Extraordinary BioMed Seminar: Translation-dependent mRNA decay pathways – where ribosome quality control (RQC) meets mRNA surveillance

mRNA translation is a main determinant of its half-life, and translation-dependent mRNA decay pathways are of particular interest due to their dual roles in regulating gene expression and mRNA quality control. My lab has focused for many years on elucidating the molecular mechanisms of one of these pathways, nonsense-mediated mRNA decay (NMD), and its biological roles beyond mRNA surveillance. More recently, we have developed a protocol that allows the easy and quick production of cytoplasmic lysates from various human cell lines that exhibit highly reproducible translation activity and are scalable. Besides many other applications, this improved human in vitro translation system provides a unique opportunity for unraveling new mechanistic insights of translation-dependent mRNA decay pathways, offering a controlled environment to dissect the molecular events that influence mRNA turnover. As a first step in this direction, we managed to recapitulate nonstop mRNA decay (NSD) in this system. Finally, a mode-of-action study of a drug that was screened for its stop codon readthrough activity led us to the discovery of a new branch of RQC that detects occluded ribosomal A sites and triggers the ubiquitination, extraction and proteosomal degradation of the occluding factor. In my talk, I will introduce you to the different translation-dependent mRNA decay pathways and present recent data from two or three of the above-mentioned ongoing research projects of the lab.