Dr. Georgios Karras
The University of Texas MD Anderson Cancer Center
Department of Genetics
Proteins are the workhorse molecules of life. These important biomolecules are synthesized as linear strings that must fold into intricate three-dimensional shapes to function properly. Specialized factors are in place to help proteins fold and function in the crowded cellular milieu and to safeguard biological robustness in the face of adversity. However, these mechanisms are readily taxed by genetic and environmental perturbations that perturb protein folding, which can lead to profound changes in phenotype and can drive disease. Our research focuses on the role of protein folding machines as epigenetic modifiers in longevity and age-related diseases. One of the most abundant protein-folding machines responding to proteotoxic stress is the heat-shock protein 90 (HSP90). We found a powerful role for HSP90 in alleviating or “buffering” the deleterious biological effects of human mutation. In addition, our work demonstrated that by buffering mutations, HSP90 renders their manifestations conditional upon proteotoxic exposures in the cellular environment. We are investigating such genotype-phenotype-environment relationships in Fanconi Anemia, a premature aging and cancer predisposition disorder. We have identified seemingly benign stressors, including dietary compounds and common drugs, that can reveal HSP90-buffered disease mutations by perturbing protein homeostasis in the cell. We are collaborating with experts in the field to understand how these relationships shape the clinical course of Fanconi Anemia and other age-related diseases. In addition, we are dissecting the links between protein homeostasis and genome integrity, two fundamental features of longevity, and their ability to shape clinical responses to chemotherapy. We are building tools and screening for small molecules to harness the principles of protein homeostasis for disease prevention and therapy. To this end, we are employing multidisciplinary approaches, ranging from quantitative genetics to high-throughput biochemistry.