The interplay between the oxygen sensors PHDs and the cell cycle

Oxygen is essential for aerobic respiration in metazoa and most organisms have evolved ways of adapting to decreased oxygen concentration (hypoxia), which can occur both in physiological and pathological situations. In mammals, the response to hypoxia involves three Prolyl Hydroxylase enzymes (PHDs 1-3), which can regulate stability of the transcription factor, HIF1-alpha, by site-specific proline hydroxylation. We recently discovered that PHD1 similarly controls the stability of Cep192, a critical component of the centrosome, thereby affecting formation of the mitotic spindle, which in turn inhibits cell division and prevents formation of cilia. This unexpected discovery links oxygen sensing with regulation of the cell cycle. We hypothesise that sensing oxygen levels is critical for the control of cell cycle progression in vivo, particularly within tissues, where oxygen levels can vary significantly. Our collaborative project will undertake a detailed investigation of the molecular mechanisms responsible for the physiological regulation of cell division in response to oxygen levels in human cells and tissues. We will study the interplay between PHD enzymes and their targets and determine how this modulates the activities of components of the cell cycle machinery. Further, we will investigate how such interactions may contribute to human kidney disease.