Study the Role of Pseudouridine Synthases in Cancer Using a Zebrafish Model

This PhD project at the University of Oxford investigates the role of pseudouridine synthases (PUS) in cancer using the zebrafish model. Pseudouridine (Ψ) is the most prevalent post-transcriptional RNA modification, especially abundant in non-coding RNAs such as rRNA and tRNA. Installed by a family of thirteen PUS enzymes, Ψ is crucial for translation, splicing, and RNA stability. Dysregulation of PUS enzymes has been implicated in various diseases, including cancer, but their biological functions remain poorly understood due to limitations in detection methods and knowledge of enzyme targets. Recent advances by the Song group include the development of 2-bromoacrylamide-assisted cyclization sequencing (BACS), enabling direct, quantitative, and base-resolution sequencing of Ψ (Nat. Methods 2024, 21, 2024). A comprehensive tRNA Ψ map has also been established, revealing the targets of each PUS enzyme (Nat. Cell Biol. 2025, 27, 2186). These breakthroughs provide a unique opportunity to study how dysregulated pseudouridylation and PUS enzymes contribute to tumorigenesis. The project addresses the challenge of linking PUS enzyme activity to tissue-specific cancer phenotypes. Zebrafish (Danio rerio) is chosen as the model organism due to its transparency, rapid genetic manipulation, and suitability for high-throughput studies. Pseudouridylation and PUS enzymes are conserved in zebrafish, which is also highly amenable to modeling various cancer types using genetic approaches (Nature 2022, 604, 354; Nature 2025, 647, 517). Research will involve CRISPR-based high-throughput screens, single-cell RNA-seq, BACS, and a range of biochemistry, molecular biology, genetics, and cell biology techniques. The student will join Ludwig Cancer Research, benefiting from the combined expertise of the Song group (chemical biology, epigenetic and epitranscriptomic sequencing) and the White group (zebrafish genetics and cancer). Skills gained will include biochemical assays, molecular biology techniques, epitranscriptomic sequencing, zebrafish genetic techniques (transgenes and CRISPR modifications), high-resolution live cell imaging, and single-cell and spatial transcriptomics. Funding is provided through Ludwig studentships, covering a tax-free stipend (£23,000 per annum) and university fees for both home and international students for four years. Applicants must apply via the University of Oxford application system for a DPhil in Clinical Medicine, using course code 'RD_CM1'. A personal statement is required, and applicants may apply for up to two Ludwig projects. Contacting the supervisors to discuss suitability is recommended. Referees must be prepared to submit references by the deadline. For project enquiries, contact Prof Chunxiao Song ([email protected]) or Prof Richard White ([email protected]). For application enquiries, contact Alexandra Ward ([email protected]). Further details and application instructions are available at the University of Oxford Graduate Admissions website.