Role of oxidative stress response in radiosensitivity

The quality of the ionizing radiation (IR) can be described in terms of its nature, photons or particles, and their corresponding energies. The energy is classified in terms of High or Low linear energy transfer that will produce a different distribution of DNA damage and other molecules in the cell either by direct action or indirect action. Indirect action leads to the production of reactive oxygen species (ROS) modifying nucleotides in DNA or free dNTPs. 8-oxo-dGTP is formed through ROS endogenously when there is an imbalance between the antioxidants defence systems and the production of ROS levels in favour of ROS, leading to an oxidative stress condition. Organisms, organs, and cell types show different degrees of radiosensitivity, and this thesis aimed to investigate the underlying mechanisms of IR induced oxidative stress and its relation with radiosensitivity. In previous studies, we identified proteins involved in radiation response with a focus on low dose radiation response. Cell models were established in which the expression of some protein/s was downregulated by knocking down/out using CRISPR/Cas9 or shRNA technology. The knockdown or knockout cells were exposed to different doses at low dose rates (LDR) or high dose rate (HDR) to investigate the role of these genes/proteins for survival (radiosensitivity), mutation induction, stress response, differentiation, etc. and they were subjected to further studies in this thesis. Publication I, cell lines with hMTH1, and MYH knockdown were established and exposed to 0.5 and 1 Gy administered at different dose rates. We found that LDR induces significantly increased levels of extracellular 8-oxo-dG compared to HDR. We also found that hMTH1 and MYH play together an important role in the protection of cells against ROS-induced mutagenicity. Publication II, the role of NRF2 was investigated for the radiosensitivity of glioblastoma cancer stem cells (CSCs). The neutrosphere cells from the U87MG cell line were irra
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.