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Dr. George Brush (seated) is studying the body’s checkpoint responses with the assistance of his laboratory team. Pictured from left are: Suzanne Marinco (research assistant), Dr. Brush, Amy Bartrand (graduate student), Dagmawi Iyasu (research assistant) and Dawn Clifford (graduate student). Tumor suppressor protein p53 has an important function. It serves as a detection center or checkpoint to make sure mutated cells don’t replicate. Research has shown p53 to be defective in more than half of cancerous tumors, indicating a breakdown in the checkpoint system. In related research, George Brush, PhD, assistant professor of pathology (oncology), is studying the molecular mechanisms underlying the DNA damage and DNA replication checkpoint responses. His studies could lead to targeted cancer therapies that better utilize the body’s natural gatekeepers and safety mechanisms to flush out dangerous cancer cells. He has been awarded a three-year grant from the American Cancer Society to investigate “Mechanisms of Mec1p and Replication Protein A in the Checkpoint Response.” Dr. Brush, who was recently recruited to WSU from Johns Hopkins, is studying the yeast model, Saccharomyces cerevisiae, because it has checkpoint mechanisms similar to those in humans. One of these checkpoint pathways is defective in the human disorder ataxia-telangiectasia, a disease that results from mutation of the ATM protein (a human homologue of yeast Mec1p) and that puts patients at high risk for cancer. A defect in the ATM inspection point delays accumulation of p53 upon ionizing radiation exposure, and also delays phosphorylation of replication protein A (RPA), a protein that is essential for healthy DNA replication, repair and recombination. Like ATM in humans, the Mec1p checkpoint protein directs RPA phosphorylation in yeast. Using biochemical and genetic testing techniques that would be difficult to perform with human cells, Dr. Brush will study the mechanisms of Mec1p and RPA in the checkpoint response to determine their function in preventing cells from acquiring deleterious genetic changes. He is working closely with other investigators from the Barbara Ann Karmanos Cancer Institute to test this work. “Because RPA is involved in many different DNA transactions and is a component of a conserved checkpoint response pathway, it serves as a prime candidate for targeting in cancer therapy,” Dr. Brush said.
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