Grant: Operating Grant

Understanding the molecular basis for many acute and chronic diseases is a daunting challenge facing the biomedical community today. It is clear that comprehending processes that control cell growth and differentiation is central to this goal, and we strive to understand how gene expression controls these processes. Many factors contribute to controlling gene expression including the environment in which genes are stored. In every eukaryotic cell, including humans, genes are housed within a spherical, membrane-enclosed compartment, termed the nucleus. The nucleus segregates the genes from the rest of the cell and controls access of molecules to the genome, and thus what genes are turned on or off. Structures termed nuclear pore complexes (NPCs) sit on the surface of the nucleus and act as sentinels, allowing only certain molecules to enter or leave the nucleus. Recent evidence from our laboratory and others suggests that this is not the only way that NPCs influence genes. We have shown that NPCs can also grab on to genes and, like puppeteers, they can alter their structure and, in this way, control whether a specific set of genes are turned on or off. Using state-of-the-art techniques, we are investigating how the NPC, in particular how one component termed Nup170p, accomplishes this feat by defining how Nup170p physically interacts with specific genes to define their structure and control their functions. As the NPCs are highly conserved in eukaryotes as diverse as humans and yeast, these studies can be conducted in a yeast model system where powerful genetic and biochemical approaches can be used to explore NPC function. It is clear that defects in NPC proteins, including those related to Nup170p, lead to diseases including heart abnormalities and cancer. Understanding their functions in nuclear organization will provide us with a critical understanding of the underlying causes of these diseases and provide an avenue for eventual rational intervention.