Research Questions:

mRNA export is an essential task in all eukaryotes due to the compartmentalization of the cell. Yet, despite the vital significance of this process to the gene expression program, many basic fundamental questions remain. These include:

How does an mRNA transit through the nuclear pore complex?

What proteins are involved in mRNA export?

How is mRNA export regulated in response to stress?

The Montpetit Lab is studying these fundamental cell biology questions with the goal of describing how components of the nuclear pore complex (NPC) direct and regulate mRNA export at a cellular, molecular and atomic level. Ultimately, this will allow us to better understand the interplay between nuclear mRNA export and the cellular gene expression program.

Background:

The eukaryotic genome is encapsulated by a double membrane bi-layer, which functions to protect and organize the genetic material. However, the presence of a physical barrier that separates events occurring in the nucleus and cytoplasm makes the transport of cargo (e.g. protein and RNA) across the nuclear envelope essential. To accomplish this, material is transported through nuclear pore complexes, which comprise one of the largest macromolecular assemblies in eukaryotic cells with an estimated mass of >60 MDa in yeast. NPCs are inserted into the nuclear envelope at fusion sites between the inner and outer nuclear membranes forming channels with eight-fold rotational symmetry. Cargo is directionally transported through these channels via interactions with soluble transport factors that permit passage through the pore. In the case of mRNA, work in different model systems has provided convincing evidence that Mex67/TAP is the major mRNA export receptor in eukaryotes. However, mRNA transport also depends on additional NPC proteins, including the cytoplasmically oriented nucleoporins Nup159, Gle1, and the conserved DEAD-box ATPase Dbp5. Interestingly, mutations in these and other transport proteins are associated with multiple human diseases (e.g. cancer and motor neuron syndromes) and can also be a target for the activity of viral proteins upon infection. Therefore, it is the hope that our research will provide a better understanding of this fundamental process and how alterations in mRNA export can result in specific human pathologies.

Approach:

We are currently employing cell biology, biochemistry, structural biology, and single molecule imaging techniques in our studies. Together these approaches provide a unique and exciting opportunity to make critical insights into the mechanism of mRNA export. We perform this research in Saccharomyces cerevisiae due to the genetic, biochemical, and cell biological tools that are available, which in combination with the comprehensive knowledge about NPC function, make budding yeast an extremely powerful model system. Moreover, the high conservation of NPC components and transport machinery make the insights that we gain from our studies directly relevant to all eukaryotes, including humans.

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