Hugues de Thé Collège de France Oncologie cellulaire et moléculaire Année 2023-2024 Exploring the World of Protein Post-translational Modifications Conférence - Tony Hunter : Crosstalk between Post-translational Modifications: The Role of Ptm Crosstalk in Protein Degradation Tony Hunter Salk Institute, La Jolla, California, USA Résumé In this lecture I will discuss the role of PTMs in increasing proteome complexity, why this is important for organisms with genomes of limited protein-coding capacity, and how the combinatorial use of PTMs on a single protein molecule can diversify signal outputs. I will go on to discuss examples of crosstalk between different PTMs in the context of transcriptional regulation mediated by posttranslational modifications of histone tails, and how different PTMs can be used to tag proteins for inducible degradation by the ubiquitin-proteasome system (UPS). The modification of proteins by ubiquitin and ubiquitin-like proteins, such as SUMO, is second only to phosphorylation in terms of the number of sites modified in the mammalian proteome. I will discuss the versatility of ubiquitylation as a regulatory mechanism, and will review the different classes of ubiquitin ligases, deubiquitylating enzymes and ubiquitin binding domains, and the different members of the ubiquitin-like protein family, such as SUMO. I will go on to discuss the discovery of RING finger E3 ubiquitin ligases, and, to illustrate their roles in PTM crosstalk, describe our own work on the c-Cbl RING domain protein as a phosphotyrosine-dependent E3 ubiquitin ligase that targets activated receptor tyrosine kinases, and the RNF4 RING domain protein as a SUMO-dependent E3 ubiquitin ligase (STUbL) that is critical in the DNA damage response. I will end with a description of how we used a budding yeast genetic screen to discover that the RNF4 E3 ligase plays a role in quality control of RNA polymerase III complex assembly, and discuss recent follow up mouse experiments on RNA polymerase III disease mutations that cause a fatal human neurogenerative disease, that could potentially be treated with a sumoylation pathway inhibitor.