Umut Kivanc Sahin

I am managing a team within the Molecular Biology & Genetics Department at Boğaziçi University. Projects in my lab aim at understanding the role of SUMO proteins in pathogenesis, as well as their potential for the development of targeted therapies for numerous diseases. I have a long-standing interest in post-translational protein modifications (PTMs) and proteolysis. During my PhD studies with Carl Blobel at Memorial Sloan-Kettering Cancer Center, I focused on a family of membrane-anchored metalloproteases named ADAMs (a disintegrin and metalloprotease). ADAMs act as molecular scissors by cleaving and releasing other membrane proteins from cells in a process referred to as “protein ectodomain shedding”. I identified two members of this family, namely ADAM10 and ADAM17, as the main sheddases and activators for all ligands of the epidermal growth factor receptor (EGFR), which has critical roles in development and cancer (Sahin et al, J Cell Biol, 2004). Identification of EGFR ligand sheddases was a crucial step toward understanding the mechanism underlying ectodomain release, with implications for designing novel inhibitors of EGFR-dependent tumors. In 2007, I started working in the group of Anne Dejean at Pasteur Institute in Paris, where I first came across with SUMO (small ubiquitin-like modifier). I established the first ever link between sumoylation and RNA interference by demonstrating that Ago2 was conjugated with this modifier (Sahin et al, 2014, Plos One). During my postdoctoral with Hugues de Thé's (College de France, Paris), together with Valerie Lallemand-Breitenbach, I uncovered the biochemical function of PML nuclear bodies (NBs). PML NBs are fascinating structures which have long been associated with Acute Promyelocytic Leukemia, an aggressive blood cancer. These phase separated, membrane-less organelles are organized by the scaffold PML protein, a powerful tumor suppressor. I identified PML NBs as nuclear sumoylation hubs, acting as entropically closed catalytic chambers that impose this specific PTM on hundreds of client proteins (Sahin et al, 2014, J Cell Biol). Importantly, we showed that for some proteins PML NB-facilitated sumoylation may be followed by ubiquitination and degradation. In parallel, we showed that PML NB-mediated sumoylation was exquisitely sensitive to interferon signaling and that SUMOs were critical for interferon-dependent anti-viral activities (Sahin et al, Nat Commun, 2014). Elegantly, it turns out that the therapeutic effect of a targeted therapy (interferon alpha and arsenic trioxide combination) in HTLV-1-infected Adult T-Cell Lymphoma patients relies on PML NB-mediated sumoylation, ubiquitination and degradation of the viral Tax oncoprotein, which drives transformation in this cancer (Sahin et al, 2015, Blood). Our current work is aimed at understanding how sumoylation plays role in major cellulaer processes and in the pathogenesis of various disorders. I also participate in a COST action called "ProteoCure", an initiative to reinforce the "proteolysis/proteostasis" community in Europe with a central goal of promoting research aiming at manipulating proteolysis to cure disease.