Baylor College of Medicine
Susan Rosenberg, Kyle Miller, Christophe Herman
Baylor College of Medicine investigators, in collaboration with a researcher from the University of Texas at Austin, propose to create ‘freeze-frame’ proteins that can trap and fluorescently label the DNA intermediates in genomic instability reactions in living cells from bacteria to human. These tools allow a new kind of in-vivo biochemistry in which transient reaction intermediates are “frozen” in living cells, quantified as fluorescent foci, mapped in the genome, and proteins that act on them identified. The freeze-frame proteins will allow identification of functions of hundreds of genes in large networks previously discovered to promote genome instability, most by unknown means. At present, research in genome instability focuses on enzymes rather than DNA structures that they affect. Genetic and other approaches can miss pathways that process damaged DNA due to the presence of redundant and parallel pathways. Likewise, therapies that target the enzymes often fail because of rapid evolution that can lead to resistance. The team would first create optimal proteins engineered to target DNA lesions called double-stranded breaks. Subsequently, the team would create a panel of freeze-frame proteins targeted to various structures present during DNA damage and repair. If successful, the proposed freeze-frame proteins could provide a direct and sensitive method to identify the amounts, types, and causes of DNA damage that occurs due to aging, stress, and diseases such as cancer and neurodegeneration and possibly point to new therapeutic directions.
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