"The Role of the WRN Helicase in DNA Metabolism and Tumorigenesis"
Cancer is a disease of genetic instability, with tumorigenesis occurring as a result of the acquisition of oncogenic mutations. The WRN helicase is important for DNA stability and metabolism in terms of its enzymatic functions as a helicase and exonuclease, as well as its associations with proteins involved in DNA repair pathways (e.g., DNA Polymerase β and BRCA1). Germ line null mutations in WRN result in Werner syndrome (WS), a rare, heritable genetic instability and cancer predisposition syndrome with features of premature aging. Furthermore, epigenetic loss of WRN expression was recently identified in common adult malignancies such as colorectal cancers. Loss of WRN function by either mechanism—germ line mutation or epigenetic silencing—leads to defects in DNA replication, repair, and telomere maintenance, and sensitizes cells to killing by important classes of cancer chemotherapeutic drugs. My aims in this project are: to use epidemiologic analysis to quantify the elevated risk of specific tumor types in Werner syndrome patients; to functionally phenotype WRN SNP polymorphisms that may influence WRN function, cancer risk and the response to therapy; and to identify cancer chemotherapeutic agents that can be used to selectively kill WRN-deficient human tumors.