Dynamics of eukaryotic junction-resolving enzyme GEN1 - DNA junction interactions

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Repair of damage to cellular DNA is extremely important to human health, and one important repair process is recombination. This involves the formation of branched structures in cellular DNA, that are then processed by enzymes. One such enzyme is called GEN1. We have recently solved the atomic structure of the GEN1 protein, and this structure has provided considerable insight into the probable mechanism of action. We now shall extend our knowledge by observation of single molecules of the enzyme as they carry out the processing of junctions, using highly sensitive fluorescence methods. We will be able to dissect the processes by which the protein binds to the DNA and assembles on the branched junction, and how it alters the structure of the DNA. We can then proceed to study the process by which the enzyme cuts the DNA of the junction at specific points, and how this is coupled to changes in structure. Our goal is a full understanding of how this enzyme achieves a well regulated processing of the junction. Our ultimate goal is to intervene in the process using small molecules, which could ultimately result in therapeutic agents.