Gene Regulation,Stem Cells&Cancer Progr. Sebastiaan van Heesch

19/03/202512:00R_473.10_AULAGene Regulation,Stem Cells&Cancer Progr.Sebastiaan van HeeschPrincess Máxima Center for Pediatric OncologyEvolutionarily young non-canonical ORFs and microproteins in childhood cancerHost: Benito Mestres, MartaAbstract:Ribosome profiling (Ribo-Seq) has proven transformative for our understanding of the human genome and proteome by illuminating thousands of noncanonical sites of ribosome translation outside the currently annotated coding sequences (CDSs). A conservative estimate suggests that at least 7000 noncanonical ORFs are translated, which, at first glance, expands the number of human protein CDSs by 30%, from ~19,500 annotated CDSs to over 26,000 annotated CDSs. Yet, additional scrutiny of these ORFs has raised numerous questions about what fraction of them truly produce a protein product and what fraction can be understood as proteins according to the conventional understanding of the term. I will discuss the current state of noncanonical ORF research, databases, and functional interpretation, focusing on whether a given ORF can be said to be “protein-coding”. I will do so in the context of childhood cancer, where we find evolutionarily young microproteins essential for cancer cell survival, and are exploring strategies targeting microproteins for the development of new (immuno)therapies.