Sandy Chang, MD, PhD
My research program focuses on telomeres, repetitive DNA sequences at the ends of chromosomes critically important for the maintenance of genome stability. Perturbation of telomere function results in increased genomic instability that can promote early aging and cancer development. My laboratory was among the first to generate a faithful mouse model of Werner Syndrome (WS), a disease marked by the development of aging phenotypes and early onset of cancer. We found that when WRN deficiency was coupled with telomere dysfunction, the combination increased genomic instability, premature aging and cancer. In the absence of both telomerase and WRN, telomeres readily underwent homologous recombination to generate long telomeres that contributed to tumor formation. Our findings thus shed light on the important link between aging and cancer by suggesting that WRN plays an important role in both of these processes. We recently discovered that the POT1 (Protection of Telomere 1) protein is an integral member of a protein complex that binds to telomeres. We conditionally deleted POT 1 in the mouse and discovered that loss of POT1 potently activates a DNA damage pathway that results in rapid onset of cellular senescence. In p53 null cells, this elevated genomic instability promotes malignant transformation and rapid onset of cancer. These results suggest that dysfunctional telomeres could either suppress tumorigenesis by initiating cellular senescence in the setting of an intact p53 pathway, or promote cancer through elevated genomic instability when p53 deficiency is mutated.