The stress response is a pathway activated by a range of cellular stresses. The release of reactive oxygen species (ROS) by the mitochondrial is an upstream response and this elicits the activation of antioxidant system that can protect against increased ROS. ROS has the ability to damage DNA, proteins and lipids and can put the cell under severe stress. ROS damage to DNA mainly involves base damage and single strand breaks. Ionizing radiation as well as UV (UVA) radiation are amongst the exogenous agents producing ROS and activating stress response through radiolysis of water and interaction with intracellular photosensitizers, respectively.
ROS not only react with DNA base in the DNA but also with free deoxy-ribonucleotide triphosphate pool (dNTP) in the cytoplasm. During replication, particular types of modified dNTP can be incorporated in to the DNA and give rise to point mutation. In addition to antioxidant system and DNA base excision repair, cells have another important mechanism to prevent ROS damage to DNA, namely a protein called MTH1, which removes damaged nucleotides from the nucleotide pool prior to their usage during repair or replication. This process results in the release of 8-oxo-dG into the serum/saliva and inhibits its usage during DNA repair or replication. Thus, if MTH1 is impaired in function or becomes saturated, the impact of ROS-induced damage to DNA arising following incorporation of damaged nucleotides could be much enhanced, and could, under these conditions make a significant contribution to the level of ROS-induced DNA damage and point mutation.
The mutagenic role of nucleotide pool oxidation in the cells exposed to ionizing and non-ionizing radiation will be discussed.