2-Oxoglutarate-dependent dioxygenases as oxygen sensors: their importance in health and disease

Abstract Since low oxygen conditions below physiological levels, hypoxia, are associated with various diseases, it is crucial to understand the molecular basis behind cellular response to hypoxia. Hypoxia-inducible factors (HIFs) have been revealed to primarily orchestrate the hypoxic response at the transcription level and have continuously attracted great attention over the past three decades. In addition to these hypoxia-responsive effector proteins, 2-oxoglutarate-dependent dioxygenase (2-OGDD) superfamily including prolyl-4-hydroxylase domain-containing proteins (PHDs) and factor inhibiting HIF-1 (FIH-1) has attracted even greater attention in recent years as factors that act as direct oxygen sensors due to their necessity of oxygen for the regulation of the expression and activity of the regulatory subunit of HIFs. Herein, we present a detailed classification of 2-OGDD superfamily proteins, such as Jumonji C-domain-containing histone demethylases, ten-eleven translocation enzymes, AlkB family of DNA/RNA demethylases and lysyl hydroxylases, and discuss their specific functions and associations with various diseases. By introducing the multifaceted roles of 2-OGDD superfamily proteins in the hypoxic response, this review aims to summarize the accumulated knowledge about the complex mechanisms governing cellular adaptation to hypoxia in various physiological and pathophysiological contexts.