Oxidative stress and mutagenicity

During oxidative stress excess levels of free radicals can react with molecules in the cell (lipids, proteins and DNA base) and modify their structure. While modified lipids and proteins are replaced with new unmodified molecules during normal cell turn-over the modified DNA bases may lead to permanent changes of the DNA sequence leading to mutations.
The research is currently focusing on the mechanisms behind mutation induction when nucleic acid attacked by reactive oxygen species (ROS). We are using UV, low dose and low dose rates of gamma radiation as well as certain weakly mutagenic chemicals to induce oxidative stress in cells. We have shown that the cellular nucleotide pool (dNTP) is a sensitive target for ROS. The ROS-modified dNTP can be incorporated into the DNA and lead to mutations during replication. Cells are equipped with different mechanism called “dNTP sanitization system” to avoid incorporation of modified base into the DNA. Basically, every single nucleotide is checked by proteins belong to sanitization system before polymerase incorporate them into the DNA. We have been particularly interested in studying how cells deal with and repair ROS-induced dNTP modifications and if dietary antioxidants can inhibit reaction between ROS and dNTP by scavenging ROS.

 

Mechanisms and biomarkers of individual sensitivity in cancer patients

The aim of cancer treatments is to increase the probability of tumour control while minimizing the unwanted acute or late therapy-induced reactions of normal tissues. It is assumed that the risk of developing side effects is related to the genetically determined intrinsic sensitivity of the patient. In collaboration with researchers at Karolinska University Hospital we have started two projects where we are studying the mechanisms involved in individual sensitivity to radiotherapy in breast and head and neck cancer.  It could be shown that head and neck cancer patients who have a mutation in GSTP1 gene are prone to suffer from mandible necrosis following treatment for for head and neck cancer. We have also discovered that oxidative stress response plays an important role in individual response to radiotherapy.