Final Report Summary - M5C RNA (Cytosine-5 methylated RNAs as stem cell regulators in normal tissues and diseases)
Many of the hundreds of known chemical modifications in RNA were discovered over forty years ago but then forgotten because suitable, sensitive tools to detect the modifications at high resolution were lacking. Through the development of novel biochemical, functional and genomics tools that detect RNA methylation genome-wide and at nucleotide resolution, this project significantly contributed to the revival of the field. Only now we are beginning to understand the whole breadth and extensive functional roles of RNA modifications in higher organisms. Over the course of this project, the Frye group spearheaded the field by providing the first mechanistic examples how RNA modifications shape normal tissue homeostasis, and how aberrant formation of RNA modifications cause devastating human diseases including neuro-developmental deficits and mitochondrial disorders. Mechanistically, the Frye group showed that RNA methylation is functionally indispensable for the correct cellular adaption of protein synthesis in response to environmental stress stimuli. This is important because these newly discovered biological roles of RNA modifications directly influence cell fate decision not only in normal tissues but also during tumour development, progression and chemotherapy resistance. Together, this project demonstrated that by understanding the role of RNA modifications in physiology and pathology, novel and powerful therapeutic drug targets for human diseases can be identified and further optimized for clinical studies.