Investigating the role of DNA polymerase iota in the development of lung cancer

U.S. National Inst/Child Hlth/Human Dev, Bethesda MD

Investigators

Abstract

? DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related deaths in the United States, and its incidence rate is largely attributed to inhalation of tobacco smoke. Tobacco smoke is traditionally composed of a potent cocktail of over 5000 chemicals, many of which are mutagenic and carcinogenic. Urethane, one compound found in cigarette smoke, is metabolized by cytochrome P450 enzymes to yield a highly reactive epoxide intermediate that can bind DNA and cause adduct formation. As a result, urethane is highly carcinogenic and a model compound for tumor induction in laboratory animals, especially lung tumor formation. Previous studies demonstrated that mice exposed to urethane can be categorized as sensitive, intermediate, or resistant to pulmonary adenoma formation, with resistance to lung tumorigenesis attributed to a locus on chromosome 18 identified as pulmonary adenoma resistance 2 (Par2). Interestingly, the Par2 interval contains the gene for Pol?, a Y-family DNA polymerase involved in lesion bypass. Further studies identified that Pol? may be a candidate for the Par2 locus, and we hypothesize it could play a role in the protection against lung tumorigenesis via error-free replication of damaged DNA induced by environmental genotoxins. We will test this hypothesis using in vitro and cellular replication assays to determine the accuracy and efficiency with which Pol? bypasses the major DNA adducts produced upon urethane exposure. To monitor Pol?'s function at the organismal level, a knock-in mouse with catalytically inactive Pol? will be employed to determine whether the sole presence of Pol? or its lesion bypass function is responsible for protecting against lung tumorigenesis. Th outcome of this proposed research will be instrumental in determining the elusive cellular role for Pol?, and could prove useful in the development of future lung cancer therapeutics.