8-oxoG). Following GSH depletion, an increase in intracellular ROS and a subsequent induction of apoptosis was measured in mOgg1−/− MEFs; as expected. Unexpectedly, an elevated basal level of ROS was identified in mOgg1-/- MEFs compared to wild type MEFs; which we suggest is partly due to the differential expression of key anti-oxidant genes. The elevated basal ROS levels in mOgg1−/− MEFs were not accompanied by a deficiency in ATP production or a large increase in 8-oxoG levels. Although 8-oxoG levels did increase following GSH depletion in mOgg1-/- MEFs; this increase was significantly lower than observed following treatment with a non-toxic dose of hydrogen peroxide. Reconstitution of Ogg1 into mOgg1−/− MEFs resulted in an increased viability following glutathione depletion, however this rescue did not differ between a repair-proficient and a repair-impaired variant of Ogg1. The data indicates that induction of apoptosis in response to oxidative stress in mOgg1−/− MEFs is independent of DNA damage and OGG1-initiated DNA repair.