Dissecting the role of the nuclear basket in regulating mRNA metabolism

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Regulating the expression of its genes is an essential task for any living organism. In eukaryotic cells, the site where the genetic information is stored, the nucleus, and the site where the information is translated into protein, the cytoplasm, is separated by a double bilipidic membrane, impermeable to large molecules. In the nucleus, the organelle where DNA is stored, the genetic information is first copied into a messenger molecule, called mRNA, which has to exit the nucleus and reach the cytoplasm to get translated into proteins. The only path to reach the site of protein synthesis is through the nuclear pore complex (NPC), a large macromolecular complex embedded in the nuclear membrane. The long-term objective of our research program is to understand how the interplay between different factors that bind to the mRNA and factors composing the NPC control efficient and selective export of mRNAs from the nucleus to the cytoplasm. To gain further insight into this essential process, we will use different biophysical, biochemical and genetic tools. First, we will use recently developed super resolution microscopy techniques that allow to follow individual mRNA molecules in real time and in nanometer resolution to determine how nuclear basket, the first structure mRNAs encounter when reaching the nuclear periphery, regulates the access of mRNPs to the NPC. Furthermore, using genomic and proteomic assays, we will investigate how cells induce changes in the composition of the NPC to change gene expression programs when cells are exposed to stress. By completing this project we will reveal important mechanistic details that underlie this essential cellular process and establish biophysical tools relevant to study different cellular processes in single molecule resolution.