Daniel JaroszWednesday, February 13th 2019 10:30 am / Centre de Recherche - Paris Amphithéâtre Constant-Burg - 12 rue Lhomond, Paris 5e Daniel Jarosz Ines Drinnenberg
Mapping biochemical drivers of phenotypic change
Survival in changing environments requires the acquisition of new heritable traits. However, mechanisms that safeguard the fidelity of DNA replication often limit raw material available to fuel such novelty. Our research centers on an intriguing solution to this paradox: intrinsic links between the folding of biological polymers and virtually every trait in an organism provide multiple avenues through which environmental stress can impact evolution, disease, and development. Stress-regulated molecular chaperones of protein folding such as Hsp90, can broadly influence whether genetic variants can produce new phenotypes. We have identified other proteins, including a protein chaperone of RNA folding, that act in a conceptually similar fashion, ‘buffering’ the consequences of accumulating mutations. I will also discuss our other efforts that focus on the 30% of eukaryotic proteins that do not adopt a single fixed structure. Many mutations associated with metazoan innovation and human diseases occur within such intrinsically disordered proteins (IDPs). Yet the function of this ‘dark matter’ of the proteome is largely unknown. We recently found that IDPs involved in gene control can commonly adopt self-templating conformations – molecular ‘memories’ heritable over long biological timescales. This echoes the paradigm-shifting biology of prion proteins. But the ~50 we discovered frequently drive adaptive gains-of-function and do not form amyloid. Most remarkably, their self-templating capacity is often conserved from yeast to humans, leading us to propose that protein-based ‘molecular memories’ might commonly drive new interpretations of the genetic code. Ultimately, we seek to explore the therapeutic potential of perturbing these mechanisms for a wide range of human pathologies, ranging from cancer to neurodegenerative disease.