*4 Year WT PhD Programme* Investigating novel Prolyl-hydroxylase targets in response to changes in oxygen

Oxygen is one of the most important molecules for life. Every member of the animal kingdom depends on oxygen to help metabolize its food and drive many critical processes in metabolism. Because oxygen is so important most organisms have evolved ways of adapting to changes in oxygen concentration that occur at times of heavy exercise or as individuals migrate to the high levels of altitude. Adaptation to hypoxia has been well studied and is known to involve three critical enzymes known as the Prolyl Hydroxylases (PHDs). The PHDs enzymatically process oxygen and use it to modify a specific amino acid, proline, on certain proteins. In humans. three PHDs exist, PHD1, PHD2 and PHD3. Until very recently, the only validated PHD enzyme targets were the Hypoxia Inducible Factor-alpha transcription factors, well known to regulate several critical pathways that allow an organism to adapt to hypoxia. However, recently, additional substrates specific for one these enzymes were discovered involved in cellular processes such cell cycle, DNA damage repair and metabolism. Furthermore, our data indicate that PHDs are post-translationally modified, which alters in some instances, substrate specificity. The project will investigate novel targets of PHD enzymes, with focus on cell cycle or DNA damage response, and how different modifications alter PHD function in cells. A number of techniques ranging from proteomics, imaging, biochemistry and molecular and cellular biology will be used.