Grant: Operating Grant

Transcription factors are proteins that help read the genes encoded within our DNA. These factors are like "lego-blocks," with three-dimensional shapes that enable them to join other proteins and build the molecular machines that interpret our genetic code. In a precisely choreographed dance, the shapes of these lego-blocks can change, causing them to change their partners and thereby control when and how different genes are read. These shape changes result from chemical modifications, such as phosphorylation, that occur in response to cellular signals. Cancers can result when this dance is directed improperly. Our broad research goal is to understand how gene reading by a family of transcription factors, called ETS, is directed in normal and cancerous cells. In particular, we are investigating how several family members can inhibit their own ability to bind DNA as part of the control process for gene reading. We use NMR (nuclear magnetic resonance) spectroscopy as a "molecular microscope" to determine the shapes of these factors with atomic detail. Excitingly, we have found that the ETS proteins are not rigid lego-blocks, but rather, are more jello-like, flickering between shapes that can or cannot bind DNA as required for each step of this dance. Indeed, the power of NMR spectroscopy lies with uncovering how protein shapes change with time. Collectively, our research will help provide the molecular "blueprint" of a cell necessary for developing methods to diagnosis, treat, and prevent ETS-related cancers.