A three-year $2 million grant from the W.M. Keck Foundation will allow Baylor College of Medicine researcher Dr. Susan Rosenberg and her colleagues (including Kyle Miller from University of Texas at Austin) to create “freeze-frame” proteins that trap and label fluorescently the transient DNA structures that define specific processes of DNA damage and repair in living cells of any kind – bacterial to human.
“This is a spinoff from the work we did with the NIH (National Institutes of Health) Director’s Pioneer Award (given in 2009),” said Rosenberg, professor of molecular and human genetics at Baylor who holds the Ben F. Love Chair in Cancer Research. Her works has centered on how the DNA in living cells becomes damaged, leading to genomic instability that affects evolution and the risks of cancer and antibiotic resistance.
With the Pioneer Award, she and her colleagues identified large networks of genes that promote genomic instability. She now needs tools that will help identify which DNA structures—which intermediate steps—are perturbed by these many genes—to learn why they destabilize genomes and cause mutations.
“We want to build new versions of synthetic-protein traps for DNA reaction intermediates,” she said. “It will allow us to take apart biochemical reactions in living cells. We call the protein-traps that we are creating to do this ‘freeze-frame’ proteins because they trap the DNA intermediates as if in a snap shot, and, by fusing them to fluorescent proteins, we can quantify the amount of the intermediate in a living cell.”
She and her colleagues have already built one such “trap" to work on breaks in double-stranded DNA and they want to build more – a toolbox for biologists working in DNA and genome instability.
Rosenberg said that the research is “high risk” with the potential for high return.
“We hope to use these tools to determine which proteins cause genomic instability, figure out the mechanisms and what protein affect them. We can apply these to tools to mutation in cancer, infectious disease and antibiotic resistance.”
Others who will take part in the work include Dr. Kyle Miller and Dr. Makkuni Jayaram of UT and Dr. Christophe Herman of Baylor.