The interplay between the oxygen sensors prolyl hydroxylase enzymes and the cell cycle

Oxygen is essential for life in multicellular organisms. Animals have evolved mechanisms to cope with decreased oxygen concentration (hypoxia), which can occur both in physiological and pathological situations. In humans, sensing and responding to changes in oxygen involves a class of proteins – prolyl-4 hydroxylase domain (PHDs) – that use oxygen to modify a specific protein, called hypoxia inducible factor (HIF), which is a master regulator of genes that helps cells handle low oxygen levels. We recently discovered that these oxygen-sensing PHD proteins also target proteins required for the key process of cell division. This unexpected finding suggests that sensing oxygen is crucial for regulating cell division, which we propose may be particularly important in tissues, where oxygen concentration can vary.

This collaborative project will build on our discovery by studying in detail the molecular mechanisms that connect oxygen-sensing enzymes and their targets to regulate cell cycle progression. We will test the hypothesis that the sensing of oxygen levels regulates cell division in human tissues and investigate how dysregulation of these mechanisms may contribute to human disease, with a major focus on diseases of the kidney, where PHD enzymes are known to have important roles.