Eukaryotic DNA damage responses: Double strand break repair and chromatin structure
Supervisor: Dr Howard Lindsay
It is estimated that every cell in the human body experiences some form of DNA damage up to 10,000 times per day. Much of this genetic damage results from the action of free radicals and reactive oxygen species produced as a consequence of normal cellular metabolism as well as exposure to mutagens in the environment. Although these can result in a wide range of DNA lesions, potentially the most lethal of these are DNA double strand breaks (DSBs). Failure to repair even a solitary DSB can result in cell death and if left unchecked, this loss of genetic integrity can lead to cancer and other developmental abnormalities. Cells have developed a range of DNA repair and checkpoint mechanisms to detect and deal with such DNA damage. We are particularly interested in the way that chromatin structure and DNA modification influences the repair of DSBs. The primary focus of this studentship will be the evolutionarily conserved Non homologous end-joining pathway (NHEJ) which is the most commonly used method of repairing DSBs in mammalian cells. This project we will use a combination of biochemical analysis using Xenopus cell-free extracts and genetic studies in yeast to study the NHEJ pathway in the context of chromatin and DNA modification. A goal of this project will be to enhance our understanding of the relationship between chromatin structure and the mechanisms that preserve genome stability.