A single oxygen-dependent chemical tag on a protein called DRG1 may control whether it stays in the cell's cytoplasm or slips into the nucleus to switch on a poorly understood repair system for damaged DNA. This matters because the tag—a hydroxyl group added by an enzyme called Jmjd7—is sensitive to oxygen levels and metabolic signals. Until now, DRG1 was known only as a protein synthesis factor in the cytoplasm. The discovery that it also enters the nucleus and interacts with an E3 ubiquitin ligase opens an entirely new signalling pathway linking translation to transcription and DNA repair. How hydroxylation governs this shuttling, and what the ligase does once activated, are complete unknowns. If the work succeeds, it will provide the first molecular framework for this pathway. Because Jmjd7 is a 2OG-oxygenase—a class of enzymes that sense oxygen and nutrients—the findings could eventually help explain how cells coordinate protein production with genome maintenance under stress. This is fundamental science with no immediate application, but similar discoveries about oxygen-sensitive enzymes have already reshaped understanding of conditions such as anaemia, cancer, and ischaemic disease.
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‘Developmentally-regulated GTP-binding proteins’ (DRG1 and 2) are highly conserved GTPase enzymes that bind to ribosomes to promote protein synthesis (translation). We recently discovered that DRG proteins are modified by hydroxylation, an emerging protein modification with largely unappreciated and poorly understood roles in fundamental cellular processes. Protein hydroxylation in humans is generally catalysed by oxygenases that are dependent on a metabolite called 2-oxogulatarate (2OG, otherwise known as alpha-ketoglutarate). These so-called ‘2OG-oxygenases’ have nutrient-sensing capabilities that can render their functions sensitive to oxygen limitation (hypoxia) and metabolic alterations. DRGs are hydroxylated by a 2OG-oxygenase called Jumonji-C-domain 7 (Jmjd7) to regulate RNA binding. However, the exact molecular functions of hydroxylation and the wider biological roles of DRGs remain elusive. Although DRGs are reported to be cytoplasmically-localised, consistent with their translation factor role, we also observe DRG1 in the nucleus, where we discovered it interacts with an E3 ubiquitin ligase of unknown function. We recently identified a candidate substrate of this orphan E3 ubiquitin ligase that is involved in nucleosome remodelling. Based on a solid foundation of pre-existing data including protein interaction assignments, functional studies, and novel models, we will now focus on understanding the importance of hydroxylation and DRG1 function in nuclear ubiquitin biology. We aim to first provide a comprehensive molecular understanding of the different protein:protein interactions in this novel signaling pathway and the signals that regulate nuclear versus cytoplasmic DRG1 localisation and target engagement. The insights gained from this work will then provide a comprehensive framework for subsequent biochemical and functional studies. We will investigate the regulation of E3 ubiquitin ligase activity by DRG1 and Jmjd7 and characterise how ubiquitylation regulates the function of the nucleosome remodelling factor. Finally, we will investigate the physiological importance of this exciting new pathway by examining its role in transcription and DNA damage repair. Together, the work will significantly advance our understanding of hydroxylase biology, elucidate how a cytoplasmic GTPase regulates a nuclear E3 ubiquitin ligase, and shed important new light on the relationship between translation and transcription-associated processes in eukaryotes. Overall, the findings will deliver important new insights into the rules of life that can be used to better understand the human diseases associated with this exciting new pathway in the future.
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