Fig. 1. Two independent hydroxylation pathways regulate HIF activity in response to cellular oxygen level. In normoxia, oxygen availability enables PHD-dependent prolyl hydroxylation of the HIF- ODD. This prolyl hydroxylation allows binding of the VHL E3 ligase leading to ubiquitylation and degradation of HIF- subunits. Oxygen availability also enables FIH-dependent asparaginyl hydroxylation of the C-TAD, blocking interaction with the p300/CBP co-activator. In hypoxia, the PHD and FIH enzymes are inactive and the lack of hydroxylation results in stable HIF- able to form a DNA-binding heterodimer with HIF-ß and recruit p300/CBP at the C-TAD.