RNA silencing has become a major focus of molecular research around the world with important implications in biotechnology and medicine. RNA silencing involves processing of dsRNA by the enzyme Dicer, into small RNAs, 21-to-25 nucleotides in length. One of the two RNA strands is then incorporated into a protein complex called RISC (RNA induced silencing complex) that invariably contains a member of the highly conserved ARGONAUTE protein family. The incorporated small RNA then guides the complex to silence partly or fully complementary RNA. RNA silencing is important for the regulation of development in animals and plants, but plays also an antiviral role in plants and invertebrates (including worms and flies). In light of the apparent importance of RNA silencing in most eukaryotes, it is surprising that molecular mechanisms regulating ARGONAUTE proteins (and RISC) turnover have received so little attention. For instance, it is unknown whether ARGONAUTE proteins remain very stable when incorporated in RISC and how many times they can operate on different mRNA targets while loaded with the same siRNA/miRNA. More importantly, intriguing questions concern ARGONAUTE protein turnover under stress conditions. For instance, it is unknown whether ARGONAUTE proteins (and RISC) are degraded during stress, a situation where siRNA/miRNA populations quickly change and RISC re-programming is expected. My research project aims to answer to these questions. The content of this program is multidisciplinary combining molecular and cell biology, genetics, biochemistry and structural biology. Based on its approaches and already pioneering data recently obtained in my lab, I believe that this ERC research project has the potential to go substantially beyond the current state of the art in this field by providing deep insights into the regulatory mechanisms that control and mediate ARGONAUTE proteins turnover, in particular during stress responses.